G.P.193: Ataxia, core myopathy, beta-ketothiolase deficiency, dentate nueclear abnormalities and learning difficulties in a pair of consanguineous siblings. A new association or double trouble?

Abstract

We describe a sibling pair, (female aged 14years and male aged 10years) with profound ataxia, moderate learning difficulties and proximal muscle weakness. The parents were first cousins and healthy with no other family history of any disorders. The family were of Pakistani origin. Both siblings were found to have a core myopathy on muscle biopsy. Further genetic investigations for causes of core myopathy (RYR1 and SEPN1) did not reveal any mutations. In addition to the myopathy, the older sibling was found to have a urine organic acid profile consistent with beta-ketothiolase deficiency. This was confirmed by finding absent fibroblast beta-ketothiolase activity, <3.4nmol/min/mg, reference value 25–69nmol/min/mg. Her clinical manner of presenting was atypical as she never had the metabolic crisis (episodes of ketoacidosis) normally associated with this organic acid disorder. She also had an abnormal brain MRI scan, showing a high signal in the dentate neuclei and she had a congenital posterior polar cataract. The younger male sibling did not have these abnormalities. Core myopathies are one of the more common causes of congenital myopathy and there are several genes implicated. To date we have not found any of these genes on either sibling. Mitochondrial beta-ketothiolase is an enzyme involved in ketogenisis, ketolysis and isoleuciene metabolism. These separate signs and clinical findings have not been described before and they may be a chance association. We however note that with consanguinity there is a possibility that there may be a autosomal recessive mode of inheritance to explain the underlying conditions.