Introduction
Homocystinuria is an inborn error of metabolism in which the enzyme cystathionine -synthase is deficient.1,2 As in the majority of enzyme deficiencies, homocystinuria is an autosomal recessive disorder because even half of the normal amount of enzyme can prevent the phenotype from developing. Cystathionine -synthase is responsible for the conversion of the amino acid methionine to cysteine. Homocysteine functions as an intermediary metabolite in the process and accumulates in the urine and blood when cystathionine -synthase is deficient. Other less common enzyme defects may also produce excessive amounts of homocysteine that result in homocystinuria. Accumulation of this intermediary results in a syndrome that has some resemblance to Marfan syndrome but also shows some major differences as well. Homocystinuria is a rare disorder with an incidence of approximately 1 in 300,000 births, whereas Marfan syndrome affects approximately 1 in 15,000.
Clinical Features
There are 2 major hypotheses to explain the development of the clinical features based on the known metabolic disturbance.1,2
- The reduced sulfhydryl groups of homocysteine or other substances that accumulate proximal to the block interfere with collagen cross-linking, thus accounting for the connective tissue manifestations.
- Alternatively, cysteine is 1 of 3 amino acids that form glutathione. Glutathione is a free radical scavenger, and a deficiency of it may result in systemic tissue damage from circulating free radicals.
Most of the clinical manifestations are related to the elevated homocysteine levels. Patients affected with homocystinuria appear normal at birth, but as the homocysteine accumulates, the clinical features gradually develop during early childhood. Phenotypically, patients with homocystinuria develop a similar appearance to patients with Marfan syndrome:
- Tall with long limbs
- Arachnodactyly
- Scoliosis (Slide 1)
- Chest deformities
- Lens dislocations
In addition, homocystinuria causes generalized osteoporosis, "tight joints," and malar flush. Elevated homocysteine can disrupt the vascular endothelium (Slide 2), and a thrombus may form at any age. Approximately one half of patients will have a major thromboembolic complication by age 28. Psychiatric disturbance and mental retardation are common in homocystinuria, with a mean intelligence quotient of 64. Patients with homocystinuria do not develop aortic aneurysms and mitral valve prolapse as often seen in patients with Marfan syndrome.
Cyanide nitroprusside is diagnostic of homocystinuria because it is used to detect homocysteine in the urine.
Radiographic Features
The most striking feature of homocystinuria is generalized osteoporosis. This is particularly apparent in the spine with biconcavity and flattening of vertebral bodies. Spine radiographs may also demonstrate scoliosis.
Treatment
The goal of treatment is early decrease of circulating homocysteine levels, preventing the development of mental retardation, and preventing ectopic lenses from forming. Most states include testing for homocystinuria as part of the routine newborn screening program.1
Over one half of patients with homocystinuria positively respond to large doses of pyridoxine (Vitamin B6) and methionine-restricted diets. These patients show clearing of homocysteine from the urine, lowering of plasma methionine and cysteine, and raising of cysteine to normal levels. A positive response to B6 and methionine-restricted diets reduces the likelihood of developing clinical manifestations. Pyridoxine is a cofactor to cystathionine -synthase.
In patients who do not respond to B6, a methionine-restricted diet is the mainstay of management. All patients must also be treated with supplementary folate because of the tendency for unsupplemented patients to develop folate deficiency. In addition, anticoagulant therapy with aspirin, sulfinpyrazone, or dipyridamole may prevent thromboembolic episodes.
Prognosis
The overall life expectancy of patients with homocystinuria is the fourth to fifth decade. The most life-threatening potential complication is massive pulmonary embolism.
References
- Wappner RS. Disorders of amino acid and organic acid metabolism. In: McMillan JA, Deangelis CA, Feagin R, et al, eds. Oski's Textbook of Pediatrics. Philadelphia, Pa: Lippincott, Williams and Wilkins; 1999:1828-1836.
- Zaleske DJ. Metabolic and endocrine abnormalities. In: Morrissy RT, Weinstein SL, eds. Lovell and Winter's Pediatric Orthopaedics. Philadelphia, Pa: Lippincott-Raven; 1996:181-182.