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Classical homocystinuria (CHU) due to Cystathionine Beta-Synthase (CBS) deficiency is rare autosomal recessive inborn error of amino acids metabolism causing accumulation of methionine and homocysteine. The clinical manifestations of CHU may include neurological deficits mostly due to thromboembolic event so the most common brain radiological findings are secondary to stroke. The management is based on pharmacological treatment and dietary restriction of methionine. We present four patients with pyridoxine non-responsive CHU, who were found to have white matter changes on brain MRI, with a review of their clinical characteristics and neurological outcome. All patients had an underlying homozygous mutation of c.1006C>T (p.R336C) in the CBS gene, hypermethioninemia due to poor adherence to diet restriction, and were diagnosed before the implementation of the National Metabolic Newborn Screening Program in Qatar. Dramatic reductions in methionine levels because of better compliance were associated with reversibility of the brain white matter lesions in two patients. Acad J Ped Neonatol 1(5) : AJPN.MS.ID.555571 (2016) Introduction Figure 1: Methionine Metabolic Pathway. Classical homocystinuria (CHU) due to Cystathionine BetaSynthase (CBS) deficiency (OMIM 236200) is a rare autosomal recessive in born error of amino acids metabolism [1]. Degradation of dietary methionine produces an intermediate compound known as homo cytosine that is mostly re-methylated to methionine. Homocysteine is also converted to cystathionine by the action of CBS which requires pyridoxine (Vitamin B6). Cystathionine Beta-Synthase deficiency due to CBS gene mutation leads to accumulation of both methionine and homocysteine, (Figure 1) [2]. The estimated prevalence of Classical homocystinuria is between 1/20,000 and 344,000. However, in Qatar it is approximately 1/1,800 births, the highest in the world [3-5]. Untreated patients may present with multisystem manifestations, such as vision problems due to myopia and ectopia lentis, osteoporosis, skeletal deformities mimicking Marfan syndrome, intellectual disability, and thromboembolic events. Neurological presentations may include seizures, extra pyramidal signs, psychiatric disturbance and focal neurological deficit due to infarction [5-7]. Neuro-imaging is not routinely done for patients with classical homocystinuria unless clinically indicated. The most common brain radiological findings are secondary to stroke: infarction, atrophy, and venous occlusion [7]. Classical homocystinuria is classified into pyridoxine responsive and none responsive types, homozygous mutation of c.1006C>T (p.R336C) in the CBS gene was attributed for most of pyridoxine non-responsive homocystinuria among Qatari patients [4]. Protein (Methionine) restricted diet and pharmacological treatment with pyridoxine (Vitamin B6), Betaine, hydroxycobalamine (Vitamin B12), and folic acid, are the corner stone in managing patients with classical homocystinuria. The aim is to control biochemical abnormalities and prevent complications.

Brain White Matter Changes in Four Patients with Classical Homocystinuria: Two of Them were Reversible