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At a glance

Genetically transmitted error of metabolism of the amino acid methionine leading to a multisystemic disorder of the connective tissue, muscles, central nervous system, and cardiovascular system. It is 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. A special consideration must be given to anesthesiologists using nitrous oxide during anesthesia. An association between its administration and the potential risk for an acute and severe thromboembolism syndrome must be taken into consideration.

Synonyms

Cystathionine Beta-Synthase (CBS) Deficiency; Homocystinemia; CBS Deficiency; Classical Homocystinuria Disease.

Nature

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

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.

Genetic inheritance

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).

Pathophysiology

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). It is caused by the deficiency of the enzyme cystathionine beta synthase, and the deficiency of folic acid, vitamin B12 and pyridoxine (vitamin B6), or mutations of related enzymes.

Diagnosis

Confirmed by findings of homocystinuria and methioninuria. P-methionine elevated in blood (up to 2 mmol/L). Homocysteine, mixed disulfide, and other sulfur-containing compounds may be present (homocysteine binds to plasma proteins by disulfide bonds). The presence of increased amounts of methionine in the cerebrospinal fluid (CSF) (homocysteine may be present) has been reported. Prenatal diagnosis is possible by measuring enzyme activity in amniocytes. The life expectancy of patients with homocystinuria is reduced if untreated. It is known that before the age of 30 years, almost one-quarter of patients will have died as a result of thrombotic complications and its consequences on the heart.

Clinical aspects

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 ...

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