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Overview of Amino Acid and Organic Acid Metabolism Disorders

By Lee M. Sanders, MD, MPH

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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

Defective Gene or Genes (Chromosomal Location)

Comments

Hyper-β-alaninemia (237400)

β-Alanine-α-ketoglutarate aminotransferase

Not determined

Biochemical profile: Elevated urinary β-alanine, taurine, γ-aminobutyrate (GABA), and β-aminoisobutyrate

Clinical features: Seizures, somnolence, death

Treatment: Pyridoxine

Methylmalonate/malonate semialdehyde dehydrogenase deficiency with 3-amino and 3-hydroxy aciduria (236795)

Methylmalonate/malonate semialdehyde dehydrogenase

ALDH6A1 (14q24.3)*

Biochemical profile: Elevated 3-hydroxyisobutyrate 3-aminoisobutyrate, 3-hydroxypropionate β-alanine, and 2-ethyl-3-hydroxypropionate

Clinical features: None to mild

Treatment: Not determined

Methylmalonic semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia

Methylmalonic semialdehyde dehydrogenase (see also Branched-chain amino acid metabolism, above)

ALDH6A1 (14q24.1)

Biochemical profile: Moderately elevated urine methylmalonate

Clinical features: Developmental delay, seizures

Treatment: No effective treatment

Hyper-β-aminoisobutyric aciduria (210100)

D(R)-3-Aminoisobutyrate:pyruvate aminotransferase

Not determined

Biochemical profile: Elevated β-aminoisobutyric acid

Clinical features: Benign

Treatment: None needed

Pyridoxine dependency with seizures (266100)

Not determined

Specific gene not determined (5q31.2-q31.3)

Biochemical profile: Elevated CSF glutamate

Clinical features: Seizure disorder refractory to conventional anticonvulsants, high-pitched cry, hypothermia, jitteriness, dystonia, hepatomegaly, hypotonia, dyspraxia, developmental delay

Treatment: Pyridoxine

GABA-transaminase deficiency (137150)

4-Aminobutyrate-α-ketoglutarate aminotransferase

ABAT (16p13.3)*

Biochemical profile: Elevated plasma and CSF GABA and β-alanine, elevated carnosine

Clinical features: Accelerated linear growth, seizures, cerebellar hypoplasia, psychomotor delay, leukodystrophy, burst suppression EEG pattern

Treatment: No known treatment

4-Hydroxybutyric aciduria (271980)

Succinic semialdehyde dehydrogenase

ALDH5A1 (6p22)*

Biochemical profile: Elevated urinary 4-hydroxybutyrate and glycine

Clinical features: Psychomotor retardation, speech delay, hypotonia

Treatment: Vigabatrin

Carnosinemia, homocarnosinosis, or both (236130, 212200)

Carnosinase

Specific gene not determined (18q21.3)

Biochemical profile: In carnosinemia phenotype, carnosinuria despite meat-free diet, elevated urine anserine after ingestion of food containing imidazole dipeptides, normal CSF

In homocarnosinosis phenotype, elevated CSF homocarnosine, normal serum carnosine

Clinical features: Usually benign; reported symptoms probably due to ascertainment bias

Treatment: None needed

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

Gamma-Glutamyl Cycle Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

γ-Glutamylcysteine synthetase deficiency (230450)

γ-Glutamylcysteine synthetase

GGLC (6p12)*

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

Pyroglutamic aciduria (5-oxoprolinuria; 266130, 231900)

Glutathione synthetase

GSS (20q11.2)*

Biochemical profile: Elevated urinary, plasma, and CSF 5-oxoproline; increased γ-glutamylcysteine; decreased glutathione level

Clinical features: Hemolysis, ataxia, seizures, intellectual disability, spasticity, metabolic acidosis

In mild form, no evidence of neurologic damage

Treatment: Na bicarbonate or citrate, vitamins E and C, avoidance of drugs that trigger hemolytic crisis in G6PD deficiency

γ-Glutamyltranspeptidase deficiency (glutathionuria; 231950)

γ-Glutamyltranspeptidase

Specific gene not determined (22q11.1-q11.2)

Biochemical profile: Elevated plasma and urinary glutathione

Clinical features: Intellectual disability

Treatment: No specific treatment

5-Oxoprolinase deficiency (260005)

5-Oxoprolinase

Not determined

Biochemical profile: Elevated urinary 5-oxoproline

Clinical features: Probably benign

Treatment: None needed

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

Glycine Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

Nonketotic hyperglycinemia (605899)

