Metabolic defects


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2-OH-Glutaric aciduria (L / D form)
3-Ketothiolase deficiency
Alpha-ketoglutaric aciduria
Argininosuccinic aciduria
Biotinidase / Multiple carboxylase deficiency
Carbohydrate deficient glycoprotein (CDG)
Carnitine palmitoyl transferase I
Carnitine palmitoyl transferase II
Carnitine transporter deficiency
Ethylmalonic encephalopathy
Fanconi Bickel Syndrome (GLUT2)
Figlu Uria (Formimino glutamic aciduria)
Fructose intolerance (Familial)
Glutaric aciduria type II (Multiple acyl-CoA dehydrogenase deficiency)
Glutaric aciduria type I (Glutaryl CoA dehydrogenase deficiency)
Glycogen storage disease due to glucose-6-phosphatase deficiency
Hartnup disease
Hyperoxaluria type I
Hyperphenylalaninemia: dihydropteridine reductase deficiency (DHPR)
Hyperprolinemia type I
Isovaleric acidemia
Long chain 3-hydroxy-acyl-CoA-dehydrogenase deficiency (LCHAD)
Lysine protein intolerance (LPI)
Maple syrup urine disease (MSUD)
Medium chain acyl-CoA-dehydrogenase deficiency (MCAD)
Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
Methylmalonic aciduria
Methylmalonyl homocystinuria
Mitochondrial DNA depletion syndrome (MDS)
Mucopolysaccharidosis (MPS)
Non-ketotic hyperglycinemia
Ornithine transcarbamylase deficiency (OTC)ext link
Phenylketonuria (PKU)
Propionic acidemia
Pyruvate carboxylase deficiencyext link
Pyruvate dehydrogenase deficiencyext link
Pyroglutamic aciduriaext link
Refsum's disease
Rett syndrome (RTT)
Short chain acyl-CoA-dehydrogenase deficiency (SCAD)
Trimethylaminuria (TMA), Fish odour disease
Tyrosinemia Type I
Very long chain acyl-CoA-dehydrogenase deficiency (VLCHAD)
Vit B12 responsive methylmalonic aciduria
Wilson’s Disease
X-Adrenoleukodystrophy (X-ALD)
Zellweger Like Syndrome Without Peroxisomal Abnormalities
Zellweger spectrum


L2-hydroxyglutaric aciduria (L-2-HGA) is characterized by the significant elevation of plasma and urinary levels of L2-hydroxyglutaric acid. L2-hydroxyglutaric acid is measured by gas chromatography of organic acids. L-2-HGA occurs in children aged 2 years, causing moderate psychomotor retardation, progressive ataxia, and extrapyramidal signs, followed by progressive decline of IQ. The MRI shows a spongiform encephalopathy and cerebellar atrophy. There is no specific treatment for this disease. Prenatal diagnosis can be made by analysing organic acids in amniotic fluid. The gene responsible for L-2-HGA has been identified recently; it is localised on chromosome 14q22.1. It has been proposed to name it duranin. This gene encodes a putative mitochondrial protein with homology to FAD-dependent oxidoreductases. D2-hydroxyglutaric aciduria (D-2-HGA) has also been observed in patients with intellectual deficit exhibiting various neurological signs, although there was no real regression. The enzyme deficiency remains to be discovered. Recently, a severe neonatal form of hydroxyglutaric aciduria has been described, but the underlying enzymatic defect remains unknown. Rare cases of both D-2 and L-2 glutaric aciduria have been reported. Antenatal diagnosis, although difficult, is feasible by enzymatic assay in amniotic fluid. *Author: Pr. J-M. Saudubray (February 2005).


Beta-ketothiolase deficiency is a defect of mitochondrial acetoacetyl-CoA thiolase (T2) involving ketone body metabolism and isoleucine catabolism. This new rare disorder is characterized by normal early development followed by a progressive loss of mental and motor skills. It is clinically characterized by intermittent ketoacidotic episodes, with no clinical symptoms between episodes. Ketoacidotic episodes are usually severe and sometimes accompanied by lethargy/coma. Some patients may have neurological impairments as a sequel of these episodes. The disorder is caused by a mutation in a gene localized to chromosome region 11q and is transmitted in an autosomal recessive manner. More than 20 mutations have been identified. T2 deficiency is characterized by urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine but its extent is variable. Acylcarnitine analysis is also useful for the diagnosis. However, the diagnosis should be confirmed by enzyme assay. Treatments of acute episodes include infusion of sufficient glucose and correction of acidosis. Fundamental management includes mild protein restriction and prophylactic glucose infusion during mild illness. This disorder has usually a favorable outcome. Clinical consequences can be avoided by early diagnosis, appropriate management of ketoacidosis, and modest protein restriction. *Author : T. Fukao (September 2004).


Alkaptonuria is characterized by the accumulation of homogentisic acid (HGA) and its oxidised product benzoquinone acetic acid (BQA), leading to a darkening of the urine when it is left exposed to air, grey-blue colouration of the eye sclera and the ear helix (ochronosis), and a disabling joint disease involving both the axial and peripheral joints (ochronotic arthropathy). Prevalence is estimated at 1-9/1 000 000. Many affected individuals are asymptomatic and unaware of their condition until adulthood; however, homogentisic aciduria may be recognised early in infancy (dark-stained diapers). Unusual pigmentation of the skin overlying cartilage throughout the body can be observed after the third decade. Muscular-skeletal symptoms begin in the third decade with back pain and stiffness, while involvement of the large peripheral joints usually occurs several years after spinal changes, often leading to end-stage joint disease requiring surgical replacement. Ochronotic peripheral arthropathy is generally degenerative in nature but joint inflammation can be observed in some cases. Joint mobility is diminished. Calcifications may be palpable, particularly in the cartilage of the ear. Signs of aortic or mitral valvulitis may be present.

Alkaptonuria, inherited as an autosomal recessive trait, involves a block of the phenylalanine and tyrosine catabolic pathway. Patients are homozygous or compound heterozygous for mutations in the homogentisate 1,2-dioxygenase (HGD) gene. More than 70 different point mutations have been described worldwide, interfering with the complex hexameric structure of the HGD enzyme. Tissue damage results from the presence of BQA, which tends to polymerize to a melanin-like pigment with a high affinity for connective tissue. This pigment is able to trigger numerous redox reactions and induce free radical production, causing further damage to the connective tissue. Although unproven, it is assumed that the polymer accumulation also causes an inflammatory response resulting in calcium deposition in affected joints. Homogentisic acid can be identified in urine using gas chromatography-mass spectroscopy. As many patients present without dark urine, it may be advisable to look for homogentisate in all patients with radiographic evidence of osteoarthritis. A spinal x-ray will reveal disk degeneration combined with dense calcification, particularly in the lumbar area. Acute intermittent porphyria (which may cause dark urine), can be ruled out by the presence of homogentisate, whereas rheumatoid arthritis, osteoarthritis or ankylosing spondylitis can be excluded by radiographs.

Family members should be referred for genetic counseling. Medical therapy may slow the rate of pigment deposition. This should minimize articular and cardiovascular complications in later life. Unfortunately, there are no preventive or curative measures for the disease to date. Dietary restriction is beneficial, but compliance is often limited. Therapeutic strategies focusing on perturbing the altered phenylalanine-tyrosine pathway have been devised (e.g. nitisinone). However, the long-term effectiveness and safety of this drug have yet to be established. Other possible approaches are aimed at exploring the effects of antioxidant biomolecules in preventing the conversion of HGA to the polymeric material deposited in the cartilaginous tissues (e.g. N-acetylcysteine). However, previous attempts with vitamin C have been proved to be largely unsatisfactory. Older individuals may require removal and fusion of lumbar discs. Hip or knee joint replacement may be necessary. Life expectancy is not significantly reduced but progressive functional decline is observed with a loss of mobility. *Author: Prof. B. Porfirio (January 2007).


Alpha-ketoglutaric aciduria (Oxoglutaric aciduria) is caused by deficiency of alpha ketoglutarate dehydrogenase (oxoglutarate dehydrogenase), an enzyme involved in the transformation of alpha ketoglutarate into succinyl-CoA in the Krebs cycle. Early clinical signs are severe. They include psychomotor retardation, hypotonia, ataxia and convulsions (the symptoms of Leigh's syndrome), as well as sudden death, myocardiopathy, and hepatic disorders. The disease is transmitted as an autosomal recessive trait. Hyperlactacidemia, increased levels of glutamine and variable degrees of glutaric aciduria are suggestive of the disorder. However, the enzyme activity should be measured for confirmation of the diagnosis, as alpha ketoglutaric aciduria is a very common non-specific finding. Prenatal diagnosis is most likely possible. There is no efficient treatment. *Author: Prof. J-M. Saudubray (March 2004).


Arginosuccinic aciduria is an autosomal recessive inherited deficiency of arginosuccinate lyase, an enzyme involved in the urea cycle. This leads to hyperammonemia and arginine deficiency. Onset occurs either soon after birth, with severe hyperammonaemic coma that often proves to be fatal, or during childhood, with hypotonia, growth failure, anorexia and chronic vomiting or behavioral disorders. Onset can also occur later with hyperammonaemic coma or behavioral disorders that simulate psychiatric disorders. Significant hepatomegaly and trichorrhexix nodosa are common observations. Diagnosis is made by the existence of hyperammonemia and by chromatography of plasmatic and urinary organic acids that shows accumulation of arginosuccinic acid (ASA) and orotic aciduria. Patients are treated with a strict lifelong diet with very low amounts of protein intake, arginine supplementation, and sometimes sodium benzoate or sodium phenylbutyrate. Antenatal diagnosis can be performed either by direct measure of citrulline and ASA in amniotic fluid or by enzymatic assay. * Author: Pr. J-M. Saudubray (March 2004).


Multiple carboxylase deficiency (pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase) is due to either a deficiency or an inherited anomaly in intracellular metabolism of biotin. Biotin is an enzymatic cofactor of these 4 carboxylases. Two genetic diseases have been identified, deficiency in biotinidase and deficiency in holocarboxylase synthetase. Deficiency in biotinidase (the enzyme that catalyses the conversion of biocytin into biotin via liberating residual lysine) presents with an accumulation of cellular biocytin and a deficiency in the 4 above mentioned biotin-dependent carboxylases. Disease usually occurs in the first year of life after age 1 to 3 month(s). The main clinical signs include coma with lactic acidosis and ketosis; various neurological signs, among which encephalopathies of any type, major hypotonia, convulsions, and Leigh syndrome. Cutaneous signs (alopecia, conjunctivitis, vesicobullous eruptions) had been described. When not treated, disease results in intellectual deficit and neurosensory hearing loss.

The disease is transmitted as an autosomal recessive trait. Diagnosis is suspected by chromatography of organic acids present in urine which reveals a characteristic accumulation of lactate, metabolites of propionate, methylcrotonic acid and conjugate derivatives of carnitine. Diagnosis is confirmed by dosage of serum biotinidase. Remarkable efficacy of treatment relies on lifelong administration of oral biotin (5 to 10 mg). Holocarboxylase synthetase allows binding of biotin to the various apocarboxylases. Deficiency in this enzyme becomes patent most often at birth or in the first weeks of life due to a clinical picture close to that of biotinidase deficiency and especially due to severe cutaneous features suggesting essential fatty acids deficiency (alopecia, vesiculobullous eruptions and dermatosis). Like for deficiency in biotinidase, diagnosis relies on chromatography of organic acids showing hyperlactacidemia, presence of characteristic organic acids as well as shape of plasma acyl-carnitine. Diagnosis is confirmed by dosage of carboxylases on culture of fibroblasts lacking or supplemented with biotin. Systematic screening of these deficiencies can now be carried out with blood samples on paper (Guthrie test). It is performed a few days after birth and analysed by an electrospray coupled with a double-focusing mass spectrograph. Treatment relies on lifelong administration of pharmacological doses of biotin, first intramuscularly and then orally. *Author: J-M. Saudubray (March 2004).


