Homocystinuria (HCU)

Genetically transmitted error of metabolism of the amino acid methionine characterized by severe myopia, Marfan-like stature with pectus excavatum, slight mental retardation, and tendency to develop spontaneous, generalized arterial, and venous thromboses under stress.

Cystathionine Beta-Synthetase (CBS) Deficiency; Homocystinemia.

Inborn error of metabolism of methionine that cannot be converted to cysteine; methionine accumulates and cysteine is lacking. Left untreated, this imbalance results in mental retardation, osteoporosis and other bone problems, dislocated lenses of the eyes, heart disease, and excessive blood clot formation.

Incidence in the general population is estimated at between 1:50,000 and 1:200,000. Cystathionine β-synthase is a vitamin B6-dependent enzyme; 50% of patients with homocystinuria show pyridoxine responsiveness, including 13% who can be completely controlled with pyridoxine alone.

Autosomal recessive. Chromosome 21q22. Carrier detection possible using methionine loading tests. An abnormal gene on chromosome 1 has been proposed as the cause of reduction in methylene tetrahydrofolate reductase ([MTHFR] or homocystinuria III).

Deficiency of cystathionine synthase (homocystinuria I) leads to a failure of transsulfuration of precursors of cysteine, an important component of collagen. The weakened collagen is responsible for many of the clinical manifestations. Two other interrelated pathways of methionine metabolism can produce accumulation of homocysteine and its metabolites: defective methylcobalamin synthesis (homocystinuria II) and abnormality in MTHFR (homocystinuria III).

Confirmed by findings of homocystinuria and methioninuria. P-methionine elevated in blood (up to 2 mmol/l). Homocystine, mixed disulfide, and other sulfur-containing compounds may be present (homocysteine binds to plasma proteins by disulfide bonds). Increased amounts of methionine in the cerebrospinal fluid (CSF) (homocystine may be present). Prenatal diagnosis possible by measuring enzyme activity in amniocytes.

Weakened collagen accounts for the clinical manifestations of subluxation of lens of eye, generalized osteoporosis, pectus excavatum, and marfanoid appearance (without joint hyperextensibility). Mental retardation is common but may be prevented by early dietary intervention. Breakage of collagen in blood vessel endothelium leads to a high incidence of thromboembolic events, causing cerebrovascular accident or myocardial infarction that frequently result in premature death of patients. Management consists of a low-methionine diet with supplements of cystine and betaine. Large doses of pyridoxine may control some of the clinical manifestations.

Patient should be receiving appropriate diet, including pyridoxine supplements. Prolonged fasting should be avoided because of risks of dehydration leading to hypercoagulability and hypoglycemia. Dextrose-containing intravenous fluids should be started preoperatively. Assess hematocrit, platelet count, and coagulation profile (prothrombin time, partial thromboplastin time).

The major hazard in the perioperative period is vascular thrombosis; this has been particularly associated with angiography and the administration of nitrous oxide. The goals of anesthetic management are to maintain peripheral perfusion and prevent dehydration. Agents should be selected to avoid excessive depression of cardiac output. Fluid therapy should be started preoperatively. Generous fluid therapy should be continued intraoperatively to maintain circulating volume. Dextran-40 solutions have been advocated to reduce platelet adhesiveness. Dextrose-containing fluids should be given to prevent hypoglycemia. The patient should be positioned carefully to avoid vascular compression and venous stasis. Calf compression devices may aid in promoting venous return from the lower extremities. The anesthetic technique should allow rapid recovery with early postoperative ambulation. A significant increase in postoperative cardiac ischemic episode has been reported after administration of nitrous oxide. Regional techniques may be contraindicated: nerve blocks may be complicated by damage to adjacent blood vessels with the potential for vascular thrombosis as a result and spinal or epidural analgesia may lead to vascular stasis. Intravenous hydration should be continued postoperatively until oral intake is reestablished.

The use of nitrous oxide is contraindicated because of its effect on homocysteine plasma concentration and thromboembolic consequences. After 48 hours of nitrous oxide administration, Badner et al. reported a significant increase in the postoperative period of cardiac ischemia in 42 patients when compared with those not receiving nitrous oxide. No other anesthetic agents are specifically contraindicated.

Marfan Syndrome: Autosomal dominant generalized connective tissue weakness with hyperextensible joints, increased risk of valvular/aortic disease, ectopia lentis, megalocornea, and pneumothorax, caused by a mutation in the fibrillin gene on chromosome 15.