Clinical Pearls & Morning Reports
Published March 7, 2018
Homocystinuria is an inherited metabolic disorder in which a deficiency of cystathionine β-synthase leads to excess accumulation of homocysteine, methionine, or both in blood and urine. Read the latest Case Record of the Massachusetts General Hospital here.
Q: Does cerebral venous sinus thrombosis most often affect men or women?
A: Cerebral venous sinus thrombosis is rare, accounting for 0.5 to 1% of all strokes, and it most often affects women younger than 50 years of age who are taking oral contraceptives or have recently given birth. The most common presenting symptom of cerebral venous sinus thrombosis is persistent headache. However, affected patients may present with seizures. Most patients with this condition have an identifiable cause, and 44% have multiple causes.
Q: What are some diseases that have overlapping features with Marfan’s syndrome?
A: There is a wide spectrum of disorders that have overlapping features with Marfan’s syndrome. These disorders are mostly due to mutations of FBN1 or of the genes encoding transforming growth factor β receptor types 1 and 2 (TGFBR1 and TGFBR2). They can be associated with skeletal abnormalities and with involvement of the vascular system, mainly in the form of arterial tortuosity, arterial dissection, or aneurysm of the sinus of Valsalva, aorta, or intracranial arteries. However, the only syndrome similar to Marfan’s syndrome that is associated with skeletal, developmental, and ocular manifestations and with vascular thrombosis is homocystinuria.
A: Homocysteine is an amino acid that is produced through transmethylation of methionine. It is metabolized into cysteine by vitamin B6–dependent cystathionine β-synthase. Remethylation of homocysteine occurs in a pathway that is catalyzed by vitamin B12–dependent methionine synthase and involves folate-dependent methylenetetrahydrofolate reductase. Dysfunction of one of these enzymes or a deficiency of vitamin B6, folate, or vitamin B12 may result in hyperhomocysteinemia. Causes of a mild-to-moderate elevation in the plasma homocysteine level include kidney disease and liver disease; use of a sample obtained when the patient had not fasted can also result in an elevated level. Most nongenetic causes of an increased homocysteine level are associated with a deficiency of vitamin B12 or folate. Drugs that interfere with vitamin B12 and folate metabolism, such as antiepileptic medications and methotrexate, may cause an elevation in the homocysteine level. An extreme elevation in the plasma homocysteine level is helpful in narrowing the differential diagnosis to the genetic causes of homocystinuria, including deficient cystathionine β-synthase, defective methylcobalamin synthesis, or abnormal methylenetetrahydrofolate reductase. A homocysteine level of more than 100 μmol per liter is typically considered to be specific for a genetic cause of homocystinuria.
A: Classic homocystinuria is a rare autosomal recessive disease that is caused by mutations of the gene encoding cystathionine β-synthase (CBS), on chromosome 21. Affected patients may have marfanoid skeletal abnormalities and premature osteoporosis. Developmental delay is a common feature of homocystinuria that helps to distinguish it from Marfan’s syndrome. Myopia often manifests in patients as young as 1 year of age, and ectopia lentis manifests between 3 years and 10 years of age. Downward lens dislocation occurs in 90% of patients with homocystinuria, whereas upward lens dislocation is common in patients with Marfan’s syndrome. Thromboembolic disease develops in 25% of patients with homocystinuria, often when they are 8 to 12 years of age; systemic or cerebrovascular thromboembolism is the cause of death in 71% of patients with homocystinuria. Seizures occur in approximately 20% of patients.