Charcot-Marie-Tooth polyneuropathy type 2A related to a mitofusin 2 gene mutation presenting as severe early-onset axonal polyneuropathy

Introduction: CMT polyneuropathies are inherited slowly progressive disorders of the peripheral nerve with variable age at onset and variable severity. To date, in CMT2 (A-F) mutations in at least five different genes and three additional chromosomal loci have been identified. CMT2A was first shown to be related to mutations in the KIF1B gene. However, recent studies have identified mutations in the gene encoding MFN2, a mitochondrial GTPase protein, in several kindreds. Here, we report a 32-year old German woman with early-onset axonal CMT due to a, probably de novo, mutation in the MFN2 gene (HMSN IIA, CMT2A, 1p36).

Methods: Molecular genetic studies were performed with informed consent of the patient. Genomic DNA was extracted from peripheral blood lymphocytes, and was used as template for PCR amplification.

Results: The patient had developed progressive steppage gait, pes cavus, and distally pronounced atrophy of the lower and upper extremities since the age of 3 and was misdiagnosed to suffer from spina bifida occulta. On neurological examination at age 31, manual muscle testing revealed paresis MRC grade 3/5 in the distal part of the upper extremities and 0/5 in the distal part of the lower extremities. Nerve conduction studies showed markedly reduced CMAP and SNAP amplitudes with mildly slowed or normal nerve conduction velocities in the lower extremities. Molecular genetic analysis of the PMP22, MPZ/P0 and Cx32 gene did not reveal any causative mutations. Direct sequence analysis of the MFN2 gene revealed a heterozygous c.281G>A, R94Q mutation. All other tested family members were clinically normal and had no mutation in the MNF2 gene (only parents tested) suggesting a de novo mutation.

Conclusions: Medical history, clinical picture and neurophysiological studies were compatible with an inherited axonal sensorimotor polyneuropathy. Molecular genetic analysis revealed a heterozygous mutation in the MFN2 gene. The identified 218G-A transition in the MNF2 gene, resulted in an Arg94-to-Gln (R94Q) substitution. To our knowledge, our patient represents the first described German individual with MNF2 gene mutation. The phenotype did not markedly differ from the ones described in the reported families with the same mutation though the other MNF2 mutations showed milder disease progression. Given the increasing number of described MNF2 mutations in CMT2A, genetic analysis should include a MNF2 screen in early-onset polyneuropathies.