Semi‐dominant mutations in MFN2 ‐related neuropathy and implications for genetic counselling

Dear Editor, We read with interest the recent publication by Piscosquito et al. (2015) on mutational mechanisms in MFN2-related neuropathy in which they described a family where the proband had a severe axonal neuropathy with pyramidal signs due to a compound heterozygous mutation in MFN2 (Piscosquito et al., 2015). One parent had a mild late onset axonal neuropathy due to a semi dominant p.R250W missense mutation and the other parent, carrying a single MFN2 null allele, was asymptomatic. MFN2 is a complicated gene diagnostically. It has a large number of variants of uncertain pathogenicity and three described patterns of inheritance including dominant, semi-dominant and recessive which can cause difficulties for genetic counselling (Verhoeven et al., 2006; Nicholson et al., 2008; Polke et al., 2011). We report a family in which two affected brothers both carried a c.749G>A, p.R250Q and c.1085C>G, p.T362R mutation of MFN2 in trans (see Table 1 for clinical details). Both brothers developed an early onset, sensory motor neuropathy. The father, who is presumed to carry the p.R250Q mutation, died aged 63 from a myocardial infarction and had no symptoms of a neuropathy. The mother who carries the p.T362R mutation has a very mild symptomatic neuropathy, diagnosed at the age of 85 with symptom onset of mild difficulty walking at age 70. She was unable to stand on her heels or toes, sensory action potentials were absent and compound muscle action potentials significantly reduced in the lower limbs. The elder brother presented in the first decade of life with difficulty running and poor balance. He underwent Achilles tendon lengthening surgery at the age of 10. He is now 53. He has length dependent weakness but with proximal involvement, requires a stick to walk and has unilateral vocal cord paralysis. Neurophysiology confirmed a length dependent sensory and motor