A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which N-glycosylation of a variety of tissue proteins is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system, muscles, and intestines) in affected infants. CDG are classified as CDG types 1 and 2 (CDG-1 and CDG-2), depending on the nature and location of the biochemical defect in the metabolic pathway relative to the action of oligosaccharyltransferase.·Type 1 disorders involve disrupted synthesis of the lipid-linked oligosaccharide precursor. ·Type 2 disorders involve malfunctioning trimming/processing of the protein-bound oligosaccharide chain. Currently, twelve CDG type-1 variants have been identified (CDG-1a to -1l) and six variants of CDG Type-2 have been described (CDG-2a to -2e).

The specific problems produced differ according to the particular abnormal synthesis involved. Common manifestations include ataxia; seizures; retinopathy; liver fibrosis; coagulopathies; failure to thrive; dysmorphic features (e.g. inverted nipples and subcutaneous fat pads) and strabismus. If an MRI is obtained, cerebellar atrophy and hypoplasia is a common finding. Ocular abnormalities of CDG-1a include: myopia, infantile esotropia, delayed visual maturation, low vision, optic pallor, and reduced rod function on electroretinography. Three subtypes of CDG 1 (a,b,d) can cause congenital hyperinsulinism with hyperinsulinemic hypoglycemia in infancy. No treatment is available for most of these disorders. Mannose supplementation has produced some benefits in a couple of the Type 1 subtypes. Several synthetic glycoconjugate compounds have been synthesized and are being tested for therapeutic efficacy.


Carnitine palmitoyltransferase I (CPT I) deficiencies are autosomal recessive inherited disorders that affect mitochondrial oxidation of long chain fatty acids (LCFA). CPT I is involved in the transfer of LCFA's from cytosol to mitochondria where they are oxidized. CPT I is inhibited by malonyl-CoA, a way of regulating mitochondrial oxidation of LCFA's. It is located within the external mitochondrial membrane. Although CPT II only has one form, human CPT I can take on two isoforms: the 'L' isoform is found in liver, while the 'M' isoform is synthesized in skeletal muscle. Since the description of the princeps case in 1981, about 10 cases have been reported. They were most likely deficiencies in the L isoform, since clinical signs were mainly fits of hypoglycemia with hypoketonemia, triggered by fasting, that led to severe neurological sequela and even sudden death. Muscular or cardiac symptoms were never described in any of the cases. Biological evidence of enzyme deficiency can be found in the liver, lymphocytes or cultured fibroblasts. When muscles were tested for CPT I activity in these patients, it was normal. As of today, only one mutation has been identified in the gene coding for CPT I. It is worth noting that no clinical description of deficiency of the muscular isoform (CPT I M) has been described. * Authors: J-P. Bonnefont and L. Thuillier, M.D. (April 2002).


Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited metabolic disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA). Three forms of CPT II deficiency have been described: a myopathic form, a severe infantile form and a neonatal form. More than 300 CPT II cases have been described with the myopathic form being the most common (myopathic form: 86%, severe infantile form: 8%, neonatal form: 6% of cases). The myopathic form is the less severe one and is characterized by recurrent attacks of rhabdomyolysis, muscle pain, and weakness triggered by prolonged physical exercise, fasting, viral illness, or extremes in temperature. The severe infantile form is characterized by a severe fasting intolerance leading to metabolic disorders such as hypoketotic hypoglycemia and hepatic encephalopathy. The lethal neonatal form includes symptoms of the infantile disease as well as dysmorphic features (e.g. cystic dysplastic kidneys).

More than 60 mutations in the CPT2 gene, resulting in general in amino acid substitutions or small deletions, cause the CPT II deficiency. Transmission is autosomal recessive. The diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or fibroblasts. The differential diagnosis for the myopathic form should include McArdle disease, Duchenne muscular dystrophy, and cytochrome c oxidase deficiency among others, and carnitine-acylcarnitine translocase deficiency (CACT) and very-long-chain acyl-CoA dehydrogenase deficiency for the infantile and neonatal forms. Prenatal diagnosis is available based on a combination of enzymatic and molecular testing. Treatment is based on avoidance of prolonged fasting (>12 hr) and a low-fat and high-carbohydrate diet. The myopathic form of CPT II has a good prognosis. The severe infantile form may lead to sudden death during infancy due, in general, to paroxysmal cardiac arrhythmias. The neonatal form is almost always lethal during the first months of life. *Authors: Profs. M. Bennett and C. Stanley (April 2010).


Hereditary carnitine deficiency in cells is a rare autosomal recessive disorder due to defective carnitine transporters. Onset exceptionally occurs after birth with coma or sudden death, but more commonly the first clinical sign is a highly progressive hypokinetic dilated cardiomyopathy that is generally associated with muscular weakness. This last sign may be major and result in proximal myopathy and amyotrophy. Hypoglycemia- and hypoketosis-linked coma or acute hepatic injuries such as Reye's syndrome may occur after periods of fasting or infections. Near-zero total plasmatic carnitine and free carnitine with normal carnitine urinary excretion is highly suggestive of the disorder. Chromatography of organic acids does not reveal any abnormal substance. Diagnosis is confirmed by analysing the oxidation of fatty acids and transportation of radioactively marked carnitine in lymphocytes or cultured fibroblasts. Patients are treated with pharmacological doses of carnitine lifelong (100 - 200 mg/Kg/day taken in thirds or fourths), and results are remarkable. Cardiomyopathy almost always regresses in less than one year leaving no sequela. * Author: Pr. J.-M. Saudubray (March 2004).


Citrullinemia is an autosomal recessive inherited condition due to argininosuccinate synthetase deficiency, an enzyme involved in the urea cycle. The deficiency causes hyperammonaemic coma, accumulation of citrulline and orotic acid, and arginine deficiency (Citrullinemia type I). Onset usually occurs soon after birth with severe hyperammonaemic coma which may be associated with lactic acidosis, but a chronic juvenile form also exists with anorexia, vomiting, hypotonia, growth and psychomotor retardation, and convulsions. Diagnosis is based on the presence of hyperammonemia and on the chromatography of plasmatic and urinary amino acids showing major elevation of citrulline, glutamine and alanine, and low levels of arginine. Another finding is orotic aciduria. Patients with citrullinemia type I are treated with a strict, lifelong diet of very limited protein intake, associated with arginine and both sodium benzoate and phenylbutyrate supplementation. Citrullinemia type II has been identified as the consequence of a deficiency of the mitochondrial aspartate glutamate carrier (citrin). The result is an intramitochondrial deficiency of aspartate. The disorder presents at two ages: in the neonatal period with a liver disease (cholestasis) with in general no symptom of hyperammonemia and normal citrulline levels; in adulthood with typical symptoms of hyperammonemia and intermediate citrulline levels (200-500 µmol/l). There is no specific treatment for this disorder. Citrullinemia type III is characterized by partial arginosuccinate synthetase deficiency with a high residual enzyme activity, the pathogenicity of which is questionable. * Author: Pr. J.-M. Saudubray (July 2005).


Cystinuria is an autosomal recessive disorder characterized by an impaired transport of cystine, lysine, ornithine and arginine in the proximal renal tubule and in the epithelial cells of the gastrointestinal tract. An elevated cystine concentration in the urinary tract is responsible for the formation of renal stones. Symptoms are those related to renal stone disease: renal colic is often the first symptom, but renal stones may also be detected following a urinary tract infection or unexpectedly found in patients undergoing an abdominal X-ray or ultrasound scan for other reasons. The estimated prevalence of cystinuria ranges from 1:2,500 in the Libyan Jewish population to 1:100,000 in some reports.

Treatment requires several different approaches: increased urine pH with alkali to improve cystine solubility, administration of large amounts of fluids to reduce urine osmolality, using molecules forming chemical bonds with the sulfhydryl domains of the cystine (like alpha-mercaptopropionylglycine and D-Penicillamine), as they lower the amount of free cystine in the urine. Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. A reliable classification should therefore only rely on genetic characterization. We propose that mutations on both alleles of SLC3A1 on chromosome 2 should be called cystinuria type A; mutations on both alleles of SLC7A9 on chromosome 19 should be called cystinuria type B; it is unlikely, although still unclear, that the occurrence of a mutation on a single allele on chromosome 2 and another on a single allele on chromosome 19 is responsible for cystinuria. If this was confirmed, it would be called type AB. * Author: Dr L. Dello Strologo (September 2003).


Ethylmalonic acid encephalopathy (EE) is defined by elevated excretion of ethylmalonic acid (EMA) with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhoea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging (MRI) abnormalities. Less than 40 cases have been described in the literature so far. The disease manifests at birth or in the first few months of life. Spastic tetraplegia may be present. In addition to increased excretion of EMA, methylsuccinic acid and C4-C6-acylglycines (isobutyryl-, isovaleryl-, 2-methylbutyryl-, hexanoylglycine) may also be found in small, but elevated, amounts in the urine. Blood levels of C4-C6-carnitines (butyryl-, isobutyryl-, isovaleryl- and hexanoylcarnitine) may be elevated. The disease is inherited in an autosomal recessive manner and is caused by mutations in the ETHE1 gene (chromosome 19q13). Diagnosis depends on the clinical picture, the results of the biochemical work-up and, more recently, genotype analysis.

As a large number of different disease-causing mutations have been identified, DNA sequencing of all seven exons of the ETHE1 gene is necessary for the molecular diagnosis. The diagnosis of EE due to ETHE1 mutations is clear if homozygosity (which should be confirmed by genotyping of the parents) or compound heterozygosity are present in the patient. In some cases, the urine and blood patterns identified in EE patients may resemble those seen in multiple acyl-CoA dehydrogenase deficiency (MADD or Glutaricaciduria type 2) but in others they resemble those seen in short chain acyl-CoA dehydrogenase deficiency (SCADD), where the only abnormalities seen may be elevated EMA in urine with or without blood elevation of butyrylcarnitine. It seems, at least in severe cases, that the clinical picture of recurrent petechiae, orthostatic acrocyanosis and chronic diarrhoea is specific for EE. However, more cases need to be identified before it can be determined whether milder cases of EE exist with clinical features like MADD or SCADD. These diseases should therefore be taken into account in the differential diagnosis of EE. In the absence of any detectable ETHE1 gene mutation, molecular analysis should include sequencing of the SCAD gene (mutations in which lead to SCADD) and, eventually, of the two electron transfer flavoprotein (ETFA and ETFB) genes and the ETFDH gene (one of which may carry mutations in patients with MADD).

Prenatal diagnosis of EE is possible in cases where the mutations on both chromosomes have been identified. Patients with EE have been treated more or less successfully with L-carnitine, riboflavin and/or Q10 supplements, as well as other vitamin therapies which may improve energy metabolism and alleviate oxidative stress. As the function of the protein encoded by the ETHE1 gene is still not known, a more rational treatment remains to be developed. The prognosis is generally poor: although milder chronic cases are known, most patients die before the age of ten years. *Author: Prof. N. Gregersen (July 2007).


Fanconi-Bickel glycogenosis (FBG) is a rare glycogen storage disease characterized by hepatorenal glycogen accumulation, severe renal tubular dysfunction and impaired glucose and galactose metabolism. The prevalence is unknown but less than 200 cases have been described in the literature so far. Onset occurs during the first few months of life with failure to thrive, polyuria and rickets related to proximal tubular losses. Growth retardation and hepatosplenomegaly resulting in a protruding abdomen are evident by early childhood. Puberty is delayed. Generalized osteopenia leading to fractures during childhood, with osteoporosis later in life, has also been reported. Some patients also display an abnormal fat distribution. FBG is transmitted as an autosomal recessive trait and is caused by homozygous or compound heterozygous mutations in the SLC2A2 gene (3q26.2-q27).

