Homocystinuria is a rare inborn error of metabolism, whose classical form is due to the autosomal recessive inherited deficiency of the pyridoxine-dependent enzyme CBS, accountable for the conversion of homocysteine into cysteine by trans-sulfuration. Affected patients tend to display an accumulation of homocysteine and methionine in plasma, urine and tissues, which presents in the form of disorders of the connective tissues, and increased risk of thromboembolism.
The clinical spectrum is broad with variable age at onset and severity of symptoms, ranging from dramatically affected children to asymptomatic adults.2,3 Thromboembolism, in particular venous thrombosis, is the leading cause of morbidity and early death, although prompt recognition and treatment may considerably improve outcomes.4 Its occurrence in homocystinuria is estimated to be as high as a quarter of affected patients5, often presenting in the form of recurrent episodes, and it can represent the first manifestation of the disease. Although thrombus pathogenesis remains unclear, a direct toxic effect of homocysteine, leading to patchy endothelial desquamation and subsequent increased platelet adhesiveness and consumption has been suggested.6 Superimposed precipitating factors, such as infections, dehydration and hormonal changes, could eventually interfere.
The high level of plasma homocysteine and methionine is the leading biochemical finding of CBS deficiency. The extreme elevation of plasma homocysteine (higher than 100 µmol/L) narrows the differential diagnosis between genetic causes of hyperhomocysteinemia and secondary causes (i.e. folate, B12 and B6 deficiencies, ongoing treatment with methotrexate, isoniazid, carbamazepine).
Anticoagulant therapy (mainly based on low molecular weight heparin) and antiedema medication are the cornerstones of the management of any acute venous cerebral thrombosis.
Specific treatment for homocystinuria aims to lower plasma homocysteine concentration to a safe level and should be started immediately after the diagnosis to prevent the occurrence of complications.
First-line therapy consists of pyridoxine and folate administration. Vitamin B12 should be monitored and supplemented if defective. For those who respond to this therapy, the target level of plasma homocysteine should ideally be < 50 µmol/L.
In pyridoxine unresponsive patients, who do not achieve acceptable homocysteine levels, a restriction in the dietary protein intake, along with supplementation of Met-free L-Amino Acids must be started. In these patients, betaine acts as a methyl group donor in the re-methylation of homocysteine to methionine and could, therefore, be associated, with the goal of total homocysteine plasma level below 120 µmol/L.7
Lifelong treatment is required, and lack of adherence to the low-protein diet is a frequent concern, particularly in adolescents and young adults.
This case enhances the importance of dosing plasma homocysteine levels in every child investigated for marfanoid habitus, given the impact of the early diagnosis and treatment in the prevention of thromboembolic events.