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* The authors have drawn substantively from the earlier version of this chapter (MMBID 7th Edition, Vol 1, Wilms Tumor, pp. 1349–1368) and gratefully acknowledge the significant contribution of the preceding primary author, Dr. Charles R. Scriver.

  • 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.

  • 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).

  • 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.

  • 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 ...

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