Diagnosis may be suspected on the basis of the clinical manifestations, radiological findings revealing rickets, and from characteristic results from laboratory investigations showing proximal renal tubular dysfunction (massive glucosuria, proteinuria, phosphaturia, hypophosphatemia, aminoaciduria and hyperuricemia). However, several cases of FBG have been detected through neonatal screening of galactose levels. Additional laboratory findings include fasting hypoglycemia, ketonuria and hypercholesterolemia. Elevated serum biotinidase activity is also found in FBG patients and has recently been proposed as a diagnostic marker for this syndrome and other glycogen storage diseases. Analysis of biopsy samples reveals liver steatosis, and glycogen accumulation in the hepatocytes and proximal renal tubular cells. The diagnosis can be confirmed by identification of a mutation in the SLC2A2 gene.

The principle differential diagnosis is type I glycogen storage disease, which is caused by glucose-6-phosphatase deficiency. Prenatal diagnosis is possible for families in which the SLC2A2 mutation has already been identified. Treatment of FBG is symptomatic revolving around compensation of the renal syndrome with replacement of water and electrolytes. Vitamin D and phosphate supplements are essential for preventing hypophosphatemic rickets. Patients should follow a galactose-restricted diabetic diet with fructose as the main source of carbohydrate. The long-term prognosis is unknown. The renal tubular dysfunction persists into adulthood but in most cases does not appear to progress to renal failure. Diet and supplements may alleviate some of the manifestations of FBG but do not result in improved growth, resulting in short stature in adulthood. *Author: Orphanet (October 2008).


Formiminoglutamic aciduria, in its moderate form and in the absence of histidine administration, is characterized by mild developmental delay and elevated concentrations of formiminoglutamate (FIGLU) in the urine. A more severe phenotype has been described in five members of a Japanese family and included severe intellectual deficit, psychomotor retardation and megaloblastic anemia. Formiminoglutamic aciduria is an autosomal recessive disease caused by a deficiency of glutamate formiminotransferase-cyclodeaminase (FTCD), an enzyme involved folic acid metabolism. *Author: Orphanet (July 2006).


Hereditary fructose intolerance is an autosomal recessive disorder due to a deficiency of fructose-1-phosphate aldolase activity, which results in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. This disorder may be as common as 1 in 20,000 in some European countries. Homozygous neonates remain clinically healthy until confronted with dietary sources of fructose, usually occurring at the time of weaning when fructose or sucrose is added to the diet. Clinical symptoms include severe abdominal pain, vomiting, and hypoglycemia following ingestion of fructose or other sugars metabolised through fructose-1-phosphate.

Prolonged fructose ingestion in infants leads ultimately to hepatic and/or renal failure and death. Patients develop a strong distaste for sweet food. The defect resides in aldolase B which catalyzes the cleavage of fructose-1-phosphate to form dihydroxyacetone phosphate and D-glyceraldehyde. Evidence for genetic heterogeneity was considered: both structural and controller mutations may exist, as well as more than one type of structural mutation. Diagnosis methods include an enzymatic liver biopsy assay to determine aldolase activity; or a fructose tolerance test: fructose is injected intravenously under controlled conditions where acute glucose, fructose, and phosphate levels are monitored. *Author: Prof. J-M. Saudubray (March 2004).


Fructosuria is generally asymptomatic. It is caused by a deficiency in hepatic fructokinase, an enzyme involved in the catabolism of fructose. This anomaly leads to abnormally elevated levels of fructose in the blood after ingestion of fructose, sucrose or sorbitol. This excess fructose is then excreted in the urine. The mode of transmission is autosomal recessive. *Author: Orphanet (June 2006).


Galactosemia is characterised by enzymatic deficiencies affecting galactose metabolism, most frequently the enzyme galactose-1-phosphate uridyl transferase (GALT), resulting in the accumulation of galactose-1-phosphate. In Europe, the disease affects approximately one newborn in 35 000. The clinical signs appear during the first days of life and include refusal to feed, vomiting, jaundice, lethargy, hepatomegaly, edema and ascites. If left untreated, the condition evolves rapidly towards hepatic and renal failure with septicemia due to gram negative Escherichia coli bacteria. Nuclear cataract develops after several days or weeks and rapidly becomes irreversible. Galactosemia is an autosomal recessive condition caused by point mutations. Three enzyme deficiencies involving the galactose metabolic pathway have been associated with the condition: galactokinase (GALK) deficiency, uridine diphosphate (UDP) galactose-4-epimerase deficiency, and most commonly, galactose 1 phosphate uridyl transferase (GALT) deficiency.

The gene encoding GALT has been localized to 9p13. Diagnosis relies on detection of galactose-1-phosphate accumulation in erythrocytes (spot test), determination of a deficiency in one of the enzymes in the galactose metabolic pathway and identification of the gene mutation. Postnatal diagnosis is systematic in some countries. In utero testing may be offered to galactosemic parents. To date, the only treatment available is a galactose-free diet. Despite this regime, neurological complications (decreasing IQ with age, verbal dyspraxia, myelin disorders) and hypergonadotropic hypogonadism (ovary dysfunction, very high levels of FSH and LH) appear during childhood.

UDP-galactose deficiency and/or accumulation of galactose-1-phosphate in utero may result in deficient galactosylation of glycoproteins (including FSH) and glycolipids (galactolipides in myelin) thus causing the complications. In addition, aberrant galactosylation may also contribute to alterations in function of the galactosylated molecules. The galactose-free diet may allow partial biosynthesis of carbohydrate chains for some glycoproteins. Research concerning the classic forms of galactosemia is essentially targeted towards developing therapeutic strategies aiming to prevent the neurological and endocrinal manifestations. These strategies revolve around limiting the accumulation of galactose and its derivatives and developing a treatment capable of stimulating secondary metabolic pathways that could metabolize the toxic derivatives of galactose and increase the level of UDP-galactose, which is necessary for the glycosylation of proteins and lipids. *Author: Dr K Petry (April 2006).


Multiple FAD dehydrogenase deficiency, also known as glutaric aciduria type II, impairs fatty acid oxidation, and also stops the oxidation of branched amino acids, lysine and glutaric acid. Complete deficiency causes severe disorders in neonates, including acidotic coma without ketosis, hypoglycemia, hyperammonaemia, hypotonia, myocardiopathy, and sometimes congenital malformations (polycystic kidneys, dysmorphic facies). Juvenile, adolescent or even adult forms have been reported but are less severe, with progressive myocardiopathy or proximal myopathy. The disease is due to a defective electron transfer flavo protein or electron transfer flavo protein dehydrogenase. Chromatography of urinary organic acids and plasmatic acyl carnitines is suggestive of the disease, showing dicarboxylic aciduria, glutaric and ethylmalonic aciduria and suberylglycine. Total carnitine levels are very low. Multiple FAD dehydrogenase deficiency (MADD) is transmitted as an autosomal recessive trait. Diagnosis is confirmed by the in vitro study of fatty acid oxidation in lymphocytes or fibroblasts and enzymatic activity. Prenatal diagnosis is available. Patients should eat regularly and limit their protein intake to moderate amounts, while fatty foods should be avoided. Carnitine is systematically given. Some cases are riboflavine sensitive (cofactor of FAD dehydrogenases). *Author: Prof. J.M. Saudubray (March 2004).


Glutaryl-Coenzyme A dehydrogenase deficiency (GDD) is an autosomal recessive neurometabolic disorder with an estimated incidence of 1:50,000 newborn Caucasians. It is caused by mutations in the glutaryl-CoA dehydrogenase gene localized on chromosome 19p13.2. Glutaryl-CoA dehydrogenase is a key mitochondrial enzyme in the catabolic pathways of the amino acids L-tryptophan, L-lysine, and L-hydroxylysine, that catalyzes the transformation of glutaryl-CoA into crotonyl-CoA. GDD is biochemically characterized by the accumulation of the dicarbonic glutaric acids, 3-hydroxyglutaric and glutaconic acids, and glutarylcarnitine.

It is clinically characterized by a distinct neuropathology but only exceptionally presents with classical metabolic symptomatology, such as hypoglycemia or acidosis. During a vulnerable period of brain development, usually between the ages 6 and 12 months, a acute encephalopathy results in bilateral striatal damage via an excitotoxic mechanism and leads to a severe dystonic dyskinetic movement disorder. The preencephalopathic phase is unremarkable but most often progressive macrocephaly is apparent. Analysis of urinary organic acids in suspected patients aims at early detection of GDD or, analysis of acylcarnitine from dried blood spots may potentially become implemented in neonatal screening programs. Following presymptomatic detection, dietary treatment, carnitine supplementation and prompt intervention to treat intercurrent illnesses can be initiated early and have been shown to prevent acute neuronal damage in the majority of affected children. *Authors: Dr S. Kölker and Pr G.F. Hoffmann (June 2003).


Glycogenosis due to glucose-6-phosphatase (G6P) deficiency or glycogen storage disease, (GSD), type 1, is a group of inherited metabolic diseases, including types A and B and characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver.Prevalence is unknown. Annual incidence at birth is around 1/100,000. Type A affects 80% of patients. The existence of other types (C, D) has not been confirmed.The disease may manifest at birth by hepatomegaly or, more commonly, between the ages of three to four months by symptoms of fast-induced hypoglycemia. Patients have enlarged liver, growth retardation, osteopenia, sometimes osteoporosis, full-cheeked round face, nephromegaly and frequent epistaxis due to platelet dysfunction. In addition, in type B, infections and inflammatory bowel disease are due to neutropenia and neutrophil dysfunction. Late complications are hepatic (adenomas and more rarely hepatocarcinoma) and renal (proteinuria and sometimes renal insufficiency).

The disease is due to a dysfunction in the G6P system, a key step in glycemia regulation. Mutations in the G6PC gene (17q21) cause a deficit of the catalytic subunit G6P-alpha restricted to expression in the liver, kidney and intestine (type A) and mutations in the SLC37A4 gene (11q23) cause a deficit of the ubiquitously expressed G6P transporter (G6PT) or G6P translocase (type B).Diagnosis is based on clinical presentation and glycemia and lactacidemia levels, after a meal (hyperglycemia and hypolactacidemia), and after three to four hour fasting (hypoglycemia and hyperlactacidemia). Uric acid, triglycerides, and cholesterol serum levels are increased. There is no glycemic response to glucagon. Molecular genetic testing enables confirmation of diagnosis. Use of liver biopsy to measure G6P activity is becoming increasingly rare.Differential diagnoses include the other glycogenoses, in particular glycogenosis due to glycogen debranching enzyme deficiency (GDE deficiency) or GSD type III, but in this case, glycemia and lactacidemia are high after a meal and low in a fasting period. Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but easily ruled out through clinical and ultrasound data.

Transmission is autosomal recessive. Genetic counseling should be offered.Management aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube and later oral addition of uncooked starch), acidosis (restricted fructose and galactose intake, oral supplementation in bicarbonate), hypertriglyceridemia (diet, cholestyramine, statines), hyperuricemia (allopurinol) and hepatic complications. Renal protection using converting enzyme inhibitors must be started should microalbuminuria be detected. Osteoporosis may require bisphosphonates. Liver transplantation, performed on the basis of poor metabolic control or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type B. Kidney transplantation can be performed in case of severe renal failure. Combined liver-kidney grafts have been performed in a few cases.With adapted management, prognosis is better: patients have almost normal life span.
Reference: link


Hartnup syndrome is a rare metabolic disorder belonging to the neutral amino acidurias and characterized by abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine). The estimated prevalence is approximately 1 in 24,000. Clinical symptoms usually appear in childhood (3 - 9 years of age), but sometimes manifest as early as 10 days after birth, or as late as early adulthood. Most subjects remain asymptomatic. Symptomatic subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), psychiatric symptoms (anxiety, emotional instability, delusions, and hallucinations), and amino aciduria. Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. Exacerbations are seen most frequently in the spring or early summer after sunlight exposure. Symptoms may also be triggered by fever, drugs, and emotional or physical stress. They progress over several days and last for 1-4 weeks before spontaneous remission occurs.

