The kidneys actively reabsorb significant amounts of amino acids. Defects of amino acid transport in the renal tubule include cystinuria and Hartnup disease, which are discussed elsewhere. Amino acid and organic acid metabolism disorders include
In addition, there are a number of other disorders of amino acid and organic acid metabolism, including those involving beta- and gamma-amino acids, the gamma-glutamyl cycle, glycine, histidine, lysine, proline and hydroxyproline, and miscellaneous other amino acid disorders.
Beta-Amino Acid and Gamma-Amino Acid Disorders
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
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Hyper-beta-alaninemia (237400*) |
Beta-alanine-alpha-ketoglutarate aminotransferase |
Biochemical profile: Elevated urinary beta-alanine, taurine, GABA, and beta-aminoisobutyrate Clinical features: Seizures, somnolence, death Treatment: Pyridoxine |
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Methylmalonate/malonate semialdehyde dehydrogenase deficiency with 3-amino and 3-hydroxy aciduria (236795*) |
Methylmalonate/malonate semialdehyde dehydrogenase |
Biochemical profile: Elevated 3-hydroxyisobutyrate 3-aminoisobutyrate, 3-hydroxypropionate beta-alanine, and 2-ethyl-3-hydroxypropionate Clinical features: None to mild Treatment: Not determined |
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Methylmalonic semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia |
Methylmalonic semialdehyde dehydrogenase (see also Branched-chain amino acid metabolism) |
Biochemical profile: Moderately elevated urine methylmalonate Clinical features: Developmental delay, seizures Treatment: No effective treatment |
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Hyper-beta-aminoisobutyric aciduria (210100*) |
D(R)-3-Aminoisobutyrate:pyruvate aminotransferase |
Biochemical profile: Elevated beta-aminoisobutyric acid Clinical features: Benign Treatment: None needed |
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Pyridoxine dependency with seizures (266100*) |
Not determined |
Biochemical profile: Elevated cerebrospinal fluid glutamate Clinical features: Seizure disorder refractory to conventional anticonvulsants, high-pitched cry, hypothermia, jitteriness, dystonia, hepatomegaly, hypotonia, dyspraxia, developmental delay Treatment: Pyridoxine |
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GABA-transaminase deficiency (137150*) |
4-Aminobutyrate-alpha-ketoglutarate aminotransferase |
Biochemical profile: Elevated plasma and cerebrospinal fluid GABA and beta-alanine, elevated carnosine Clinical features: Accelerated linear growth, seizures, cerebellar hypoplasia, psychomotor delay, leukodystrophy, burst suppression electroencephalographic pattern Treatment: No known treatment |
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4-Hydroxybutyric aciduria (271980*) |
Succinic semialdehyde dehydrogenase |
Biochemical profile: Elevated urinary 4-hydroxybutyrate and glycine Clinical features: Psychomotor retardation, speech delay, hypotonia Treatment: Vigabatrin |
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Carnosinemia, homocarnosinosis, or both (236130*, 212200*) |
Carnosinase |
Biochemical profile: In carnosinemia phenotype, carnosinuria despite meat-free diet, elevated urine anserine after ingestion of food containing imidazole dipeptides, normal cerebrospinal fluid In homocarnosinosis phenotype, elevated cerebrospinal fluid homocarnosine, normal serum carnosine Clinical features: Usually benign; reported symptoms probably due to ascertainment bias Treatment: None needed |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. GABA = gamma-aminobutyrate. |
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Gamma-Glutamyl Cycle Disorders
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
|
Gamma-glutamylcysteine synthetase deficiency (230450*) |
Gamma-glutamylcysteine synthetase |
Biochemical profile: Aminoaciduria, glutathione deficiency Clinical features: Hemolysis, spinocerebellar degeneration, peripheral neuropathy, myopathy Treatment: No clear treatment; avoidance of drugs that trigger hemolytic crisis in G6PD deficiency |
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Pyroglutamic aciduria (5-oxoprolinuria; 266130*, 231900*) |
Glutathione synthetase |
Biochemical profile: Elevated urinary, plasma, and cerebrospinal fluid 5-oxoproline; increased gamma-glutamylcysteine; decreased glutathione level Clinical features: Hemolysis, ataxia, seizures, intellectual disability, spasticity, metabolic acidosis In mild form, no evidence of neurologic damage Treatment: Sodium bicarbonate or citrate, vitamins E and C, avoidance of drugs that trigger hemolytic crisis in G6PD deficiency |
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Gamma-glutamyltranspeptidase deficiency (glutathionuria; 231950*) |
Gamma-glutamyltranspeptidase |
Biochemical profile: Elevated plasma and urinary glutathione Clinical features: Intellectual disability Treatment: No specific treatment |
|
5-Oxoprolinase deficiency (260005*) |
5-Oxoprolinase |
Biochemical profile: Elevated urinary 5-oxoproline Clinical features: Probably benign Treatment: None needed |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. G6PD = glucose-6-phosphate dehydrogenase. |
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Glycine Metabolism Disorders
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
|
Nonketotic hyperglycinemia (605899*) |
Glycine cleavage enzyme system |
Biochemical profile: Elevated plasma and cerebrospinal fluid glycine Clinical features: In fetuses, severe hiccups In neonatal form, severe hiccups, hypotonia, seizures, myoclonus, apnea, death In infantile and episodic forms, seizures, intellectual disability, episodic delirium, chorea, vertical gaze palsy In late-onset form, progressive spastic diplegia, optic atrophy, but no cognitive impairment or seizures Treatment: No effective treatment; in some patients, temporary benefit from sodium benzoate and dextromethorphan In some patients with specific mutations, benefit from cofactor therapy with pyridoxine (GLDC mutations) or folinic acid (AMT mutations) |
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P protein |
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H protein |
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T protein |
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L protein |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. |
