The introduction of amino acid analysis to clinical diagnostic practice during the 1960s led to the discovery of multiple disorders of amino acid catabolism, transport, and synthesis. Most have been described in detail in the preceding chapters. A few remaining disorders of amino acid modification or salvage are presented in Table 140-1.
Table 140-1Miscellaneous Disease-Causing Genetic Disorders of Amino Acid Metabolism |Favorite Table|Download (.pdf) Table 140-1 Miscellaneous Disease-Causing Genetic Disorders of Amino Acid Metabolism
|Disorder ||Clinical Presentation ||Metabolic Derangement ||Genetics ||Diagnostic Tests |
|Aminoacylase 1 deficiency (OMIM 609924) ||Unspecific neurologic abnormalities (intellectual disability, seizures, hypotonia, motor delay) in many but not all affected individuals ||Increased urinary excretion of N-acetylated amino acids (methionine, glutamic acid, alanine, leucine, glycine, valine, isoleucine) ||AR, ACY1 gene on 3p21.2 ||Urinary organic acids; genetic testing |
|Aminoacylase 2 deficiency (Canavan disease, OMIM 271900) ||Infantile-onset dystonia, blindness, intellectual disability, seizures macrocephaly, early death ||Increased excretion of N-acetyl-aspartate (NAA) in urine ||AR, ASPA gene on 17p13.2 ||Urinary organic acids; high NAA peak in NMR spectroscopy; enzyme analysis; genetic testing |
|Prolidase deficiency (OMIM 170100) ||Variable inflammatory and ulcerative skin lesions, mainly on legs; recurrent airway infections during childhood; intellectual impairment; and mild facial dysmorphism ||Massive excretion of imidodipeptides (with C-terminal proline or hydroxyproline, particularly alanylproline and glycylproline) ||AR, PEPD gene on 19q13.11 ||Special laboratory dipeptide analysis in urine; enzyme analysis; genetic testing |
|Carnosinemia and homocarnosinosis (carnosine dipeptidase 1 deficiency, OMIM 236130) ||Inconsistent association with developmental disorder, spastic diplegia, and neurodegeneration ||Increased plasma and urine concentration of the histidine dipeptides carnosine and anserine; in severe cases, also of homocarnosine ||AR, CNDP1, gene on 18q22.3 ||Amino acids in plasma and urine; carnosinase activity; genetic testing |
|Glycine N-methyltransferase deficiency (OMIM 606664) ||Mild hepatomegaly, transaminasemia ||Isolated accumulation of methionine and SAM ||AR, GNMT gene on 6p21.1 ||Amino acids, homocysteine, and S-adenosylmethionine in plasma |
|Hyperprolinemia type 2 (delta-1-pyrroline-5-carboxylate dehydrogenase deficiency, OMIM 239510) ||Global developmental disorder, seizures ||Defect in catabolism of proline leads to gross accumulation of proline and its precursor pyrroline-5-carboxylate ||AR, ALDH4A1 gene on 1p36.13 ||Amino acids and pyrroline-5-carboxylate in plasma or urine, enzyme assay, genetic testing |
Amino acid analysis was initially targeted to subjects with unexplained symptoms, often neurologic in nature. Due to this ascertainment bias, a few of the newly described disorders were initially believed to cause disease before their benign nature was recognized. The most prominent example is histidinemia, which is relatively common and was included in universal newborn screening programs for many years. Other examples of apparently benign biochemical phenotypes are listed in Table 140-2.
Table 140-2Genetic Disorders of Amino Acid Metabolism With Doubtful Clinical Significance