Hartnup syndrome is an autosomal recessive disorder caused by mutations in the SLC6A19 gene (5p15.33). SLC6A19 encodes a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in the kidneys and intestine. Treatment includes nicotinamide supplements (40 to 200 mg per day). Neutral hyperaminoaciduria (determined by urine chromatography) is the diagnostic hallmark. Pellagra is the main differential diagnosis. Blue diaper syndrome, ataxia-telangiectasia, hydroa vacciniforme, pityriasis alba, and xeroderma pigmentosum should be excluded. All patients benefit from a high-protein diet, sunlight protection, and avoidance of photosensitizing drugs. Some patients may respond to a tryptophan-rich diet. Patients with severe central nervous system involvement require neurologic and psychiatric treatment. *Author: Orphanet (June 2007).


Hawkinsinuria is an inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin ((2-l-cystein-S-yl-4-dihydroxycyclohex-5-en-1-yl)acetic acid), in the urine. The prevalence is unknown, but the disease appears to be very rare with only a small number of affected families reported in the literature. Symptoms manifest in infants fed on formula or cow's milk or after weaning from breast milk. The disorder is transmitted as an autosomal dominant trait and is caused by an A33T mutation in 4-hydroxyphenylpyruvic acid dioxygenase (4-HPPD), an enzyme that catalyses the conversion of hydroxyphenylpyruvate to homogentisate. The diagnosis is confirmed by detection of characteristic tyrosine metabolites by organic acid analysis of the urine. Patients are treated with ascorbic acid and a low-protein diet (in particular, restricted phenylalanine and tyrosine intake). On this diet, the patients grow normally and the metabolic acidosis resolves. The prognosis for Hawkinsinuria patients is good: although patients continue to excrete hawkinsin in their urine, the symptoms improve significantly after the first year of life and the children appear to be asymptomatic by the time they reach late childhood. *Author: Orphanet (December 2006).


Histidinemia is a disorder of histidine metabolism caused by a defect in histidase. The enzyme defect results in elevated urinary excretion of histidine and its metabolites, in high concentration of histidine in blood and cerebrospinal fluid (CSF), and in decreased concentration of urocanic acid in blood and skin. The incidence of histidinemia in North America is estimated to be 1/12,000, according to a newborn screening program of more than 20 million newborns. This metabolic disorder seems to be benign in most affected individuals, although, under unusual circumstances, the disorder may be harmful and lead to the central nervous system (CNS) disease noted in a few histidinemic patients. Maternal histidinemia is believed to be benign. Low-histidine diet lowers the blood histidine level but seems not to be indicated, at least for most patients, given the apparent lack of consequences of the disorder in many cases. This disorder is transmitted as an autosomal recessive trait. The human histidase gene, histidine ammonia-lyase (HAL), has been localized to chromosome 12q22-q24.1. The molecular characteristics and the precise impairment of histidase in histidinemia have not yet been determined. *Author: Prof. H. Levy (April 2004).


Classical homocystinuria due to cystathionine beta-synthase (CbS) deficiency is characterized by the multiple involvement of the eye, skeleton, central nervous system, and vascular system. According to data collected from countries that have screened over 200,000 newborns, the cumulative detection rate of CbS deficiency is 1 in 344,000. In some areas, the reported incidence based on clinical cases is approximately 1 in 65,000. More recently, screening based on CbS mutations has led to reported incidences as high as 1 in 20,000. Patients are normal at birth and, if left untreated, the disease course is progressive. Eye anomalies include ectopia lentis (85% of the cases), with high myopia. Skeletal changes include genu valgum and pes cavus, followed by dolichostenomelia, pectus excavatum or carinatum and kyphosis, or scoliosis and osteoporosis. Thromboembolism, affecting both large and small arteries and veins, is the most striking cause of morbidity and mortality. Intellectual deficiency rarely manifests before the first to second year of life. Clinically significant psychiatric illness is found in 51% of cases. Involvement of the liver, hair, and skin has also been reported.

The disease is an autosomal recessively inherited disorder of methionine metabolism, caused by mutations in the CBS gene (21q22.3). CbS normally converts homocysteine to cystathionine in the transsulfuration pathway of the methionine cycle and requires pyridoxal 5-phosphate as a cofactor. The other two cofactors involved in methionine remethylation include vitamin B12 and folic acid. Clinical diagnosis of CbS deficiency is confirmed by blood amino acid analysis (including total homocysteine measurement), assays of CbS enzyme activity, or by screening for CBS mutations. If the disease is diagnosed in the newborn infant, as ideally it should be, the aim of treatment must be to ensure the development of normal intelligence and prevent the development of other complications. Later, it aims at preventing life-endangering thromboembolic events and further escalation of the complications. There are currently three recognized modalities of treatment. For those that are pyridoxine responsive, the treatment includes pyridoxine in pharmacological doses in combination with folic acid and vitamin B12 supplements. In pyridoxine nonresponsive individuals, the recommended treatment is a methionine-restricted, cystine-supplemented diet in combination with the pyridoxine, folic acid and vitamin B12 supplementation. Betaine anhydrous is a methyl donor that may lead to lowering of homocysteine levels in these individuals and can be used as an adjunct to such a diet. It obtained EU marketing authorization as an orphan drug for the treatment of homocystinuria in 2007. *Author: Dr S. Yap (July 2007).


Hyperlysinemia is a lysine metabolism disorder characterised by elevated levels of lysine in the cerebrospinal fluid and blood. Variable degrees of saccharopinuria are also present. The prevalence is unknown. The disorder was first reported in individuals with neurological problems and intellectual deficit. However, subsequent studies conducted to avoid ascertainment bias identified pronounced hyperlysinemia in otherwise asymptomatic individuals, suggesting that isolated hyperlysinemia is not associated with a clinical phenotype. One mother with hyperlysinemia gave birth to a normal baby. Hyperlysinemia is transmitted as an autosomal recessive trait. It is caused by a deficiency of the bifunctional enzyme alpha-aminoadipate semialdehyde synthase (AASS gene, 7q31.3). This enzyme has both lysine-ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH) activity, and catalyses the first two steps of lysine degradation. In hyperlysinemia, both enzymatic functions of alpha-aminoadipate semialdehyde synthase are defective. A low lysine diet may be of benefit in some cases. *Author: Orphanet (October 2006).


Inherited hyperornithinemia is characterized by mitochondrial ornithine aminotransferase deficiency. Onset may occur in neonatal period with hyperammonaemic coma; however, normal ammonemia levels are rapidly and definitely restored soon after. The main clinical manifestation of the disease is gyrate atrophy of the choroid and retina that begins during childhood with myopia and night blindness, followed by concentric shrinking of the visual field (tunnel vision) and a peculiar aspect of retinopathy on the funduscopy. The electroretinogram soon goes flat. Patients often develop subcapsular posterior cataract between the ages of 10 and 20 and become virtually blind between the ages of 40 and 50. Most have normal intelligence, although some may be moderately retarded and exhibit proximal muscular disorders.

It is transmitted as an autosomal recessive trait. Mitochondrial ornithine aminotransferase is involved in the transamination of ornithine and alpha ketoglutarate into delta-I-pyroline-5-carboxylate and has vitamin B6 for a cofactor. Two genetic forms have been described: a pyridoxine responsive form and a pyridoxine unresponsive form. Diagnosis is made by demonstrating major plasma and urinary hyperornithinemia on the chromatography of amino acids, and confirmed by measuring enzymatic activity in lymphocytes or cultured fibroblasts. Patients are all tested for pyridoxine sensitivity during 2 weeks by receiving 500 mg to 1g of pyridoxine daily. As a result, ornithine-sensitive patients demonstrate normal plasma and urinary ornithinemia and should receive lifelong ornithine supplements. Ornithine-resistant patients should follow a diet with limited protein intake and may be supplemented with proline, although its efficiency is still controversed. *Author: Prof. J.M. Saudubray (March 2004).


Primary hyperoxaluria type 1 is a rare metabolic disorder transmitted as an autosomal recessive disease. It is due to a defect of the peroxysomal hepatic enzyme L-alanine: glyoxylate aminotransferase (AGT). The defect in AGT, which normally converts glyoxylate to glycine, results in an increase of the glyoxylate pool, which is converted to oxalate. The first symptoms occur before one year of age in 15 percent and before 5 years of age in 50 percent of cases. The infantile form is characterized by chronic renal failure due to massive oxalate deposition. In other patients, urolithiasis develops with infections, hematuria , renal colics or acute renal failure due to complete obstruction. End-stage renal failure occurs before 15 years of age in half the cases and the resulting increase of circulating oxalate leads to its deposition in tissues causing cardiac conduction defects, hypertension, distal gangrene, and reduced joint mobility and pain. Hyperoxaluria is associated with increased excretion of glycolate. The absence of AGT activity can be confirmed by liver biopsy.

A prenatal diagnosis can be made on liver biopsy or by DNA analysis either using polymorphic markers located in the AGXT gene region on chromosome 2q36-37 when the family is informative or looking at the mutation when it has been detected in a sibling. Treatment includes high fluid intake to maintain high urine output above 3 liters/1,73m2/day, pyridoxine supplement (AGT coenzyme) and alkalinization of urine. Renal transplantation alone does not correct the metabolic disorder, which will recur in the graft. Combined liver and kidney transplantation is probably the treatment of choice in young children: transplantation should be performed before or very soon after starting dialysis in order to prevent extrarenal complications. Hyperoxaluria type 2 is extremely rare and is due to glycerate dehydrogenase deficiency. * Author: Prof P.Niaudet (March 2004).


Dihydropteridine reductase (DHPR) deficiency, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterine deficiency. Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases. DHPR deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate. DHPR activity can be measured by means of a technique adapted to dry blood samples. When left untreated, DHPR deficiency leads to neurological signs at age 4 or 5 months, although clinical signs are often obvious from birth. The principal symptoms include: psychomotor retardation, tonicity disorders, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficult swallowing. The treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophane). Folic acid intake prevents progressive deficits of cerebral folates, while antifolates, such as cotrimoxazole are dangerous. *Author : Prof J.L. Dhondt, MD (February 2005).


Hyperprolinemia type I is an inborn error of proline metabolism characterized by elevated levels of proline in the plasma and urine. The prevalence is unknown. The disorder is generally considered to be benign but associations with renal abnormalities, epileptic seizures and other neurological manifestations, as well as certain forms of schizophrenia have been reported. It is transmitted as an autosomal recessive trait and is caused by mutations in the proline dehydrogenase or proline oxidase gene (PRODH or POX, 22q11.2). *Author: Orphanet (September 2006).


Isovaleric acidemia is caused by a deficit in isovaleryl CoA dehydrogenase which affects leucine metabolism. The disease is transmitted by autosomal recessive inheritance. The estimated prevalence in the general population of Europe is 1/100 000. As of the first days of life, newborns can present vomiting, dehydration, coma and abnormal movements. Biological examinations show metabolic acidosis with ketosis, hyperammonemia, neutropenia, thrombopenia, hypocalcemia. Treatment is based on a moderate restriction of proteins in the diet and oral administration of glycine and carnitine which assure effective clearance of isovaleryl CoA. *Author: Orphanet (October 2005).


Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) is one of the constituents of mitochondrial trifunctional protein (see Mitochondrial trifunctional protein deficiency). The isolated deficiency of the LCHAD activity is an autosomal recessive inherited condition, marked with hypotonia, hypoketotic hypoglycemia during long fast or infections, usually associated with hypertrophic cardiomyopathy before the age of 2. Most patients later develop retinopathy and peripheral neuropathy. Heterozygous mothers may develop a HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets) during the last trimester of pregnancy when fetus is affected. Mutation G1528C is very frequent (90% of mutant alleles) in LCHAD-deficient patients. The study of urinary organic acids and plasma acylcarnitines allows suspecting the diagnosis but cannot differentiate LCHAD deficiency from trifunctional protein deficiency. Diagnosis can only be affirmed by identifying the G1528C mutation or by measuring the enzymatic activity. Prenatal diagnosis is available and involves measuring the LCHAD activity and identifying the G1528C mutation in chorionic villi (directly or cultured) or in cultured amniocytes. * Author: Dr C. Vianey-Saban (March 2004).


Lysinuric protein intolerance (LPI) is a very rare inherited multisystem condition caused by disturbance in amino acid metabolism. It is mainly found in Italy and Finland where prevalence is 1/60,000. The metabolic disturbance in LPI causes increased renal excretion and reduced absorption from intestine of cationic amino acids, and orotic aciduria. Patients affected by LPI may present with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, bone marrow abnormalities, osteopenia, episodes of hyperammonaemic coma, mental retardation, altered immune response, chronic renal disease, and lung involvement (mostly pulmonary alveolar proteinosis - PAP - and, to a lesser extent, interstitial lung disease). Pulmonary involvement represents a major cause of impaired clinical course and fatal outcome. LPI is inherited according to autosomal recessive modality. It is caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in the kidney and intestine. LPI is caused by mutations of solute carrier family 7A member 7 (SLC7A7) located at chromosome 14q11.2. Diagnosis requires amino acid assays in plasma and urine where increased urinary excretion and low plasma concentration of lysine, arginine, and ornithine indicate positive diagnosis. Treatment revolves around protein-restricted diet and supplement of lysine, ornithine, and citrulline. The complication of pulmonary alveolar proteinosis has been reported to be successfully treated by whole lung lavage. Prognosis varies depending on pulmonary complications. *Author: Dr M. Luisetti (November 2007).


Maple syrup urine disease (MSUD), also called branched-chain ketoaciduria, is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is a type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine. MSUD is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDH), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products in the blood and urine. The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup. Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage, and eventually die. From early infancy, symptoms of the condition include poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline.
Maple syrup urine disease can be classified by its pattern of signs and symptoms, or by its genetic cause. The most common and severe form of the disease is the classic type, which appears soon after birth. Variant forms of the disorder may appear later in infancy or childhood and are typically less severe, but still involve mental and physical problems if left untreated.
There are several variations of the disease:

  • Classic Severe MSUD
  • Intermediate MSUD
  • Intermittent MSUD
  • Thiamine-responsive MSUD
  • E3-Deficient MSUD with Lactic Acidosis

A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage. As these three amino acids are required for proper metabolic function in all people, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm. Usually, patients are also monitored by a dietitian. Their diet must be adhered to strictly and permanently. However, with proper management those afflicted are able to live healthy, normal lives and not suffer the severe neurological damage associated with the disease.


Acyl-CoA dehydrogenase, medium chain (MCAD) deficiency is an inborn error of mitochondrial fatty acid oxidation, inherited as an autosomal recessive trait. MCAD is an electron transfer flavoprotein (ETF) dependant enzyme, located in mitochondrial internal matrix. Clinically, the disease is characterized by acute episodes of hypoketotic hypoglycemia with hepatomegaly (pseudo Reye syndrome), triggered by fasting or infections, which occur generally within the two first years of life. There is neither muscle nor cardiac involvement. Diagnosis is suspected by a characteristic profile of urinary organic acids, plasma medium chain fatty acids and plasma acylcarnitines. A prevalent point mutation (A985G) has been identified (90% of muted alleles). The identification of this mutation and/or the measurement of MCAD activity in cultured fibroblasts allows the confirmation of the diagnosis. Treatment involves huge glucose infusion and eventually L-carnitine supplementation. The prognosis is good if fasting and catabolic states are avoided. * Author : Dr C. Vianey-Saban (March 2004).


MELAS (Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) is a progressive neurogenerative disorder characterized by acute neurological episodes resembling strokes associated with hyperlactatemia and mitochondrial myopathy. The exact prevalence of the disease is unknown. Patients usually present during childhood or early adulthood with acute crises, which may be triggered by infection or physical exercise. These crises associate cephalalgia, vomiting and sometimes pseudo-stroke signs, such as confusion, hemiparesia and hemianopsia. They often occur in patients with chronic symptoms such as muscle weakness, deafness, diabetes, short stature, cardiomyopathy, developmental delay, learning difficulties, memory loss or attention disorders.

The disease is caused by mitochondrial DNA mutations. At least 10 different mutations have been identified but 80% of the cases are due to the 3243A>G mutation in the leucine transfer RNA gene (tRNA Leu). This mutation is therefore often referred to as the MELAS mutation despite its association with diverse clinical presentations: its prevalence in the general population of Europe has been estimated at 1/6250. Mutation 3271T>C in the tRNA Leu gene is associated with the syndrome in a further 7.5% of patients. Diagnosis of MELAS syndrome relies on the clinical presentation and brain imaging. Magnetic resonance imaging may reveal numerous hyperintense T2 lesions in cerebral white and grey matter, while computerized tomography shows cerebral atrophy and basal ganglia calcifications. They show that the lesions are not confined to vascular territories and thus that the acute episodes are not typical strokes. Abnormal accumulation of lactate is frequent in blood and almost constant in cerebrospinal fluid. Muscle biopsy is abnormal in approximately 85% of patients. It shows abnormal mitochondrial proliferation (ragged red fibers) and muscle fibers with a cytochrome c oxidase defect. Analysis of muscle respiratory chain activities may reveal complex I deficiency or a combined deficiency of complexes I and IV.

Identification of the causal mutation has to take into account the constant heteroplasmy i.e. its coexistence with a residual population of wild type mitochondrial DNA. Mutation proportions may differ considerably between tissues, but it is most often very high (above 90%) and may therefore be investigated in blood. Genetic counseling is very arduous in MELAS syndrome due to the heteroplasmy. Mitochondrial DNA mutations are transmitted according to maternal inheritance. An affected man cannot transmit the disease. The mutation will be transmitted along the maternal lineage but its proportion is essentially unpredictable. Although higher proportions of the mutation in the blood of the mother result in a higher risk of having a child with severe phenotype, there are many examples of extreme segregation of the mutation from mother to child, which prevent efficient genetic counseling at an individual level.

The possibility heterogeneity in the proportion of the mutation between tissues theoretically hampers prenatal diagnosis. Very few proper clinical trials have been conducted with MELAS patients. A recent one has found dichloracetate to have negative effects in the medium-term. Spontaneous evolution of the disease with acute crises, remission and recurrence makes it difficult to evaluate the clinical improvement reported in some MELAS patients treated with supportive treatments (including coenzyme Q10 and its analogue idebenone, creatine monohydrate and arginine) or the deleterious impact of treatment such as valproic acid (an antiepileptic drug reported to provoke stroke-like episodes). Prognosis of MELAS syndrome is poor. Patients may die during one stroke-like episode and, along with recurrent episodes, they often develop mental deterioration, loss of vision and hearing, as well as severe myopathy, potentially leading to loss of autonomy. *Author: Dr A. Lombès (July 2006)*.


Methylmalonic aciduria, vitamin B12 unresponsive, mut 0 is due to methylmalonyl-CoA-mutase deficiency, an enzyme that is common to the catabolism of valine, isoleucine, methionine, and threonine. Methylmalonyl-CoA-mutase transforms methylmalonate into succinate. Onset is usually infantile with ketoacidotic coma, dehydration, hyperammonemia, and leucothrombocytopenia. A subacute form begins during early childhood with vomiting, hypotonia, growth and psychomotor retardation. Finally there is a later form characterized by recurrent ketoacidotic comas. Complications include growth and psychomotor retardation, pancreatitis glomerulointerstitial nephropathy, and acute central grey nuclei disorders causing extrapyramidal signs. The disease is transmitted as an autosomal recessive trait. Diagnosis is based on urinary organic acids and plasmatic acyl carnitine chromatography that show high level of methyl malonic acid and proprionyl carnitine. Amino acids chromatography reveals hyperglycinemia with a large total and free hypocarnitinemia. Diagnosis is confirmed by measuring methylmalonate-CoA-mutase enzyme. Antenatal diagnosis is feasible. Patients should follow a strict, lifelong diet with limited protein intake. Treatment otherwise includes carnitine and antibiotics to destroy intestinal bacteria that produce propionic acid. *Author: Prof. J.M. Saudubray (March 2004).


Methylmalonic aciduria with homocystinuria is a metabolic disorder consisting of an impaired vitamin B12 metabolism. The combination of abnormal excretion of methylmalonic acid and derived components, increased total or free plasma homocystine (>100 micromole/L), and normal to low plasma methionine is strongly suggestive of impaired absorption, transportation, binding, or intracellular metabolism of vitamin B12. Methylcobalamin, one of vitamin B12's derived products, acts as cofactor to homocystine methyltransferase, while adenosyl cobalamin, another derived product, is a cofactor of methylmalonic-CoA-mutase. Apart from transcolabamine II deficiencies, three genetic deficiencies have been identified by cellular complementation: the CBLC and CBLD group that may be involved in defective cytoplasmic cobalamin reductase, and the CBLF group causing impaired transportation of cobalamin bound to transcobalamin II out of lysosomes. CBLC is the only frequent disorder of the three. Several clinical forms have been described: an infantile form with acidotic coma, hypotonia, microcephaly, convulsions, megaloblastic anemia, and leukopenia; another more severe infantile form with multiorgan failure, cardiomyopathy, retinopathy, and hemolytic uremic syndrome; and finally a juvenile form with onset during childhood or adolescence that causes psychiatric disorders or subacute combined spine degeneration. Chromatography of organic acids and amino acids is suggestive of the disease, but diagnosis is confirmed by studying complementation groups of cobalamin in fibroblasts. Patients are treated with intramuscular injections of hydroxocobalamin, oral betaine and folic acid. Antenatal diagnosis is feasible. * Author: Pr. J-M. Saudubray (March 2004).


The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mtDNA copy number in affected tissues without mutations or rearrangements in the mtDNA. MDS may be a relatively common neurogenetic disorder of infancy and childhood. In one report, 11% of young children (<2 years old) referred for weakness, hypotonia, and developmental delay had mtDNA depletion. MDS is phenotypically heterogeneous, manifesting either as a hepatocerebral form, a myopathic form, a benign "later-onset" myopathic form or a cardiomyopathic form. Children usually present in infancy with hypotonia, lactic acidosis, and elevated serum creatin kinase (CK). Some of them also have severe, often fatal hepatopathy or renal involvement mimicking the De Toni-Fanconi syndrome. A reduced activity of the respiratory chain and, more importantly, a low mtDNA/nDNA ratio in affected tissues confirm clinical diagnosis. MDS is thought to be a primary process. Depletion of mtDNA can also be secondary (as seen in inclusion body myositis) or iatrogenic (as seen in patients treated with nucleoside analogs). MDS often strikes recurrently in families with a possible autosomal recessive inheritance, suggesting a genetic defect in the nuclear DNA. Actually, mutations in the nuclear-encoded mitochondrial deoxyguanosine kinase (DGUOK) and deoxythymidine kinase (TK2) genes have been associated with the hepatocerebral and myopathic forms of MDS, respectively. These two genes encode mitochondrial salvage pathway enzymes, which are involved in mtDNA synthesis via supply of deoxyribonucleotides (dNTPs). Muscle weakness and exercise intolerance may be responsive to Coenzyme Q supplementation. *Authors: Drs R. Carrozzo and S. Lucioli (February 2004).


