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Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations

From Molecular Medicine Laboratory and ANZAC Research Institute (G.A.N., D.Z.), Clinical Sciences Building, Concord Hospital, Australia; Service et Laboratoire de Neurologie (C.M., F.S., J.-M.V.), CHU Dupuytren, 87042 Limoges Cedex, France; and Institute for Neuromuscular Research (S.G., M.R., R.A.O.), The Children’s Hospital at Westmead, NSW, Australia.

Address correspondence and reprint requests to Dr Nicholson, Molecular Medicine Laboratory and ANZAC Research Institute, Clinical Sciences Building, Concord Hospital, NSW 2139, Australia garthn{at}med.usyd.edu.au

Objective: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations.

Methods: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined.

Results: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations.

Conclusion: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.

Abbreviations: AFO = ankle foot orthosis; BAER = brainstem evoked response; CMAP = compound muscle action potential; CMT = Charcot-Marie-Tooth; FDS = functional disability score; HMSN = hereditary motor and sensory neuropathy; LL = lower limb; MNCV = motor nerve conduction velocity; N = normal; ND = not done; NR = no response; SEOAN = severe early-onset axonal neuropathy; SNAP = sensory nerve action potential; UL = upper limb; VER = visual evoked response; WC = wheelchair.

*Drs. Nicholson and Magdelaine contributed equally to this publication.

The CMT Association of Australia supported research at The Children’s Hospital at Westmead and Concord Hospitals.

Disclosure: The authors report no conflicts of interest.

Received August 23, 2007. Accepted in final form January 23, 2008.