Homocystinuria, an autosomal recessive disease (1:200,000 livebirths) involving connective tissue, the brain, and the vascularsystem, is caused by a deficiency of cystathionine β-synthase. In the normal metabolism of the sulfur amino acids, methionine gives rise to cystine; homocysteine is a pivotal intermediate (Fig. 53-2). When cystathionine β-synthase is deficient, homocysteine accumulates in the blood and appears in the urine. Another result is enhanced reconversion of homocysteine to methionine, resulting in an increase in the concentration of methionine in the blood. The neonatal screening test most commonly used measures methionine. An excess of homocysteine produces a slowly evolving clinical syndromethat includes dislocated ocular lenses; long, slender extremities; malar flushing; and livedo reticularis. Arachnodactyly, scoliosis, pectus excavatum or carinatum, and genu valgum are skeletal features. Mental retardation, psychiatric illness, or both may be present. Major arterial or venous thromboses are a constant threat.
Confirmation of the diagnosis requires demonstration of elevated total homocysteine in the blood. A plasma amino acid profile reveals hypermethioninemia. Measurement of cystathionine β-synthase is not clinically available, but numerous mutations in the gene are known and can be tested.
There are two clinical forms of homocystinuria. In one form, activity of the deficient enzyme can be enhanced by the administration of large doses of pyridoxine (100 to 1000 mg/day). Folate supplementation is added to overcome folate deficiency if folate is trapped in the process of remethylation of homocysteine to methionine. This pyridoxine-responsive form comprises about 50% of cases and is the more likely form to be missed by neonatal screening because the methionine concentrations are not always above the screening cutoff. The second form is not responsive to pyridoxine therapy. The accumulation of homocysteine is controlled with a methionine-restricted diet and cystine and folate supplementation. The use of supplemental betaine (trimethylglycine), a donor of methyl groups for remethylation of homocysteine to methionine, also has a role in the management of pyridoxine-unresponsive patients. Diet and betaine are sometimes required to control plasma homocysteine, even in pyridoxine-responsive patients. The prognosis is good for infants whose plasma homocysteine concentration is controlled.
Figure 53-2 Metabolism of methionine and homocysteine. (1) Methionine adenosyltransferase, (2) S-methyltransferase, (3) S-adenosylhomocysteine hydrolase, (4) cystathionine β-synthase, (5) cystathionase, (6) homocysteine methyltransferase, (7) betaine-homocysteine methyltransferase.
Maple syrup urine disease (MSUD) is an autosomal recessivedisease, also called branched chain ketoaciduria. A deficiencyof the decarboxylase initiates the degradation of the ketoacid analogs of the three branched chain amino acids—leucine, isoleucine, and valine (Fig. 53-3). Classic MSUD is rare(1:250,000) in the general population but much more commonin some population isolates (Pennsylvania Mennonites 1:150).The American College of Medical Genetics neonatal screeningpanel includes MSUD.