There are two main types: I-H (Hurler syndrome) which is the most severe form of mucopolysaccharidosis type I (MPS I), and I-S (Scheie syndrome), a mild form of MPS I. MPS I is a rare lysosomal storage disease, characterized by skeletal deformities and a delay in motor and intellectual development. The prevalence of MPS I has been estimated at 1/100,000, with Hurler syndrome accounting for 57% of cases or a prevalence of approximately 1/175,000. The most important features of Hurler syndrome are skeletal deformities and a delay in motor and intellectual development. Patients present within the first year of life with musculoskeletal alterations including short stature, dysostosis multiplex, thoracic-lumbar kyphosis, progressive coarsening of the facial features including large head with bulging frontal bones, depressed nasal bridge with broad nasal tip and anteverted nostrils, full cheeks and enlarged lips, cardiomyopathy and valvular abnormalities, sensorineuronal hearing loss, enlarged tonsils and adenoids, and nasal secretion. Developmental delay is usually observed between 12 and 24 months of life and is primarily in the speech realm with progressive cognitive and sensory deterioration.

Hydrocephaly can occur after the age of two. Diffuse corneal compromise leading to corneal opacity becomes detectable from three years of age. Other manifestations include organomegaly, hernias and hirsutism. Hurler syndrome is caused by mutations in the IDUA gene (4p16.3) leading to complete deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate. Transmission is autosomal recessive. Early diagnosis is difficult because the first clinical signs are not specific, but it is very important to allow early treatment. Diagnosis is based on detection of increased urinary excretion of heparan and dermatan sulfate by 1,9-dimethylmethylene blue (DMB) test and glycosaminoglycan (GAG) electrophoresis, and demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available. Differential diagnoses include the milder form of mucopolysaccharidosis type 1, the Hurler-Scheie syndrome, although this form is associated with developmental delay with only slight cognitive impairment.

Differential diagnoses also include mucopolysaccharidosis type VI or mucopolysaccharidosis type II, although the former (type VI) is not associated with intellectual impairment. Antenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known. Genetic counseling is recommended. Management should be carried out by a multidisciplinary team and should include physiotherapy to maintain range of movement. Bone marrow or umbilical cord blood transplant has been successful and can preserve neurocognition, improve some aspects of the somatic disease and increase survival. However it is associated with many risks and most of the positive effects occur within the first few years after the graft only. The enzyme substitute (laronidase) obtained EU marketing authorization as an Orphan drug in 2003. Given through weekly infusions it leads to improvement of lung function and joint mobility. Early treatment slows the progression of the disease, but it is not efficient against neurological lesions. Life expectancy for Hurler syndrome is reduced, with death occurring before adolescence due to serious cardiovascular and respiratory complications. *Author: Prof. M. Beck (April 2010).


Mucopolysaccharidosis type 2 (MPS 2) is a lysosomal storage disease belonging to the group of mucopolysaccharidoses. It is present at birth in between 1/72 000 and 1/132 000 males. The clinical picture ranges from severe (the most frequent form) with early psychomotor regression, to the milder form. Infants are normal at birth, and symptoms appear progressively. Clinical signs of the severe form include hernias, facial dysmorphism (macroglossia, constantly opened mouth, coarse features), hepatosplenomegaly, limited joint motion, carpal tunnel syndrome, dysostosis multiplex, small size, behavioural disorders and psychomotor regression leading to intellectual deficit, deafness, cardiac and respiratory disorders, and cutaneous signs (skin with an orange peel appearance on the scapula and thighs). The corneas are usually clear. Moderate forms are characterized by normal intelligence, milder dysmorphism and dysostoses, and prolonged survival.

MPS II results from iduronate-2-sulfatase (IDS) deficiency, which leads lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate (DS) and heparan sulfate (HS). The causative gene has been located on Xq28 and approximately 320 mutations have been reported. MPS II is the only MPS transmitted as an X-linked recessive trait. Although only boys are theoretically affected, approximately 12 cases of affected girls have been described: in most cases, skewed X inactivation led to the preferential expression of the mutated X chromosome. Diagnosis is based on detection of increased levels of DS and HS in the urine and confirmed by the demonstration of the enzyme deficiency in the serum, leukocytes or fibroblasts. To exclude multiple sulfatase deficiency (Austin disease), the enzymatic activity of another sulfatase should also be assessed.

MPS I in boys constitute the other differential diagnosis. In women at risk of being a carrier, analysis of enzyme activity cannot provide a conclusive evaluation of their status, as a non-random X inactivation could occur. They should undergo genetic testing when the mutation has been identified in the propositus. Prenatal diagnosis (by measuring IDS activity or by mutation analysis in trophoblasts or amniocytes) is only performed when the fetus is male. In addition to symptomatic treatment, which requires a multidisciplinary approach, allogenic bone marrow grafting is not recommended as it does not prevent intellectual degradation. In 2007, enzyme replacement therapy with infusion of the recombinant enzyme idursulfase obtained EU marketing authorisation as an Orphan drug for long-term treatment of patients. Clinical trials have shown an improvement in walking abilities and in respiratory involvement and significant results on the size of the liver or the spleen and the cardiac involvement. However, improvement of neurological signs has not been reported. For patients with the most severe form, life expectancy is markedly reduced, death generally occurring before the age of 20, as a result of cardio-respiratory complications. In the moderate forms, patients survive well into adulthood, sometimes even after the age of 60 for those less severely affected. *Authors: Drs I. Maire and R. Froissart (February 2007).


Mucopolysaccharidosis type III (MPS III) is a lysosomal storage disease belonging to the group of mucopolysaccharidoses and characterized by severe and rapid intellectual deterioration. The disorder is underdiagnosed (due to the generally very mild dysmorphism); it is the most frequent MPS in the Netherlands and Australia with respective prevalences of 1/53 0000 and 1/67 000. The frequency of the different subtypes varies between countries: subtype A is more frequent in England, the Netherlands and Australia and subtype B is more frequent in Greece and Portugal, whereas types IIIC and IIID are much less common. The first symptoms appear between the ages of 2 and 6 years, with behavioural disorders (hyperkinesia, aggressiveness) and intellectual deterioration, sleep disorders and very mild dysmorphism. The neurological involvement becomes more prominent around the age of 10 years with loss of motor milestones and communication problems. Seizures often occur after the age of 10. A few cases of attenuated forms have also been reported.

Deficiencies in one of the four enzymes required for HS degradation are responsible for each of the MPS III subtypes: heparan sulfamidase for MPS IIIA, alpha-N-acetylglucosaminidase for MPS IIIB, alpha-glucosaminide N-acetyltransferase for MPS IIIC, and N-acetylglucosamine-6-sulfate sulfatase for MPS IIID. The four genes coding for these enzymes have been located (MPS IIIA on 17q25, MPS IIIB on 17q21, MPS IIIC in the pericentromeric region of chromosome 8, MPS IIID on 12q14), and numerous mutations have been identified. Transmission is autosomal recessive for each type of MPS III. Diagnosis is based on detection of increased levels of heparan sulfate (HS) in urine. Demonstration of one of the four enzyme deficiencies in cultivated leukocytes or fibroblasts allows determination of the type of MPS III. For types IIIA and IIID, the measurement of the activity of another sulfatase is compulsory for exclusion of multiple sulfatase deficiency (Austin disease).

When mutations have been identified in the index patient, heterozygous individuals in the family can be accurately detected. In the absence of any efficient treatment, prenatal diagnosis (by mutation analysis or measurements of enzyme activity in trophoblasts or amniocytes) is the only option available to parents with a risk of transmitting the disease. Allogenic bone marrow grafts are contraindicated as they do not slow the mental deterioration, even in patients engrafted pre-symptomatically. Gene therapy is currently under investigation in animal models for the IIIA and IIIB subtypes. The neurological degradation accompanied by multiple complications requires a multidisciplinary management to allow adapted symptomatic treatment. The prognosis is poor with death occurring in most cases of type IIIA at the end of the second decade. Longer survival times (30/40 years) have been reported for the B and D subtypes. *Authors: Drs R. Froissart and I. Maire (February 2007).


Mucopolysaccharidosis type IV (MPS IV) is a lysosomal storage disease belonging to the group of mucopolysaccharidoses, and characterized by spondylo-epiphyso-metaphyseal dysplasia. It exists in two forms, A and B. Prevalence is approximately 1/250 000 for type IVA but incidence varies widely between countries. MPS IVB is even rarer. MPS IVA is a spondylo-epiphyso-metaphyseal dysplasia generally diagnosed during the second year of life, after walking acquisition. Skeletal deformities (platyspondyly, kyphosis, scoliosis, pectus carinatum, genu valgum, long bone deformities) become more pronounced as the child grows. Joint hyperlaxity is accompanied by frequent luxations (hips, knees). The skeletal involvement not only leads to impairment in walking and daily activities, but also to growth arrest at around 8 years of age and a definitive size of 1m to 1.50m, depending on the severity of the disease. Potential nervous complications are secondary to skeletal deformations. From the age of 5 to 6 years, hypoplasia of the odontoid vertebra combined with joint hyperlaxity leads to an instability at the level of the first two cervical vertebras, with a risk of spinal cord compression. Extra-skeletal manifestations include respiratory problems, hepatomegaly, valvulopathies, hearing loss and corneal clouding. Intelligence is normal. The clinical picture is quite similar to that of type IV B and two forms cannot be clinically distinguished as the severity of symptoms varies in both types. A deficiency in one of the two enzymes required for the degradation of keratan sulfate (KS) is responsible for the MPS IV subtypes: N-acetylgalactosamine-6-sulfate sulfatase in MPS IVA, and beta-D-galactosidase in MPS IVB.

The genes coding for both enzymes have been located and cloned (GALNS on 16q24 and GLB1 on 3p) and mutations have been identified (118 for GALNS). Transmission is autosomal recessive in both cases. Diagnosis is based on detection of increased urinary KS excretion (not constant) and galactosyloligoaccharide excretion in MPS IVB. It is confirmed by the demonstration of enzymatic deficiency in cultured leucocytes or fibroblasts. Enzymatic study allows other osteochondrodysplasias to be excluded. The distinction between MPS IVB and GM1 gangliosidosis type 3 is often difficult in children, even if 9 out of 59 GLB1 mutations are associated with MPS IVB. Heterozygous individuals can be detected in families with known mutations and prenatal diagnosis is possible (through molecular analysis or enzyme measurements in trophoblasts or amniocytes). General anaesthesia may be problematic in patients with MPS type IV, due to intubation difficulties. As allogenic bone marrow transplants are not effective against the bone manifestations, treatment is symptomatic (prosthesis, surgery, neck consolidation by vertebral fusion). Recombinant enzyme therapy targeted towards the bone tissue is currently being developed. Prognosis depends on the severity of the disease and on the quality of care, which can allow patients to survive beyond the age of 50. *Authors: Drs I. Maire and R. Froissart (February 2007).


Mucopolysaccharidosis type VII (MPS VII) is a very rare lysosomal storage disease belonging to the group of mucopolysaccharidoses. Less than 40 patients with neonatal to moderate presentation have been reported since the initial description of the disease by Sly in 1973. However, the frequency of the disease may be underestimated as the most frequent presentation is the antenatal form, which remains underdiagnosed. Clinical signs are extremely variable: there are prenatal forms with non-immune hydrops fetalis, and severe neonatal forms with dysmorphism, hernias, hepatosplenomegaly, club feet, dysostosis, severe hypotonia and neurological disorders that ultimately lead to profound intellectual deficit and small stature in patients that survive. Finally, there are also very mild cases that are discovered during adolescence or adulthood following presentation with thoracic kyphosis.

