Discussion
“Homocystinuria is the second most common treatable aminoacidopathy” after phenylketunuria.1 Homocysteine, an intermediate metabolite of methionine catabolism, can be removed in 2 ways. Cystathionine β-synthase (CBS) is an enzyme that catalyzes Hcy irreversibly by the means of B6 as the cofactor. This is called transsulfuration.2,3
In the second way, methionine is rebuilt through remethylation, by means of either methylenetetrahydrofolate reductase or methionine synthase. In the first pathway, Hcy is converted into methionine in the presence of coenzyme, methylcobalamine. Folic acid is the substrate in this reaction.2,3
Mutation in the encoding gene of each of these enzymes can result in homocystinuria. The most common genetic disorder is CBS deficiency (homocystinuria type I).4 The reported worldwide incidence of this rare autosomal recessive disorder is between 1 in 50 000 and 1 in 200 000.5
The clinical manifestation of CBS deficiency is diversely heterogenous; however, 4 organs are dominantly affected, namely “central nervous system, eye, skeletal, and vascular system.”6 These patients are often normal at birth. Homocysinuria, due to CBS deficiency, usually manifests itself as ocular lens subluxation, which results in severe myopia and iridiodonesis. In a large number of patients, ectopic lentis occurs by the age of 8 years.4,7
Skeletal abnormalities in homocystinuria are a common manifestation similar to what is seen in Marfan syndrome. These abnormalities consist of fair wooly hairs, blue eyes, livedo reticularis, limitation of joint mobility, scoliosis, high-arched palate, pes cavus, pectus excavatum or pectus carinatum, and genu valgum and osteoporosis, especially of vertebrae and long bones.7
Central nervous system involvement includes progressive mental retardation, seizure, dystonia, behavioral and personality disorder, and stroke due to thromboembolic syndromes.4,8 Premature vascular events are the major causes of early death and morbidity.7
Vascular injury is proposed to be due to “endothelial dysfunction, smooth muscle proliferation, extracellular matrix modification, lipoprotein oxidation, and increased thrombin production.”9
Endothelial dysfunction is the result of nitric oxide release impairment, thereby disturbing vasodilation and facilitating platelet aggregation.10 Although it had been mentioned in earlier studies that hyperhomocysteinemia provokes intima hypertrophy and resultant increased intima–media thickness,11 some of the recent observation have failed to show this correlation.12
Similarly, in this case, no evidence of increased intima–media thickness was detected on carotid Doppler; nevertheless, significant narrowing of internal carotid artery was observed unilaterally. This is in consistent with 2 studies that claimed the plasma level of Hcy was higher in carotid artery stenosis,13,14 although in the latter, the serum Hcy level was not correlated with pulsatility index in the stenoocclusive state of the proximal internal carotid.
Correlation between Hcy and dystonia has been shown in several studies; Muller et al demonstrated that the serum Hcy was significantly higher in primary dystonia than in control.15 While some believe that dystonia is due to microinfarct in the basal ganglia,16 others assume that neurotoxic effect of Hcy can be responsible for developing dystonia.17 In this case, the brain MRI did not reveal any abnormality in basal ganglia, however, having experienced deep white mater infarct would have predisposed this patient to manifest dystonia more vigorously. Furthermore, remarkable response of dystonia to high dose of pyridoxine might be suggestive of some reversible effect of Hcy, while lowering Hcy did not alter arterial stenosis.