Metabolic Defects

The tests performed at PLIEM Laboratory can be utilized to test for over 700 metabolic disorders. The following list includes metabolic disorders which have been observed in the South African population groups. It however does not include all metabolic disorders which are still tested for by tests performed at PLIEM Laboratory:

Isovaleric acidemia is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. It can present with severe neonatal ketoacidosis leading to death, but in milder cases recurrent episodes of ketoacidosis of varying degree occur later in infancy and childhood. 

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The features of propionic acidemia are episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. Outstanding chemical features are hyperglycinemia and hyperglycinuria. This disorder is not to be confused with hereditary glycinuria (138500), which is presumably transmitted as a dominant.

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Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life.

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(Various subtypes which include enzymatic (in link below) and cofactor deficiencies)

Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. This form is unresponsive to B12 therapy. Various forms of isolated methylmalonic aciduria also occur in a subset of patients with defects in the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl) and are classified according to complementation group.

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In addition to genetic defects of the tricarboxylic acid cycle, other mechanisms for recessively inherited congenital lactic acidosis include inborn errors of pyruvate metabolism and inborn errors of oxidative phosphorylation

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Mevalonic aciduria, the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase 

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PC deficiency may be categorized into 3 phenotypic subgroups. Patients from North America (‘group A’) have lactic acidemia and psychomotor retardation, whereas those from France and the United Kingdom (‘group B’) have a more complex biochemical phenotype with increased serum lactate, ammonia, citrulline, and lysine, as well as an intracellular redox disturbance in which the cytosolic compartment is more reduced and the mitochondrial compartment is more oxidized. 

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Brown et al. (2004) reported 2 unrelated patients with pyruvate dehydrogenase deficiency. The first patient, the son of first-cousin parents, was investigated at age 3 months because of lactic acidosis and hypotonia. Two previous sibs had died early, one with lactic acidosis. 

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Multiple carboxylase deficiency (MCD) is an autosomal recessive metabolic disorder characterized primarily by cutaneous and neurologic abnormalities. Symptoms result from the patient’s inability to reutilize biotin, a necessary nutrient.

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(various subtypes within this disease group have been described example: 3-methylglutaconyl-CoA hydratase deficiency OR Barth syndrome or MEGDEL syndrome)

3-METHYLGLUTACONIC ACIDURIA, TYPE I; MGCA1

BARTH SYNDROME; BTHS

3-METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME; MEGDEL

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting

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Primary hyperoxaluria type I is an autosomal recessive disorder characterized by an accumulation of calcium oxalate in various bodily tissues, especially the kidney, resulting in renal failure. Affected individuals have decreased or absent AGXT activity and a failure to transaminate glyoxylate, which causes the accumulated glyoxylate to be oxidized to oxalate. This overproduction of oxalate results in the accumulation of nonsoluble calcium oxalate in various body tissues, with pathologic sequelae 

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Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (GA1; 231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case 

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Alkaptonuria is an autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of the cardiac valves .

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Glutathione synthetase deficiency, or 5-oxoprolinuria, is an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The metabolic defect results in decreased levels of cellular glutathione, which overstimulates the synthesis of gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline

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Alpha-methylacetoacetic aciduria, also known as 3-ketothiolase deficiency, is an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone.

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SCAD deficiency is an autosomal recessive metabolic disorder of fatty acid beta-oxidation. Clinical features are variable: a severe form of the disorder can cause infantile onset of acidosis and neurologic impairment, whereas some patients develop only myopathy. With the advent of screening for inborn errors of metabolism, patients with putative pathogenic mutations but who remain asymptomatic have also been identified

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Inherited deficiency of medium-chain acyl-CoA dehydrogenase is characterized by intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma with medium-chain dicarboxylic aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels. The disorder may be severe, and even fatal, in young patients

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Inborn errors of mitochondrial fatty acid beta-oxidation include medium-chain acyl-CoA dehydrogenase deficiency (201450), short-chain acyl-CoA dehydrogenase deficiency (201470), and very long-chain acyl-CoA dehydrogenase deficiency.

VLCAD deficiency can be classified clinically into 3 forms: a severe early-onset form with high incidence of cardiomyopathy and high mortality; an intermediate form with childhood onset, usually with hypoketotic hypoglycemia and more favorable outcome; and an adult-onset, myopathic form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria after exercise or fasting

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Primary systemic carnitine deficiency is due to a defect in the high-affinity carnitine transporter expressed in muscle, heart, kidney, lymphoblasts, and fibroblasts. This results in impaired fatty acid oxidation in skeletal and heart muscle. In addition, renal wasting of carnitine results in low serum levels and diminished hepatic uptake of carnitine by passive diffusion, which impairs ketogenesis 

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CPT I deficiency is an autosomal recessive metabolic disorder of long-chain fatty acid oxidation characterized by severe episodes of hypoketotic hypoglycemia usually occurring after fasting or illness. Onset is in infancy or early childhood

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Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. The infantile form usually presents between 6 and 24 months of age with recurrent attacks of hypoketotic hypoglycemia causing loss of consciousness and seizures, liver failure, and transient hepatomegaly. Some children also have heart involvement with cardiomyopathy and arrhythmia. Episodes are triggered by infections, fever, or fasting. Laboratory studies usually indicate hyperammonemia, metabolic acidosis, and hypoketotic hypoglycemia with elevated levels of creatine kinase 

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The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death

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The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death

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Hereditary tyrosinemia type I is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The disorder is characterized by progressive liver disease and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. Onset varies from infancy to adolescence. In the most acute form patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinemia. Untreated, patients die from cirrhosis or hepatocellular carcinoma at a young age

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The major clinical features of maple syrup urine disease are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation.