The disease is caused by beta-D-glucuronidase deficiency, which leads to accumulation of several glycosaminoglycans (dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS)) in lysosomes. The causative gene has been located on 7q21-q22 and more than 40 mutations have been identified. Transmission is autosomal recessive. Diagnosis is suspected after detection of increased levels of urinary glycosaminoglycan (either CS alone or CS+HS+DS) excretion, although this sign may be absent in adult forms. Diagnosis is confirmed by demonstration of beta-D-glucuronidase deficiency in cultured leucocytes or fibroblasts. Pseudo deficient alleles make mild forms more difficult to identify and prenatal diagnosis difficult. Differential diagnosis includes other types of MPS and oligosaccharidosis. The determination of enzymatic activity in leucocytes allows heterozygous individuals to be detected for the severe forms. When the two mutations have been identified in the index patient, the detection of heterozygous relatives can be accurately performed.

Diagnosis is essential in forms with in utero presentation in order to avoid the recurrence of pregnancies leading to in utero death or to late termination of the pregnancy. In the absence of any efficient treatment, prenatal diagnosis (by molecular analysis or measurement of enzyme activity in trophoblasts or amniocytes) is offered to parents with an affected child. Multidisciplinary management allows adapted symptomatic treatment, which is essential for improving the quality of life of the patients. In late-onset forms, treatment is mainly orthopedic. Bone marrow transplantation has been attempted for one mild case. Multiple assays of other specific treatments are being performed in animal models: allogenic bone marrow transplantation, gene therapy and enzyme replacement therapy (with recombinant enzyme or intraperitoneal implants of autologous genetically modified fibroblasts or “neo-organs”). Prognosis is poor for antenatal forms, most often leading to death in utero. Neonatal and childhood forms have a very limited life expectancy, whereas milder forms have a prolonged survival. *Authors: Drs I. Maire and R. Froissart (February 2007).


Non ketotic hyperglycinemia with is relatively frequent among inborn errors of newborns. It is transmitted as an autosomal recessive trait. It affects hepatic glycine cleavage, which is the main source of monocarbon radicals. Onset is generally neonatal with coma, severe hypotonia, myoclonic seizures, and microcephaly. The disease usually progresses to severe mental retardation and tetrapyramidal syndrome. The electroencephalogram yields a characteristic hypoactive and pseudoperiodic chart with burst suppression. Biological findings are massive levels of glycine in plasma, urine, and especially cephalospinal fluid, while serine is low. The diagnosis is confirmed by measuring enzymatic activity in the liver. A few cases with later onset have been described (patients present with nonspecific encephalopathy), as well as transient neonatal cases, which first present with a favourable disease course, whose long term outcome is finally disappointing. Treatment is based on sodium benzoate and dextromethorphane, but its efficiency has not been demonstrated. Genes encoding N or P subunit may carry different mutations. Antenatal diagnosis using a chorion villus sample may be performed by studying glycine cleavage (not reliable method) or by gene analysis if the mutation is known * Author: Pr. J.-M. Saudubray (March 2004) *


Phenylketonuria is a hereditary metabolic disease, characterized by deficiency of phenylalanine hydroxylase, an enzyme necessary for the transformation of phenylalanine into tyrosine. Untreated, phenylketonuria leads to mental retardation, sometimes profound, as well as hypopigmentation. Dietary phenylalanine restriction allows patients to lead almost normal lives. Phenylalanine is toxic to fetal development and severe disorders occur in the children of women whose phenylketonuria is untreated during pregnancy. These women must be informed that they must plan pregnancy and begin dietary restrictions in the preconceptional period. The incidence of this disease is 1/17 000 in France, where routine neonatal screening has been set up. Since 1970, approximately 1600 infants with phenylketonuria have thus been diagnosed and treated in this country. Strict metabolic control is necessary during the first 10 years of life, after which the diet can be progressively enlarged. Dietary restriction must resume before any pregnancy. Advances in treatment: a study published in 2002 showed that some patients deficient in phenylalanine hydroxylase are sensitive to pharmacological doses of tetrahydrobiopterin (BH4), a cofactor of this enzyme is essential for the transformation of phenylalanine into tyrosine. Some patients treated with this cofactor have normal levels of phenylalanine intake. While only a few patients have so far received this alternative treatment, the results of intermediate and long-term experiments are currently being evaluated. *Author: Prof. F. Feillet (March 2006).


Propionic acidemia is a frequent autosomal recessive disorder due to propionyl-CoA carboxylase deficiency. Genes causing the disease code for two alpha or beta subunits. A few cases are biotin responsive, a propionyl-CoA carboxylase cofactor. Clinical signs - which are close to those seen in methyl malonic acidemia -appear soon after birth and include ketoacidotic coma, hyperammonemia and convulsions. Onset may be later with recurrent coma or hypotonia, digestive disorders, and intellectual deficit. Apart from acute metabolic decompensation, the major complications are neurological disorders (central grey nuclei), cardiomyopathies, and acute pancreatitis. Diagnosis is made by chromatography of urinary organic acids and plasmatic acylcarnitines with evidence of propionic acid and other derived products. Patients should follow a very strict diet with limited protein intake. Treatment otherwise includes carnitine and alternated cures of antibiotics to destroy intestinal bacteria that produce propionic acid. Treatment by liver transplantation is reserved to only very severe cases. Antenatal diagnosis is feasible. * Author: Pr. J.M. Saudubray (March 2004).


Refsum disease, biochemically characterized by phytanic acid accumulation, belongs to the group of leucodystrophic diseases. Prevalence of the disease is of 1 case per 1 000 000 and males and females are equally affected. Initial signs usually appear around the age of 15, but they can also manifest during childhood or at the age of 30 - 40 years. The first symptom is hemeralopia (loss of vision in the dark), followed by episodes of chronic distal motor polyneuropathy. Other associated signs include perceptive deafness, anosmia, cerebellous ataxia and sometimes, severe intellectual deficiency. Over the course of time cutaneous signs appear (ichtyosis), along with polyepiphyseal dysplasia, myocardiopathy, elevated protein in cerebrospinal fluid, and pigmentary retinitis that may result in blindness.

Refsum disease is transmitted as an autosomal recessive trait. This disorder results from phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) accumulation, which leads to lesions essentially in retina, brain and peripheral nervous system. In most cases, the causative mutation is in the PHYH gene (or PAXH, localized in 10pter - p11.2) encoding the peroxysomal enzyme phytanoyl-CoA hydroxylase (PhyH), which alpha-oxidizes phytanic acid and allows the first step of its degradation. Another mutation was recently identified in PEX7 gene, localised in 6q22-24. It codes for the peroxine 7 receptor, which allows the import of PhyH in peroxysomes. Diagnosis is brought by the biologic evidence of phytanic acid in plasma and urines. Heterozygotes can be detected. As phytanic acid comes exclusively from food (green vegetables and herbivore animals), a strict diet helps symptoms regress partly. Nevertheless, altered audition and vision as well as anosmia can persist. *Authors: Profs. N. Baumann and J.C. Turpin (April 2006).


Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting the central nervous system. RTT primarily affects females, making it one of the most common genetic causes of severe intellectual disability in females. Prevalence is estimated at 1/9,000 in girls under the age of 12, whereas prevalence in the general population is estimated at approximately 1/30,000. Classical RTT is characterised by apparently normal development for the first 6-18 months of life followed by the loss of acquired fine and gross motor skills and the ability to engage in social interaction, and the development of stereotypic hand movements. Scoliosis is seen in most patients by the age of 25. There is a wide variability in the rate of disease progression and severity, and several atypical variants are recognised. In addition, a number of males with a phenotype comparable to females with classical or atypical RTT have been described, as well as rare males with a severe neonatal-onset encephalopathy and prominent breathing abnormalities.

Despite the identification of mutations in the X-linked gene methyl CpG-binding protein 2 (MECP2) in the majority of RTT patients, the aetiology remains unclear. More recently mutations in two other genes, cyclin-dependent kinase like 5 (CDKL5) and Netrin G1, have been identified in patients with a clinical phenotype that strongly overlaps with RTT. The diagnosis of RTT is clinical, based on Trevathan diagnostic criteria, recently revised following a meeting of an expert group of the European Pediatric Neurology Society. Differential diagnosis includes autism and Angelman syndrome; cataract, retinopathy, or optic atrophy; history of perinatal or postnatal brain damage; confirmed inborn error of metabolism or neurodegenerative disorder; acquired neurological disorder due to severe head trauma or infection. Storage disorder is usually excluded by the presence of organomegaly.

As pathogenic MECP2 mutations in RTT patients are mostly de novo, the recurrence risk for future pregnancies is low, although gonadal mosaicism has been reported. Prenatal screening should be discussed for families with a proband having a pathogenic mutation. Management is mainly symptomatic, focused on optimising each patient's abilities. A multidisciplinary approach (involving dieticians, physiotherapists, occupational therapists, speech therapists and music therapists) is most effective. Attention should be paid to scoliosis and the development of spasticity, as well as to the development of effective communication strategies. Psychosocial support for families is essential. Pharmacological approaches aim at improving sleep disturbances, breathing disturbances, seizures, stereotypic movements and general well-being. As RTT patients have an increased risk of life threatening arrhythmias associated with a prolonged QT interval, avoidance of a number of drugs is recommended. The clinical picture evolves in stages over a number of years and prognosis is poor. *Authors: Dr S. L. Williamson and Prof. J. Christodoulou (November 2007)*.


Acyl-CoA dehydrogenase, short chain (SCAD) deficiency is an inborn error of mitochondrial short-chain fatty acid oxidation. Few patients with this disorder have been documented so far. SCAD is an electron transfer flavoprotein (ETF) dependant enzyme, located in mitochondrial internal matrix. SCAD deficiency may present during the first weeks of life with muscle tone abnormalities, hypoglycemia and vomiting. More frequently however, it presents in a milder and aspecific form with hypotonia and developmental delay. Biochemical parameters allow to suspecting this diagnosis: over excretion of urinary ethylmalonic acid, and sometimes also of methylsuccinic acid and butyrylglycine. Butyrylcarnitine is often increased in plasma. A muscle biopsy is required to measure SCAD activity; diagnosis can also be confirmed by molecular study of the gene. Genetic anomalies include many deletions and 2 specific mutations (625G> A and 511C>T frequently observed in general population. Thus, other genetic or environmental factors should play a role (which remains unknown) in patients who express clinical features of the disease.
* Author: Dr C. Vianey-Saban (March 2004)*


Trimethylaminuria is a metabolic disorder characterized by a body malodour similar to that of decaying fish. Prevalence is unknown. The condition is present from birth but may only become apparent when children are weaned and/or when food that contains trimethylamine (TMA) precursors (such as choline, lecithin and carnitine) is introduced into their diet. Patients exhibit a body odour resembling that of decaying fish, as a result of excretion of excessive amounts of TMA in sweat, saliva, urine, breath, and vaginal secretions. The odour may be enhanced following exertion, temperature rises, and emotional changes, and may occur intermittently. The malodour is known to increase in women just prior to and during menstruation. Affected individuals may manifest a variety of psychosocial disorders such as a withdrawn personality, social isolation, obsessive personal cleansing, clinical depression, interrupted schooling, marital disharmony, and suicidal intent. Some cases of trimethylaminuria have been reported to occur in association with other clinical entities, such as the Prader-Willi syndrome, seizures, and behavioral disturbances.

