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237 SLC25A46 mutations cause a spectrum of disorders including CMT2 with optic atrophy
  1. Carolynne Doherty1,
  2. Menelaos Pipis1,
  3. Andrea Cortese1,
  4. Roy Poh2,
  5. James Polke2,
  6. Robert Pitceathly1,
  7. Alexander Rossor1,
  8. Mary Reilly1
  1. 1Queen Square Centre for Neuromuscular Diseases
  2. 2Neurogenetics unit, UCL Queen Square Institute of Neurology


Case A 20-year-old female had symptom onset age 7 of bilateral foot drop and distal lower limb atrophy. Nerve conduction studies demonstrated a length dependent axonal motor and sensory neuropathy. At 16 her vision deteriorated to 3/36 right, 6/60 left. Visual evoked potentials were borderline compatible with bilateral optic atrophy. Metabolic and structural causes were excluded.

Examination At age 18 examination demonstrated bilateral foot drop and a positive knee bob sign. There was asymmetrical distal limb atrophy. Fundi were pale. Reflexes were brisk in upper limbs and knees with absent ankles and mute plantars.

Results The 56-gene Bristol axonal neuropathy panel revealed a non-pathogenic TRPV4 mutation. Mutations in OPA1, OPA3, POLG, ATPase 6 and 8 were not identified. Exome sequencing in the research setting demonstrated compound heterozygous SLC25A46 mutations. One mutation was confirmed in each of her parents.

Discussion Mutations in SLC25A46 are associated with spectrum of disorders encompassing pontocerebellar hypoplasia (including lethal congenital cases), Leigh Syndrome, Progressive myoclonic ataxia with optic atrophy and neuropathy, and hereditary motor and sensory neuropathy type 6B, sometimes with associated features such as cerebellar ataxia and spasticity. We present a case of CMT2 with optic atrophy due to heterozygous mutations and discuss the literature.

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