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Histidine Metabolism Disorders
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
|
Histidinemia (235800*) |
Histidine ammonia-lyase |
Biochemical profile: Elevated plasma histidine Clinical features: Frequently benign; neurologic manifestations in some patients Treatment: Low-protein diet For symptomatic patients only, controlled histidine intake |
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Urocanic aciduria (276880*) |
Urocanase |
Biochemical profile: Elevated urine urocanic acid Clinical features: Possible mild intellectual disability, mild ataxia, nystagmus, and tremor Treatment: None needed |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. |
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Lysine Metabolism Disorders
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
|
Hyperlysinemia (238700*) |
Lysine:alpha-ketoglutarate reductase |
Biochemical profile: Hyperlysinemia Clinical features: Muscle weakness, seizures, mild anemia, intellectual disability, joint and muscular laxity, ectopia lentis; sometimes benign Treatment: Limited lysine intake |
|
2-Ketoadipic acidemia (245130*) |
2-Ketoadipic dehydrogenase |
Biochemical profile: Elevated urine 2-ketoadipate, 2-aminoadipate, and 2-hydroxyadipate Clinical features: Benign Treatment: None needed |
|
Glutaric acidemia type I (231670*) |
Glutaryl CoA dehydrogenase |
Biochemical profile: Elevated urinary glutaric acid and 2-hydroxyglytaric acid Clinical features: Dystonia, dyskinesia, degeneration of the caudate and putamen, frontotemporal atrophy, arachnoid cysts Treatment: Aggressive treatment of intercurrent illness, carnitine Protein, lysine, and tryptophan restriction |
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Saccharopinuria (268700*) |
Alpha-aminoadipic semialdehyde-glutamate reductase |
Biochemical profile: Elevated urine lysine, citrulline, histidine, and saccharopine Clinical features: Intellectual disability, spastic diplegia, short stature, electroencephalographic abnormality Treatment: No clear treatment |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. |
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Proline and Hydroxyproline Metabolism Disorders
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
|
Hyperprolinemia, type I (239500*) |
Proline oxidase (proline dehydrogenase) |
Biochemical profile: Elevated plasma proline and urinary proline, hydroxyproline, and glycine Clinical features: Usually benign; hereditary nephritis, nerve deafness Treatment: None needed |
|
Hyperprolinemia, type II (239510*) |
Delta1-pyrroline-5-carboxylate dehydrogenase |
Biochemical profile: Elevated plasma proline and pyrroline-5-carboxylate (P5C); elevated urinary P5C, delta1-pyrroline-5-carboxylate, proline, hydroxyproline, and glycine Clinical features: During childhood, seizures, intellectual disability During adulthood, benign Treatment: None needed |
|
Delta1-pyrroline-5-carboxylate synthetase deficiency (138250*) |
Delta1-pyrroline-5-carboxylate synthetase |
Biochemical profile: Low plasma proline, citrulline, arginine, and ornithine Clinical features: Hyperammonemia, cataracts, intellectual disability, joint laxity Treatment: Avoidance of fasting |
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Hyperhydroxyprolinemia (237000*) |
4-Hydroxyproline oxidase |
Biochemical profile: Hydroxyprolinemia Clinical features: Disease association not proven Treatment: None needed |
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Prolidase deficiency (170100*) |
Prolidase |
Biochemical profile: Amino acid profile normal in unhydrolyzed urine, but excessive proline and hydroxyproline in acid-hydrolyzed urine Clinical features: Skin ulcers, frequent infections, dysmorphic features, immunodeficiency, intellectual disability, chronic lung disease Treatment: Proline supplement, Mn++ and ascorbic acid, essential amino acids, blood transfusion (packed red blood cells), topical proline and glycine ointment |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. |
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Miscellaneous Amino Acid and Organic Acid Metabolism Disorders
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
|
Sarcosinemia (268900*) |
Sarcosine dehydrogenase |
Biochemical profile: Elevated plasma sarcosine Clinical features: Benign; intellectual disability reported Treatment: None needed |
|
D-glyceric aciduria (220120*) |
D-glycerate kinase |
Biochemical profile: Elevated urinary D-glyceric acid Clinical features: Chronic acidosis, hypotonia, seizures, intellectual disability Treatment: Bicarbonate or citrate for acidosis |
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Hartnup disease (234500*) |
System B(0) neutral amino acid transporter |
Biochemical profile: Neutral aminoaciduria Clinical features: Atrophic glossitis, photodermatitis, intermittent ataxia, hypertonia, seizures, psychosis Treatment: Nicotinamide |
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Cystinuria (220100*) |
Renal dibasic amino acid transporter |
Biochemical profile: Elevated urinary cystine, lysine, arginine, and ornithine Clinical features: Nephrolithiasis, increased risk of impaired cerebral function Treatment: Maintenance of fluid intake, bicarbonate or citrate, penicillamine or mercaptopropionylglycine |
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Type I |
Heavy subunit |
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Types II and III |
Light subunit |
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Iminoglycinuria (242600*) |
Renal transporter of proline, hydroxyproline, and glycine |
Biochemical profile: Elevated urinary proline, hydroxyproline, and glycine but normal plasma levels Clinical features: Probably benign Treatment: None needed |
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Guanidinoacetate methyltransferase deficiency (601240*) |
Guanidinoacetate methyltransferase |
Biochemical profile: Elevated guanidinoacetate, decreased creatine and phosphocreatine Clinical features: Developmental delay, hypotonia, extrapyramidal movements, seizures, autistic behavior Treatment: Creatine supplementation |
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Cystinosis |
See table Lysosomal Transport Defects |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. |
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