Glycine cleavage enzyme system

Biochemical profile: Elevated plasma and CSF glycine

Clinical features: In neonatal form, 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 Na benzoate and dextromethorphan

P protein

GLDC (9p22)*

H protein

GCSH (16q23)*

T protein

ATM (3p21)*

L protein

Not determined

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

Histidine Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

Histidinemia (235800)

Classic: l-Histidine ammonia-lyase (liver and skin)

Variant: l-Histidine ammonia-lyase (liver only)

HAL (12q22-q23)*

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

Urocanic aciduria (276880)

Urocanase

Not determined

Biochemical profile: Elevated urine urocanic acid

Clinical features: Probably benign

Treatment: None needed

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

Lysine Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

Hyperlysinemia (238700)

Lysine:α-ketoglutarate reductase

AASS (7q31.3)*

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

Not determined

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

(19q13.2)*

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 possibly helpful

Saccharopinuria (268700)

α-Aminoadipic semialdehyde-glutamate reductase

AASS (7q31.3)*

Biochemical profile: Elevated urine lysine, citrulline, histidine, and saccharopine

Clinical features: Intellectual disability, spastic diplegia, short stature, EEG abnormality

Treatment: No clear treatment

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

Proline and Hydroxyproline Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

Hyperprolinemia, type I (239500)

Proline oxidase (proline dehydrogenase)

PRODH (22q11.2)*

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)

Δ1-Pyrroline-5-carboxylate dehydrogenase

P5CDH (1p36)*

Biochemical profile: Elevated plasma proline and pyrroline-5-carboxylate (P5C); elevated urinary P5C, Δ1-pyrroline-5-carboxylate, proline, hydroxyproline, and glycine

Clinical features: During childhood, seizures, intellectual disability

During adulthood, benign

Treatment: None needed

Δ1-Pyrroline-5-carboxylate synthetase deficiency (138250)

Δ1-Pyrroline-5-carboxylate synthetase

PYCS (10q24.3)*

Biochemical profile: Low plasma proline, citrulline, arginine, and ornithine

Clinical features: Hyperammonemia, cataracts, intellectual disability, joint laxity

Treatment: Avoidance of fasting

Hyperhydroxyprolinemia (237000)

4-Hydroxyproline oxidase

Not determined

Biochemical profile: Hydroxyprolinemia

Clinical features: Disease association not proven

Treatment: None needed

Prolidase deficiency (170100)

Prolidase

PEPD (19q12-q13.11)*

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

Treatment: Proline supplement, Mn++ and ascorbic acid, essential amino acids, blood transfusion (packed RBC), topical proline and glycine ointment

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

Miscellaneous Amino Acid and Organic Acid Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

Sarcosinemia (268900)

Sarcosine dehydrogenase

Specific gene not determined (9q34)

Biochemical profile: Elevated plasma sarcosine

Clinical features: Benign; intellectual disability reported

Treatment: None needed

D-glyceric aciduria (220120)

D-glycerate kinase

Not determined

Biochemical profile: Elevated urinary D-glyceric acid

Clinical features: Chronic acidosis, hypotonia, seizures, intellectual disability

Treatment: Bicarbonate or citrate for acidosis

Hartnup disease (234500)

System B(0) neutral amino acid transporter

SLC6A19 (5p15)*

Biochemical profile: Neutral aminoaciduria

Clinical features: Atrophic glossitis, photodermatitis, intermittent ataxia, hypertonia, seizures, psychosis

Treatment: Nicotinamide

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

Type I (220100)

Heavy subunit

SLC3A1 (2p16.3)*

Types II and III (600918)

Light subunit

SLC7A9 (19q13.1)*

Iminoglycinuria (242600)

Renal transporter of proline, hydroxyproline, and glycine

Not determined

Biochemical profile: Elevated urinary proline, hydroxyproline, and glycine but normal plasma levels

Clinical features: Probably benign

Treatment: None needed

Guanidinoacetate methyltransferase deficiency (601240)

Guanidinoacetate methyltransferase

GAMT (19p13.3)*

Biochemical profile: Elevated guanidinoacetate, decreased creatine and phosphocreatine

Clinical features: Developmental delay, hypotonia, extrapyramidal movements, seizures, autistic behavior

Treatment: Creatine supplementation

Cystinosis

*Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database at http://www.ncbi.nlm.nih.gov/omim).

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Drugs Mentioned In This Article

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  • SABRIL
  • CUPRIMINE
  • R-GENE 10
  • DELSYM

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