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Overview of Amino Acid and Organic Acid Metabolism Disorders

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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Topic Resources

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.

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Beta-Amino Acid and Gamma-Amino Acid Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Comments

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

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

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

Hyper-beta-aminoisobutyric aciduria (210100*)

D(R)-3-Aminoisobutyrate:pyruvate aminotransferase

Biochemical profile: Elevated beta-aminoisobutyric acid

Clinical features: Benign

Treatment: None needed

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

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

4-Hydroxybutyric aciduria (271980*)

Succinic semialdehyde dehydrogenase

Biochemical profile: Elevated urinary 4-hydroxybutyrate and glycine

Clinical features: Psychomotor retardation, speech delay, hypotonia

Treatment: Vigabatrin

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

* 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

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

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

* 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)

P protein

H protein

T protein

L protein

* 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

Urocanic aciduria (276880*)

Urocanase

Biochemical profile: Elevated urine urocanic acid

Clinical features: Possible mild intellectual disability, mild ataxia, nystagmus, and tremor

Treatment: None needed

* 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

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

* 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

Hyperhydroxyprolinemia (237000*)

4-Hydroxyproline oxidase

Biochemical profile: Hydroxyprolinemia

Clinical features: Disease association not proven

Treatment: None needed

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

* 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

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

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

Type I

Heavy subunit

Types II and III

Light subunit

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

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

Cystinosis

* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database.

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