Chapter 144. Other Disorders of Amino Acid Metabolism

Jean-Marie Saudubray

Other Disorders of Amino Acid Metabolism: Introduction

Imidazole-Dipeptide Metabolism Defects: Carnosine and Homocarnosinemia

The enzyme defects, clinical manifestations, metabolic disturbances, and treatment of these disorders are presented in Table 144-1.

Table 144-1. Miscellaneous Amino Acid Disorders

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Table 144-1. Miscellaneous Amino Acid Disorders

Disorder

Enzyme Defect

Clinical Presentation

Metabolic Derangement and Diagnostic Tests

Treatment

Carnosinemia1,2

Serum carnosinase

Mental retardation, seizures, or asymptomatic (no disease)

Plasma and urines AAC: high carnosine and anserine on meat-containing diet

None

No 1-methylhistidine excretion

Low carnosinase activity in serum

Homocarnosinosis3

Serum carnosinase

Spastic diplegia, mental retardation, or asymptomatic (no disease) similar to carnosinemia

Homocarnosine 30 to 50 times normal in CSF

None

Low carnosinase activity in serum

Prolidase deficiency4

Peptidase D (exopeptidase prolidase)

Skin lesions, recalcitrant ulcerations on of the lower legs from infancy to late adolescence.

Massive excretion of imidodipeptide (dipeptides containing N-terminal proline or hydroxyproline, particularly glycylproline) detected by partition and elution chromatography and by direct chemical-ionization mass spectrometry

Oral ascorbate

Characteristic facies

Enzyme analysis in hemolysates, leucocytes, or fibroblasts

Manganese (cofactor of the enzyme): questionable efficiency

Recurrent infections

DNA testing

Risk factor for the development of systemic lupus erythematosus

Histidinemia5

Histidine ammonia-lyase

Probably normal variant

Hyperhistidinemia and histidinuria at AAC

None

Urocanase deficiency6

Urocanase

Progressive psychomotor retardation seizures

High urocanic excretion

None

Enzyme analysis

Acetyl aminoaciduria7

Aminoacylase I

Still undefined; probably normal variant

N-acetyl amino acid excretion at AAC

None

Enzyme analysis

DNA testing

N-Acetylaspartic aciduria8

Aspartoacylase (aminoacylase II)

Canavan disease

Acetyl aspartic aciduria at organic acid analysis by GCMS

None

Enzyme analysis in fibroblasts

DNA testing

Trimethylaminuria (TMA) AR9,10

Flavin-containing monooxygenase 3 (FMO3)

Episodic offensive body odor, after sweating or after egg or fish ingestion (fish odor syndrome)

High excretion of trimethylamine (TMA) with elevation of TMA/TMA-N-oxide measured by NMR spectroscopy on urines after a dietary load in TMA

Counseling and adjustments to diet and lifestyle

DNA testing

Low choline diet

2-week courses of metronidazole

Dimethylglycinuria11,12

Dimethylglycine dehydrogenase

Unpleasant fish odor of the body and urines

Massive dimethylglycine accumulation in plasma and urines measured by NMR spectroscopy

Restriction of dietary choline

DNA testing

AAC, amino acid chromatography; AR, autosomal recessive.

Imidazole dipeptides derive their name from the imidazole ring of histidine. Carnosine (beta alanine histidine) is found in skeletal muscles and the brain, where it may be a neurotransmitter. It is hydrolyzed by two isozymes. Cytosolic carnosinase displays a very broad dipeptidase activity but does not hydrolyze anserine or homocarnosine. Serum carnosinase, also found in the cerebrospinal fluid, hydrolyzes carnosine and anserine but hydrolyzes homocarnosine very poorly. Anserine (beta alanine-1-methylhistidine) is normally absent from human tissues and body fluids but may be derived from the diet and is found in patients with serum carnosinase deficiency. Homocarnosine (gamma aminobutyryl histidine) is a brain dipeptide. It is hydrolyzed by serum but not by cytosolic carnosinase. The physiological function of homocarnosine is unknown. It may act as a reservoir of GABA in some parts of the brain. The relationship between symptoms observed in serum carnosine–deficient patients and biochemical findings is uncertain.

