Nemaline myopathy and secondary mitochondrial dysfunction of complex I

Abstract

Introduction: Nemaline myopathy (NM) is a heterogeneous muscular congenital myopathy that is slowly progressive or non-progressive. Case report: Our patient was born at 41+6 weeks of gestation, following an uneventful pregnancy .On day four, she presented with weight loss of >10% and hypotonia. The results of the investigations were all normal: investigations included creatine kinase, plasma amino-acids, ammonia level, acylcarnitine profile, lactate and blood gases. Brain magnetic resonance imaging at 3 months of age was normal. Genetic screening for Spinal muscular atrophy (SMA1), myotonic dystrophy (DM1), congenital myasthenic syndrome and Prader-Willi syndrome were all negative. Her echocardiography was normal. Electromyography and nerve conduction studies of the biceps and rectus femoris showed normal sensory responses and there was polyphasic motor units of low amplitude and short duration in the biceps and rectus femoris. The findings suggested a primary muscular disorder of unknown origin. Her skeletal muscle biopsy from right quadriceps which was done at the age of one year showed “thread like” inclusions seen both on light and electron microscopy confirming the diagnosis of NM. The histology also showed normal mitochondria in placement, number and morphologic structure. In addition it showed a moderately low enzyme level of complex I. Mitochondrial whole genome sequencing using the patients skeletal muscle-derived DNA sample detected a known pathogenic mutation, m4298 G>A, at a very low level of heteroplasmy (approximately 10%) in the MTTI (mt-tRNA) gene. The subsequent genetic testing for the most frequent genetic variants associated with nemaline myopathy showed heterozygosity for ACTA1 c.760A > C p.(Asn 254 His). The ACTA1 sequence variant has not been previously reported in the literature. Further assessment of her skeletal muscle biopsy using a quadruple immune-histochemical assay indicated normal levels of both NDUFB8 and COX1 immuno expression. Conclusion: We are describing a severe neonatal onset phenotype of genetically confirmed congenital NM.