Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency

Inborn errors of metabolism are caused by inherited defects in the enzyme protein or cofactors that metabolize proteins, carbohydrate, and fat. Between 3% and 6% of sudden infant death syndrome, sudden unexpected death in infancy and sudden unexpected death in childhood are likely due to inherited metabolic conditions. Some clinical presentations can mimic non-accidental injury. The most frequently implicated disorders include defects of fatty acid oxidation and ketogenesis, congenital lactic acidosis, urea cycle disorders, organic acidurias and carbohydrate disorders. Appropriate samples should be collected and stored when death is imminent or at postmortem in order to reach an accurate diagnosis.

Deaths: Inherited Metabolic Disease and Sudden Unexpected Death – Pathology

Cysthiatonine beta-synthase (CBS) deficiency (CBSD) is an autosomal recessive rare disorder caused by variations on CBS that leads to impaired conversion of homocysteine (Hcy) to cystathionine. Marked hyperhomocysteinemia is the hallmark of the disease. The administration of pyridoxine, the natural cofactor of CBS, may reduce total plasma Hcy. Patient phenotype is classified on pyridoxine responsivity in two groups: pyridoxine-responsive and non-responsive patients. Ectopia lentis, bone deformities, developmental delay, and thromboembolism are the classic signs and symptoms of the disease. Early diagnosis and treatment impact patients’ natural history. Therapy aims to lower promptly and maintain Hcy concentrations below 100 μmol/L. Depending on the patient’s phenotype, the treatment goals could be obtained by the administration of pyridoxine and/or betaine associated with a methionine-restricted diet. CBSD could be diagnosed in the early days of life by expanded newborn screening (ENS), however, the risk of false negative results is not negligible. In Emilia-Romagna (Italy), during the first 10 years of screening experience, only three cases of CBSD identified have been diagnosed, all in the last two years (incidence 1:118,000 live births). We present the cases and a comprehensive review of the literature to emphasize the role of ENS for early diagnosis of CBSD and its potential pitfalls, reiterating the need for a more effective method to screen for CBSD.

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Cystathionine Beta-Synthase Deficiency: Three Consecutive Cases Detected in 40 Days by Newborn Screening in Emilia Romagna (Italy) and a Comprehensive Review of the Literature

Cerebral sinovenous thrombosis is unusual during childhood and requires early and accurate management because of its detrimental consequences. We report on the case of a 2-year-old boy with mild psychomotor delay, who presented with nonfebrile acute ataxia. A brain computed tomographic (CT) scan showed complete thrombosis of the superior sagittal sinus, confirmed by magnetic resonance angiography and associated with a right frontal hemorrhagic infarction. Systematic screening for thrombophilia revealed homocystinuria linked to cystathionine β-synthase deficiency with underlying compound heterozygosity. The evolution was favorable after anticoagulant therapy, specific diet, and vitamin supplementation. This case is of interest because of the unusual clinical presentation as a pediatric cerebral sinovenous thrombosis. Furthermore, homocystinuria is rarely revealed by cerebral sinovenous thrombosis at the onset of the disease and should systematically be ruled out in pediatric stroke.

CÃ©cile Saboul

Papers

Inaugural Cerebral Sinovenous Thrombosis Revealing Homocystinuria in a 2-Year-Old Boy