Prolidase Deficiency

The hallmark biochemical finding of this disorder is massive hyperexcretion of a large number of imidodipeptides (dipeptides with an N-terminal proline or hydroxyproline particularly glycylproline) due to a deficiency of the exopeptidase prolidase (or peptidase D).

Histidine Ammonia-Lyase Deficiency

Histidinemia due to histidine ammonia-lyase deficiency has been recognized for some time, since amino acid chromatography programs were performed in persons with mental retardation. It is now recognized as a probable normal variant.

Acetylated Aminoacidurias: Aminoacylase I and II Deficiency

Aminoacylase I deficiency is responsible for a massive excretion of neutral acetyl amino acids, detected by amino acid chromatography of urine. The pathological significance of this finding is still unknown. Aminoacylase II (aspartoacylase II) deficiency is responsible for Canavan disease, a severe early infantile leukodystrophy that is biochemically characterized by a massive accumulation of acetyl aspartate in brain and body fluids, where it is detectable by gas chromatography-mass spectrometry analysis of the urines and by brain NMR spectroscopy.

Trimethylaminuria and Dimethylglycinuria

These two disorders cause the fish odor syndrome characterized by intermittent or constant excretion of volatile compounds that have an unpleasant fishy odor.1-12

References

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1. Perry TL, Hansen S, Tischler B, Bunting R, Berry K. Carnosinemia. A new metabolic disorder associated with neurologic disease and mental defect. N Engl J Med. 1967;277(23):1219-1227.

2. Cohen M, Hartlage PL, Krawiecki N, Roesel RA, Carter AL, Hommes FA. Serum carnosinase deficiency: a non-disabling phenotype? J Ment Defic Res. 1985;29(Pt 4):383-389.

3. Lenney JF, Peppers SC, Kucera CM, Sjaastad O. Homocarnosinosis: lack of serum carnosinase is the defect probably responsible for elevated brain and CSF homocarnosine. Clin Chim Acta. 1983;132(2):157-165.

4. Ledoux P, Scriver CR, Hechtman P. Expression and molecular analysis of mutations in prolidase deficiency. Am J Hum Genet. 1996;59(5): 1035-1039.

5. Lam WK, Cleary MA, Wraith JE, Walter JH. Histidinaemia: a benign metabolic disorder. Arch Dis Child. 1996;74(4):343-346.

6. Kalafatic Z, Lipovac K, Jezerinac Z, Juretic D, Dumic M, Zurga B, et al. A liver urocanase deficiency. Metabolism. 1980;29(11):1013-1019.

7. Sass JO, Mohr V, Olbrich H, Engelke U, Horvath J, Fliegauf M, et al. Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism. Am J Hum Genet. 2006;78(3):401-409.

8. Matalon R, Michals K, Kaul R. Canavan disease: from spongy degeneration to molecular analysis. J Pediatr. 1995;127(4):511-517.

9. Lee CW, Yu JS, Turner BB, Murray KE. Trimethylaminuria: fishy odors in children. N Engl J Med. 1976;295(17):937-938.

10. Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. 1998;7(5):839-845.

11. Moolenaar SH, Poggi-Bach J, Engelke UF, Corstiaensen JM, Heerschap A, de Jong JG, et al. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study. Clin Chem. 1999;45(4):459-464.

12. Binzak BA, Wevers RA, Moolenaar SH, Lee YM, Hwu WL, Poggi-Bach J, et al. Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency. Am J Hum Genet. 2001;68(4):839-847.

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Chapter 144. Other Disorders of Amino Acid Metabolism

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Other Disorders of Amino Acid Metabolism: Introduction

Imidazole-Dipeptide Metabolism Defects: Carnosine and Homocarnosinemia

Prolidase Deficiency

Histidine Ammonia-Lyase Deficiency

Acetylated Aminoacidurias: Aminoacylase I and II Deficiency

Trimethylaminuria and Dimethylglycinuria

References

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