Case details We report a sibling pair who presented with mixed upper and lower motor neuron signs with a rare mitochondrial fusion protein disorder.
Case 1: An 18 month old boy child, born at full-term after an uneventful delivery, presented with motor delay and hypotonia. At 3 months of age he was investigated for an apnoeic and floppy episode. At that time MRI brain and spine was normal. On examination at 18 months he had lower limb muscle atrophy, hypotonia and brisk reflexes. Electrophysiology revealed axonal neuropathy and the repeat MRI showed periventricular hyperintensities. Serum and CSF lactate and muscle biopsy for histopathology and respiratory chain enzymes were normal. Genetic studies revealed a heterozygous missense variant in exon 18 of the MFN–2 gene.
Case 2: His older half-sister now 10 years of age initially was hypotonic in infancy and later developed spasticity and atrophy with brisk reflexes. Electrophysiology showed severe sensory motor axonal neuropathy. Brain MRI shows periventricular hyperintensities. She has also got the same mutation as her brother. She was also found to have heterozygous missense mutation in PMP22 gene which was present in her mother as well, but absent in her brother. Therefore, we conclude PMP22 mutation is not causally related.
Discussion Mitofusin–2 (MFN–2) is a protein required for mitochondrial fusion that in humans is coded by the MFN–2 gene. Mutations in MFN–2 are mainly responsible for Charcot Marie Tooth disease type 2A (CMT2A). Other less common features of MFN–2 dysfunction are spasticity, progressive external ophthalmoplegia and rarely optic atrophy, deafness, ataxia, white matter periventricular involvement and cognitive decline.
Conclusion Our cases are not only rare but also had unusual presentation of MFN–2 mutation. They demonstrated spasticity with brisk reflexes clinically but had severe neuropathy on electrophysiology. We recommend that MFN–2 mutation testing should be considered in any child presenting with unexplained neurological examination with contradictory neurophysiological results and periventricular hyperintensities.