Arterial Stroke as an Isolated Manifestation of Homocystinuria in an Infant

Dear Sir,

Pediatric stroke has remained an under-recognized nosological entity among pediatricians.[1] The incidence of pediatric stroke is 1–6 per 100,000 children/year.[2] The risk factors for pediatric stroke differ as compared with adults with stroke. These include arteriopathies, vasculitis, hematologic disorders and coagulopathies, trauma, heart disorders, and metabolic disorders such as mitochondrial disorders, urea metabolic disorders, homocystinuria, aminoaciduria, glutaric acidemia Type I, lysosomal disorders, Fabry's disease. Homocystinuria is an inborn error of amino acid metabolism commonly associated with stroke. However, stroke as the presenting clinical manifestation leading to an investigation for homocystinuria is unusual.[3] Hereby, we report an infant presenting with right hemiplegia and left middle cerebral artery territory (MCA) infarct. Investigations showed that homocystinuria was the underlying etiology.

A 1-year-old male child was brought with a history of sudden onset weakness of right upper and lower limbs with facial deviation to the left of 1 day duration. There was no preceding fever, headache, trauma, vomiting, or loose stools. On day 2 of admission, he had episodes of the right focal motor seizures without generalization. He was immunized for age, and his developmental history was normal. He was born to a nonconsangunious marriage. General physical examination was normal. Anthropometry was normal. Systems examination was unremarkable. Neurologically, he was conscious, cooperative. He was able to make sounds. Fundus examination was normal. There was right upper motor neuron facial palsy. Muscle power was 1/5 in the right upper and lower limb. Plantars were mute. The skull and spine were normal. Brain magnetic resonance imaging showed acute infarct in the left basal ganglia and angiogram within normality limit [Figure 1]. Complete hemogram, renal, hepatic, and functions were normal. Carotid Doppler was normal. Two-dimensional echocardiography was normal. Cerebrospinal fluid analysis was normal. Plasma lactate was within normal limits. Serum antinuclear antibody, antiphospholipid antibodies were negative. Protein C, S and antithrombin levels were normal, negative factor V Leiden mutation. Serum homocysteine was mildly raised, Vitamin B12 was normal. Urine for homocysteine was positive. Tandem mass spectroscopy showed an abnormal amino acid pattern in the form of hypermethioninemia. A diagnosis of homocystinuria was made. Genetic testing for enzyme abnormality could not be done due to nonavailability. He was started on aspirin, levetiracetam, pyridoxine, folate, Vitamin B12 supplements, and low protein diet. During his hospital stay, he had improvement in his muscle power to 4/5.

Figure 1.

Brain magnetic resonance imaging diffusion-weighted imaging axial view (a and b) bright signal in the right basal ganglia and corona radiata (red arrow); apparent diffusion coefficient axial view (c and d) corresponding dark signal (red arrow); magnetic resonance angiogram brain (e) and neck vessels (f) is normal

Homocystinuria is an autosomal recessive inborn error of amino acid metabolism wherein there is a defect in the transsulfuration pathway (Type I) or methylation pathway (Types II and III). The catabolism of methionine produces cysteine, with homocysteine as an intermediate. The conversion of homocysteine to cystathionine requires a pyridoxal phosphate-dependent enzyme, cystathionine ß synthase (transsulfuration pathway). The majority of homocysteine is normally remethylated to methionine. This is catalyzed by the enzyme methionine synthase, which requires a metabolite of folic acid (5-methyltetrahydrofolate) as a methyl donor and a metabolite of Vitamin B12 (methylcobalamin) as a cofactor. Deficiency of cystathionine β synthase results in accumulation of homocysteine and reconversion of homocysteine to methionine.[4] Type I homocystinuria due to cystathionine β synthase is characterized by developmental delay, mental retardation, skeleton abnormalities resembling Marfan syndrome, ectopia lentis, and thromboembolic episodes. Type II homocystinuria is characterized by homocystinuria, hypomethionemia, and megaloblastic anemia. This is due to defect in the formation of methylcobalamin. Type III homocystinuria is characterized by homocystinemia, homocystinuria, and low levels of methionine. This is due to deficiency of the enzyme methyltetrahydrofolate reductase.[5]

In Type I homocystinuria, thromboembolic episodes involve both large and small cerebral blood vessels. It can occur at any age. The possible cause of vascular disease in homocystinuria includes endothelial cell damage, smooth muscle cell proliferation, lipid abnormalities, upregulation of prothrombotic factors and downregulation of antithrombotic factors, or endothelial-derived nitric oxide. Treatment in Type I homocystinuria is high dose pyridoxine, which is as a coenzyme for the enzyme cystathionine β synthase. If unresponsive to pyridoxine therapy, betaine has also produced clinical improvement.

Our patient presented with acute ischemic stroke in the MCA territory. All other workup for pediatric stroke was negative except for urine positivity for homocysteine and hypermethioninemia. This is unusual for homocystinuria to present in infancy with arterial thrombosis in the absence of any of the other manifestations of homocystinuria (developmental delay, mental retardation, skeletal abnormalities, marfanoid habitus, and lens dislocation).

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