G.P.157: Clinical and pathological features associated with mutations in MICU1

Abstract

Mutations in the MICU1 gene have been shown to cause a condition with overlapping clinical and pathological features between muscular dystrophy, congenital myopathy and mitochondrial disease. The molecular defect results in mitochondrial dysfunction secondary to disruption of calcium uptake. We present the clinical/pathological features in a cohort of 18 patients. Patients presented between birth and 8years with a mild, relatively static, proximal myopathy associated with high Creatinine Kinase (2000–10,000iu/L), learning difficulties and frequent microcephaly. At follow up (5–28yrs), all remained ambulant but variable extrapyramidal symptoms had developed in the majority by the end of the 1st decade. Other features suggestive of mitochondrial dysfunction included peripheral neuropathy, icthyosis, stroke like episodes, episodic weakness, ataxia and cataracts. Cardiomyopathy was not seen. Serum and CSF lactate were normal where tested. Two had low free carnitine. Other metabolic investigations were normal. One had abnormal signal change in globus pallidus on MRI at 10yrs. All had abnormal muscle biopsies, with myopathic features; diffuse variation in fibre size, increased internal and central nuclei and clusters of regenerating fibres without pronounced fibrosis or fatty infiltration. Necrotic fibers were rare and fibre typing was preserved. Focal areas devoid of mitochondria (minicores) were observed in both type I and type II fibres. Respiratory chain enzyme activity, where tested, was normal. All had mutations in the MICU1 gene, 2 different homozygous splice site mutations (12 and 4 cases respectively) and a deletion in a kindred of 2 cases. Although the numbers are small, there appears to be some correlation between genotype and phenotype. Testing for MICU1 mutations should be considered in children with a static proximal myopathy associated with a high CK and CNS involvement when immunohistochemical studies do not identify a protein defect.