Trimethylaminuria is caused by excretion of excessive amounts of the malodorous free amine, TMA in body secretions. It may occur as an autosomal recessively inherited disorder or in an acquired form. The former is caused by homozygous or compound heterozygous mutations in the flavin-containing monooxygenase-3 (FMO3; 1q24.3) gene resulting in a defect in the hepatic microsomal oxidase system which metabolizes malodorous TMA into odourless trimethylamine N-oxide. Numerous FMO3 mutations have been described and a carrier frequency of approximately 1% has been proposed in a British study. Chronic liver disease may also lead to excretion of excessive amounts of TMA, as a result of defective TMA metabolism. Trimethylaminuria is diagnosed by measuring excretion of free urinary TMA. Molecular genetic studies and TMA-precursor loading tests may be performed to confirm the diagnosis. However, unawareness of the condition, the need for specialist investigations, and the inability of some individuals to identify the malodour can delay diagnosis.

Differential diagnoses include local causes of altered olfactory perception, poor personal hygiene, systemic causes of malodour (such as chronic hepatic or renal disease) and other conditions such as genitourinary infections. Genetic counseling should be offered to patients with the inherited form of the disease. No curative treatment is available. An explanation of the nature of the condition is vital in the management of these patients. TMA-precursor controlled diets (i.e. avoidance or reduction of the consummation of marine fish, peas, liver and eggs) and short-course treatments with antibiotics (metronidazole or neomycin) or lactulose, may help to reduce body odour. Antiperspirants, deodorants, frequent bathing, and the use of soaps with a pH value of 5.5 - 6.5 are also helpful adjuncts. Introduction to support groups is also an important aspect of patient care. Prognosis depends on accompanying psychosocial phenomena or associated disorders. *Author: Dr. G. Arseculeratne (May 2009).


Tyrosinemia type 1 is an inborn error of amino acid metabolism characterized by hepatorenal manifestations. Prevalence is estimated at 1 in 2 million. The early-onset acute form of the disorder manifests between 15 days and 3 months after birth with hepatocellular necrosis associated with vomiting, diarrhea, jaundice, hypoglycemia, edema, ascites and gastrointestinal bleeding. Septicemia is a frequent complication. Renal tubular dysfunction occurs and is associated with phosphate loss and hypophosphatemic rickets. A later onset form has also been described and manifests with vitamin-resistant rickets caused by renal tubular dysfunction. If left untreated, neurologic crises with porphyria, polyneuritis and dystonia may occur in the acute form of the disorder and in rare cases may be the presenting features of the disease. Malignant hepatocellular carcinomas are frequent. The disorder is transmitted as an autosomal recessive trait and is caused by deficiency of fumarylacetoacetate hydrolase (FAH, 15q23-q25), an enzyme involved in the degradation of tyrosine.

FAH deficiency leads to inhibition of delta-aminolevulinate dehydratase, a key enzyme in the synthesis of porphobilinogens. Diagnosis is confirmed by detection of increased urinary excretion of delta-aminolevulinic acid and a characteristic gas chromatography urine profile showing increased levels of succinylacetone. Assays of FAH activity in fibroblasts are also feasible and may be useful for diagnosis. Prenatal diagnosis is possible through analysis of metabolites, enzyme studies or through molecular testing for families in which the disease-causing mutation has already been identified. Treatment revolves around administration of nitisinone (NTBC), which obtained European marketing authorization in 2005 as an orphan drug for the treatment of tyrosinemia type 1, in combination with a protein-restricted diet to prevent hypertyrosinemia. Despite treatment, malignant hepatocellular carcinomas (characterized by an increase in alpha fetoprotein) still develop in some patients and require liver transplantation.
*Author: Prof. P. De Lonlay (June 2007).


Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inborn error of mitochondrial long-chain fatty acid oxidation, inherited as an autosomal recessive trait. VLCAD is an electron transfer flavoprotein (ETF) dependant enzyme, located in mitochondrial internal matrix. The severe form of the disease is characterized by recurrent episodes of hypoketotic hypoglycemia, often associated with hypertrophic cardiomyopathy with pericardial effusion, or arrhythmia, which can lead to a cardiorespiratory arrest. These symptoms can occur during the neonatal period and, in all cases, before the second year of age. The treatment includes glucose infusion and high caloric supply with medium chain triglycerides in order to stop lypolysis, and L-carnitine supplementation (50 to 100 mg/kg/day). During late childhood and adulthood, the disease can present as exercise intolerance, muscle pain, recurrent episodes of rhabdomyolysis, triggered by fast, cold, fever or prolonged exercise. Urinary organic acid profile is poorly informative. Conversely, plasma long-chain fatty acid (C14:1) and acylcarnitine profiles allow to suspect the diagnosis. The disease is confirmed by the measurement of VLCAD activity in cultured skin fibroblasts, lymphocytes or tissue biopsies. Prenatal diagnosis is available by enzyme measurement in trophoblastic cells (biopsy or cultured cells) or amniotic fluid cells. Molecular study reveals a high number of mutations.
* Author: Dr C. Vianey-Saban M.D. (March 2004).


Vitamin B12 responsive methylmalonic aciduria is characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia, and intellectual deficit. The disorder is clinically similar to methylmalonic aciduria due to methylmalonyl-CoA-mutase deficiency, although symptoms are usually less severe. Isolated accumulation of methylmalonic acid may be caused by insufficient intake, defective absorption, transportation, or intracellular metabolism of vitamin B12. Vitamin B12 is a precursor of adenosyl cobalamin and a cofactor of methylmalonyl-CoA-mutase. Three genetic disorders have been identified using the complementation technique: mut-, CBLA and CBLB. All three are transmitted as autosomal recessive traits and may lead to methylmalonic aciduria that can be cured totally or in part by administering vitamin B12. Mut- is due to a methylmalonyl CoA mutase anomaly, which affects the binding site of adenosine cobalamine. CBLA may be due to defective reduction of cobalamin, while CBLB may result from adenosyl transferase deficiency. Antenatal diagnosis is feasible. Patients are treated with a diet that limits protein intake, but more importantly by intramuscular injections of vitamin B12, followed by per weight intake, with or without carnitine. Carnitine is mainly effective in cases associated with CBLA mutation. * Author: Pr. J-M. Saudubray (March 2004).


Wilson disease is an autosomal recessive disorder characterized by the toxic accumulation of copper, mainly in the liver and central nervous system. It is a rare disease with an estimated incidence in France of between 1/30 000 and 1/100 000 new cases per year. The prevalence is estimated at 1 in 25 000. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Diagnosis depends the clinical and phenotypic evidence for the disease and on the detection of the associated genetic anomalies. The disease results from mutations in the ATP7B gene on chromosome 13. The discovery of the gene has led to a better understanding of cytosolic copper trafficking and its relationship with ceruloplasmin synthesis. This disease can be efficiently treated by chelation and zinc therapy. Liver transplantation is the recommended therapy for patients with fulminant hepatitis, or in those with relentless progression of hepatic dysfunction despite drug therapy. * Author: Dr J.Ch. Duclos-Vallée (March 2006).


X-linked adrenoleukodystrophy (X-ALD) is characterized by progressive demyelinisation of the central nervous system (CNS) (brain and/or spinal cord) and peripheral adrenal insufficiency. The incidence is 1/17,000 births, including hemizygotes and heterozygous women who very often present with symptoms. Prevalence is estimated at 1/20,000. The cerebral forms of juvenile X-ALD (45% of the cases) affect previously healthy 5 to 12 year-old boys. The first manifestations are moderate cognitive deficits, followed by progressive demyelinisation of the central nervous system, with diminished visual acuity, central deafness, cerebellar ataxia, hemiplegia, convulsions and dementia leading to a neurodegenerative state or death within several years. The adult form, adrenomyeloneuropathy (AMN), is characterized by the onset of spastic paraparesia between 20 and 45 years of age, associated with gait disturbances, urinary disorders and sexual dysfunction. The disease progresses towards severe paraplegia complicated by cerebral demyelinisation in 30% of cases.

Transmission is X-linked recessive, except for 8% of de novo mutations. More than 471 different mutations of the ABCD1 gene have been described. Tissue build-up of very long chain fatty acids (VLCFA) has been observed. Clinical diagnosis is confirmed by the demonstration of high concentrations of VLCFA in plasma or fibroblasts. Screening of heterozygous women is based on the measurement of VLCFA concentrations in plasma (95% reliability), the study of the X-ALD protein in fibroblasts or monocytes/lymphocytes and the search for the ABCD1 gene mutation. Genetic counseling is used to identify women at risk of being carriers, boys not yet presenting with neurological symptoms (in order to provide early therapy), and ALD patients with adrenal insufficiency, as it can be life-threatening in absence of any treatment. Prenatal diagnosis can be performed (after chorionic villus sample at 10-12 weeks of gestation). Allogeneic bone-marrow transplantation, when performed at an early stage of the disease, can stabilize and even reverse cerebral demyelinisation in boys with the cerebral form. Two young patients have received, as part of a gene therapy trial, autologous bone-marrow transplants, genetically corrected ex vivo. The results, so far (6 months and one year postoperative), are promising. Neuroprotective treatments for AMN are currently being studied. Lorenzo's oil (mix of unsaturated long chain fatty acids) could reduce the risk of brain damage, when given before the age of six. *Author: Prof. P. Aubourg (November 2007).


Zellweger-like syndrome with normal peroxisomal function is a rare anomaly characterized by facial dysmorphism, profound hypotonia, intellectual deficit, and metabolic anomalies. It has been described in two sibs born to a consanguineous couple. The facial dysmorphism and clinical course resemble those found in Zellweger syndrome, but no peroxysomal defect is found in these patients. Muscular respiratory chain and dicarboxylic acid deficiencies were reported. Mitochondriopathy of autosomal recessive inheritance is hypothesised. Prognosis is very poor. *Author: Orphanet (February 2005).


Zellweger syndrome is a rare peroxisomal metabolic-dysplasia disorder characterized by dysmorphic craniofacial features, profound hypotonia, seizures, and liver and renal dysfunction. It occurs in every 1 in 50,000 to 100,000 births. Infants with Zellweger syndrome present with flattened facies, large anterior fontanel, split sutures, prominent high forehead, flattened occiput, upslanting palpebral fissures, broad nasal bridge, epicanthal folds, and hypoplastic supraorbital ridges. Macrocephaly or microcephaly, high arched palate, protruding tongue or micrognathia and redundant neck skin folds may be present. Cataracts, glaucoma, pigmentary retinopathy, nystagmus and optic nerve atrophy may be seen. Visual changes and loss are progressive. Sensorineural hearing loss may be present. Hepatomegaly, jaundice, pyloric hypertrophy, and severe hydronephrosis are common manifestations. Cryptorchidism and hypospadias (males) and clitoromegaly (females) may occur. Skeletal abnormalities are frequent. The function of the central nervous system is severely affected (profound muscular hypotonia, hyporeflexia or areflexia, severe intellectual deficiency).

A genetic defect in the PEX1 gene (and subsequent alteration the function of the peroxisome organelle and prevent the breakdown of very-long-chain fatty acids, VLCFA) is the most common cause of Zellweger syndrome. Impaired metabolism results in the accumulation of toxic metabolites and damages developing neural cells. The disease is transmitted as an autosomal recessive trait. Zellweger syndrome is often suspected on physical diagnosis and definitively confirmed with biochemical evaluation. Magnetic resonance imaging can be used as an adjunct method (revealing polymicrogyria). Hydronephrosis may have been suspected on prenatal ultrasounds. The main differential diagnoses include neonatal adrenoleukodystrophy and infantile Refsum's disease; other disorders to be excluded are Usher syndrome, and disorders with severe hypotonia. Prenatal screening for VLCFA and plasmalogen synthesis can be performed on cultured amniocytes and chorionic villus sampling in suspected or high-risk pregnancies. A multidisciplinary supportive care for the infants and families should be offered. Most infants with Zellweger syndrome die within the first year of life secondary to progressive apnea or respiratory compromise related to infection or intractable epilepsy. Genetic counseling allows parents to understand the natural history and progression of the disease and to determine the risk for future pregnancies. * Author: Orphanet (January 2008).


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