Adult-Onset Progressive Spastic Paraparesis Due to a Novel, Heteroplasmic Mitochondrial tRNAGlu (m.14685A>G) Gene Mutation (P02.022)

Objective: We report a 45 year old lady with a five year history of progressive spastic paraparesis and ataxia. Background There was visual impairment – cataracts aged 8 and primary photo–receptor retinopathy, bilateral sensory–neural deafness as a teenager and stroke–like episodes as an adult. She was initially believed to have Usher9s syndrome and then congenital rubella following evidence of bilateral basal ganglia calcification on MRI brain. Family history was unremarkable, a male sibling had spina–bifida whilst her maternal grandmother had multiple sclerosis. Design/Methods: Investigations revealed elevated plasma lactate, with no evidence of CSF abnormalities, or CSF rubella RNA and rubella specific intrathecal antibodies. Brain MRI demonstrated progressive atrophy of the cerebral hemispheres and spinal cord, and the existing basal ganglia and thalamic calcifications. Muscle biopsy revealed numerous COX-deficient fibres, some of which showed “ragged-red” changes. Results: Having excluded common mtDNA mutations, sequencing of the entire mitochondrial genome was undertaken, identifying a novel, heteroplasmic m.14685G>A tRNAGlu (MTTE) variant affecting an evolutionary conserved nucleotide within the TψC arm of the mt-tRNAGlu molecule. Single fibre PCR analysis revealed segregation of m.14685G>A mutation with the COX deficiency, confirming pathogenicity of this novel mt-tRNA mutation. She died of broncho-pneumonia. Autopsy revealed generalised cerebral atrophy with dense calcification of the lentiform nuclei with neuronal loss and gliosis. Mutation analysis of post-mortem skeletal and cardiac muscle tissues confirmed the m.14685G>A MTTE gene mutation at intermediate levels of heteroplasmy (42% and 68% respectively) whilst genetic analysis of the family indicated that the mutation had arisen sporadically. Conclusions: This is an unusual presentation of adult–onset spastic paraparesis related to mitochondrial dysfunction, due to a novel, pathogenic mtDNA mutation. Mitochondrial diseases are an important differential of Usher9s syndrome which can manifest into adulthood, and of perinatal infections (TORCH complex) which can involve the eye and CNS with focal cerebral calcification. Disclosure: Dr. Gnanapavan has nothing to disclose. Dr. Alston has nothing to disclose. Dr. Lax has nothing to disclose. Dr. Yarham has nothing to disclose. Dr. Everett has nothing to disclose. Dr. Hewazy has nothing to disclose. Dr. O9Donovan has nothing to disclose. Dr. Dean has nothing to disclose. Dr. Taylor has nothing to disclose.