Early-onset Charcot-Marie-Tooth patients with mitofusin 2 mutations and brain involvement

Abstract

Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot-Marie-Tooth disease (CMT). A prospective brain MRI study was performed on 18 early-onset CMT patients with MFN2 mutations, and a high frequency (39%) of brain abnormalities was found. Early-onset patients showed multiple scattered or confluent brain lesions that involved gray matter as well as white matter. Patterns of brain involvement in early-onset patients differed from those of late-onset patients and other hereditary peripheral neuropathies. In addition, one CMT patient demonstrated a brain lesion before the development of peripheral neuropathy.

Missense mutations ofmitofusin 2in axonal Charcot–Marie–Tooth neuropathy: polymorphic or incomplete penetration?

“…FC519 also has a daughter (34) who is a CMT2A patient, while her mother (57) is an asymptomatic carrier. As for FC527, both the father and son acquired the CMT2A phenotype and showed cosegregation and concurrence with early reports (Zü chner et al 2004;Chung et al 2006Chung et al , 2010Verhoeven et al 2006).…”

“…We have also reported this mutation twice in two Korean families with early-onset severe phenotype for one family (FC280) and late-onset mild phenotype for the other (FC169) (Chung et al 2006, Creatine kinase: normal range in our laboratory B185 IU/l: ND 0not done. Chung et al 2010). The credibility of this single nucleotide polymorphism (SNV) as the causative mutation is thus attributed to several groups reporting the same mutation from different ethnic groups.…”

Axon Transport and Neuropathy

“…For example, approximately 10% to 20% of patients with MFN2 mutations develop optic nerve degeneration (CMT6/hereditary motor and sensory neuropathy V) and some have long upper motor axon involvement (CMT6/hereditary motor and sensory neuropathy VI). 39,40 Future studies to identify how particular MFN2 mutations mechanistically relate to differing clinical symptoms will be invaluable for understanding how alterations in this complex protein cause axonal neuropathy. 41 Another molecule associated with dominant and recessive inheritance of CMT is ganglioside-induced differentiationassociated protein-1 (GDAP1; OMIM no.…”

Pitt-Hopkins Syndrome in a Boy With Charcot Marie Tooth Disease Type 1A: A Rare Co-occurrence of 2 Genetic Disorders

“…There are reports of various types of Charcot Marie Tooth disease with brain involvement, such as Charcot Marie Tooth disease type 2 with mitofusin 2 mutations, Charcot Marie Tooth disease X, Charcot Marie Tooth disease 4D, and hereditary neuropathy with liability to pressure palsy. 7 Patients with early-onset Charcot Marie Tooth disease with mitofusin 2 have a higher frequency of both gray and white matter involvement, whereas the brain lesions in Charcot Marie Tooth disease X, Charcot Marie Tooth disease 4D, and hereditary neuropathy with liability to pressure palsy patients are confined to the white matter. 7 However, clinically significant language or cognitive impairment has not been reported in those cases.…”

“…7 Patients with early-onset Charcot Marie Tooth disease with mitofusin 2 have a higher frequency of both gray and white matter involvement, whereas the brain lesions in Charcot Marie Tooth disease X, Charcot Marie Tooth disease 4D, and hereditary neuropathy with liability to pressure palsy patients are confined to the white matter. 7 However, clinically significant language or cognitive impairment has not been reported in those cases. There are no reports of radiological or clinical central nervous involvement in patients with Charcot Marie Tooth disease type 1A.…”