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  1. Five β- and γ-amino acids occur in free forms in mammalian (including human) tissues and body fluids: β-Alanine and R-β-aminoisobutyric acid (AiB) are pyrimidine catabolites of uracil and thymine, respectively; S-β-AiB is a catabolite of L-valine; β-leucine is a precursor of α-leucine; and γ-aminobutyric acid (GABA) is a derivative of L-glutamate and, to a minor extent, of L-ornithine via putrescine.

  2. β-alanine and GABA also occur as imidazole dipeptides that are products of carnosine synthetase activity. The major dipeptides are carnosine (β-alanyl-L-histidine), anserine (β-alanyl-1-methyl-L-histidine, which is not a constituent of human tissues), and homocarnosine (β-aminobutyryl-L-histidine, which is present only in the brain in humans).

  3. GABA is a major inhibitory neurotransmitter; β-alanine and carnosine also may have neurotransmitter functions. Carnosine (and anserine) may act as an intracellular buffer and antioxidant in skeletal muscle during anaerobic glycolysis.

  4. Several disorders of β-alanine metabolism are known, notably the following:

    i. Dihydropyrimidine dehydrogenase (EC deficiency (autosomal recessive) is a disorder of uracil and thymine catabolism that affects endogenous synthesis of β-alanine and R-β-AiB. One form is an inborn error of metabolism that has onset early in life and features one or more of the following symptoms: convulsions, psychomotor retardation, hypertonicity, microcephaly, autism, and growth retardation. The pharmacogenetic form presents after exposure to the anticancer agent 5-fluorouracil. Clinical manifestations include myelosuppression, gastrointestinal and cutaneous findings, and neurologic toxicity, occasionally with a fatal outcome. Enzyme activity is negligible in the inborn error of metabolism and up to half of normal in the pharmacogenetic form. Circadian fluctuation in enzyme activity may influence enzyme activity determination significantly.

    ii. Dihydropyrimidinuria (dihydropyrimidinase [EC] deficiency) is recognized by urinary excretion of excessive dihydrouracil and dihydrothymine. The clinical course is characterized by neurologic abnormalities, although two asymptomatic patients with dihydropyrimidinuria have been identified. Inheritance is probably autosomal recessive, and liver biopsy is necessary for enzymatic confirmation of the defect. Probands would be expected to manifest toxicity to 5-fluorouracil.

    iii. Nuclear magnetic resonance (NMR) spectroscopy revealed the presence of ureidopropionate (N-carbamyl-β-alanine) and ureidobutyrate (N-carbamyl-β-amino isobutyric acid) in the urine of an 11-month-old girl who presented with developmental delay, dystonia, scoliosis, and microcephaly. A novel enzyme assay using [14C]-N-carbamyl-β-alanine in homogenate of biopsied liver derived from the patient confirmed a β-alanine synthase deficiency. Two frameshift alleles were detected in the relevant gene through the use of genomic DNA derived from the patient.

    iv. Hyper-β-alaninemia (two cases) is associated with impaired neurologic development. Elevated levels of β-alanine and GABA may occur in urine, plasma, and⁄or cerebrospinal fluid (CSF). Complex hyperaminoaciduria (β-alanine, GABA, β-AiB, and taurine) in the index case was explained by combined saturation and inhibition of a β-amino acid-preferring transport system in the nephron. The enzyme defect (β-alanyl-α-ketoglutarate transaminase, EC or; tentatively identified in the second proband) would be expected to have an effect on GABA metabolism secondarily. Pharmacologic doses of pyridoxine (precursor of the transaminase cofactor) ameliorated the metabolic phenotype in the index proband and the clinical phenotype in the second patient.

    v. Another disorder with impaired β-alanine catabolism is characterized by a characteristic urine metabolite pattern that is consistent with combined malonic⁄methylmalonic semialdehyde dehydrogenase deficiency. Impaired oxidation of β-alanine has been demonstrated in skin fibroblasts derived from two of four patients. A single (putative) pathologic allelle has been identified in one patient.

  5. Hyper-β-AiBuria is a benign “metabolic polymorphism” that is present in human populations (5 to 10 percent in Caucasians and 40 to 95 percent in Asian populations). R-β-AiB is the form that is excreted. The enzyme deficiency is hepatic R-β-AiB-pyruvate transaminase (EC that is inherited as an (incompletely) autosomal recessive trait; heterozygotes can have modestly elevated β-AiB excretion, with their enzyme activity intermediate between that of low excretors (homozygous normal) and that of high excretors (homozygous mutant).

  6. There are three disorders of GABA metabolism: GABA transaminase deficiency, a rare disorder, is associated with seizures and profound psychomotor retardation. Distinctive clinical and metabolic phenotypes seem to differentiate the disorder from hyper-β-alaninemia despite the fact that both conditions appear to include impaired GABA and β-alanine homeostasis. Deficiency of the GABA-α-ketoglutarate transaminase (EC has been documented in white cells derived from one patient, with autosomal recessive inheritance. The human cDNA is available, and a single disease-associated allele has been identified.

  7. Deficiency of succinic semialdehyde dehydrogenase (EC, also called 4-hydroxybutyric aciduria, is associated with retardation in mental, motor, and language development and with muscular hypotonia (>150 cases known). Early development may be normal or delayed. The principal metabolic derivative (4-hydroxybutyrate) of the deficient enzyme’s natural substrate accumulates in patients' physiological fluids. Deficient dehydrogenase activity is demonstrated readily in white cells with fluorometric assays. The relevant human gene maps to chromosome 6p22, and inheritance is autosomal recessive.

  8. Two disorders of dipeptide catabolism—serum carnosinase (EC deficiency and “homocarnosinosis”—are apparently one disorder. Although neurologic signs occur in some patients, the majority of patients are healthy. The association of clinical disease with the metabolic disorder is either coincidental or a consequence of unidentified variables in environment and⁄or genotype. Both disorders involve deficient serum carnosinase activity that is more extreme in homocarnosinosis. Serum and cytosolic carnosinases are different enzymes; tissue carnosinase activity is normal in probands. Homocarnosine accumulation in CSF is explained by a deficiency of serum carnosinase activity. The phenotype (serum carnosinase deficiency “homocarnosinosis”) is autosomal recessive. Heterozygotes have partial enzyme deficiency but no metabolic abnormalities. Serum carnosinase activity is normally low in infancy, and this may lead to an erroneous diagnosis of hereditary serum carnosinase deficiency.

  9. Pyridoxine-dependent seizures, which previously were thought to involve GABA synthesis or degradation, have been shown to involve genes that are involved in L-lysine degradation (see OMMBID Supplement 86.1)

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