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Gyrate atrophy of the choroid and retina due to deficiency of ornithine aminotransferase is clinically characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. Characteristic chorioretinal atrophy with progressive constriction of the visual fields leads to blindness at the latest during the sixth decade of life. Patients generally have normal intelligence

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Ornithine transcarbamylase deficiency is an X-linked inborn error of metabolism of the urea cycle which causes hyperammonemia. The disorder is treatable with supplemental dietary arginine and low protein diet.

Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis.

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Severe vomiting spells beginning at the age of 9 months and mental retardation were features of the first reported case, offspring of first-cousin parents; McMurray et al. (1962) found citrulline in very high concentration in serum, spinal fluid, and urine. (The amino acid citrulline gets its name from its high concentration in the watermelon Citrullus vulgaris.) Visakorpi (1962) also described a case of citrullinuria. Ammonia intoxication is another manifestation.

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Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle. Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis.

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Most patients with GCE have the neonatal phenotype, presenting in the first few days of life with lethargy, hypotonia, and myoclonic jerks, and progressing to apnea, and often to death. Those who regain spontaneous respiration develop intractable seizures and profound mental retardation. In the infantile form of GCE, patients present with seizures and have various degrees of mental retardation after a symptom-free interval and seemingly normal development for up to 6 months. In the mild-episodic form, patients present in childhood with mild mental retardation and episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, patients present in childhood with progressive spastic diplegia and optic atrophy, but intellectual function is preserved and seizures have not been reported

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Classic homocystinuria is an autosomal recessive metabolic disorder of sulfur metabolism. The clinical features of untreated homocystinuria due to CBS deficiency usually manifest in the first or second decade of life and include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome 

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Cystinuria is an autosomal disorder characterized by impaired epithelial cell transport of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the proximal renal tubule and gastrointestinal tract. The impaired renal reabsorption of cystine and its low solubility causes the formation of calculi in the urinary tract, resulting in obstructive uropathy, pyelonephritis, and, rarely, renal failure 

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First described by Baron et al. (1956), this disorder is characterized by a pellagra-like light-sensitive rash, cerebellar ataxia, emotional instability, and amino aciduria. Scriver et al. (1985) suggested the existence of 2 forms of Hartnup disease: in the classic form the defect is expressed in both intestine and kidney; in a variant form it is expressed only in kidney. In the United States, cases of the full-blown clinical disorder are not seen, probably because of super-adequate diet.

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Adrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.

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Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells. However, not all patients show all these features. All patients have accumulation of an unusual branched-chain fatty acid, phytanic acid, in blood and tissues. Other variable features include cardiac dysfunction, nerve deafness, ichthyosis, and multiple epiphyseal dysplasia

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Congenital disorders of glycosylation, previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are caused by defects in mannose addition during N-linked oligosaccharide assembly. CDGs can be divided into 2 types, depending on whether they impair lipid-linked oligosaccharide (LLO) assembly and transfer (CDG I), or affect trimming of the protein-bound oligosaccharide or the addition of sugars to it (CDG II)

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Matthijs et al. (1997) identified phosphomannomutase-1 (PMM1; 601786) by database searching for human cDNAs with similarity to Candida or yeast phosphomannomutase. Biochemical studies of PMM1 and phosphomannomutases from rat and human liver provided evidence for the existence in mammals of a second phosphomannomutase with different kinetic and antigenic properties.

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The mucopolysaccharidoses are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function.

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Mucopolysaccharidosis II is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme iduronate sulfatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues, and organs. Patients with MPS II excrete excessive amounts of chondroitin sulfate B (dermatan sulfate) and heparitin sulfate (heparan sulfate) in the urine

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aucher disease is an autosomal recessive lysosomal storage disorder due to deficient activity of beta-glucocerebrosidase. As a result of this deficiency, there is intracellular accumulation of glucosylceramide (GlcCer, glucosylcerebroside) primarily within cells of mononuclear phagocyte origin, which are the characteristic ‘Gaucher cells’ identified in most tissues

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Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body

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Glycogen storage disease II, an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form (Pompe disease), cardiomyopathy and muscular hypotonia are the cardinal features; in the juvenile and adult forms, involvement of skeletal muscles dominates the clinical picture 

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Krabbe disease is an autosomal recessive lysosomal disorder affecting the white matter of the central and peripheral nervous systems. Most patients present within the first 6 months of life with ‘infantile’ or ‘classic’ disease manifest as extreme irritability, spasticity, and developmental delay (Wenger et al., 2000). There is severe motor and mental deterioration, leading to decerebration and death by age 2 years. 

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Classic galactosemia is an autosomal recessive disorder of galactose metabolism. Most patients present in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycemia, renal tubular dysfunction, muscle hypotonia, sepsis, and cataract. Long-term complications include mental retardation, verbal dyspraxia, motor abnormalities, and hypergonadotropic hypogonadism 

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Fructose intolerance becomes apparent in infancy at the time of weaning, when fructose or sucrose is added to the diet. Clinical features include recurrent vomiting, abdominal pain, and hypoglycemia that may be fatal. Long-term exposure to fructose can result in liver failure, renal tubulopathy, and growth retardation. Older patients who survive infancy develop a natural avoidance of sweets and fruits. Ali et al. (1998) provided a detailed review of the biochemical, genetic, and molecular basis of aldolase B deficiency in hereditary fructose intolerance. 

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Trimethylaminuria results from the abnormal presence of large amounts of volatile and malodorous trimethylamine within the body. This chemical, a tertiary aliphatic amine, is excreted in the urine, sweat (ichthyohidrosis), and breath, which take on the offensive odor of decaying fish

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