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Large Kindred Evaluation of Mitofusin 2 Novel Mutation, Extremes of Neurologic Presentations, and Preserved Nerve Mitochondria

Christopher J. Klein, MD; Grace W. Kimmel; Sean J. Pittock, MD; JaNean E. Engelstad; Julie M. Cunningham, PhD; Yanhong Wu, PhD; Peter J. Dyck, MD
Arch Neurol. 2011;68(10):1295-1302. doi:10.1001/archneurol.2011.225.
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Background Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations.

Objective To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred.

Patients An American kindred of Northern European and Cherokee American Indian descent.

Results Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls.

Conclusions Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.

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Figure 1. Identified new MFN2 mutation and affected kindred. A, DNA sequencing results showing the identified missense alteration within MFN2 at nucleotide base 436 C→T with resultant amino acid change of leucine (Leu) to phenylalanine (Phe) at codon position 146 CTC→TTC: Leu146Phe. B, The examined American kindred of Northern European and Cherokee Indian descent with genetic testing (indicated by asterisk) revealing the affected status associated with the demonstrated base alteration. In addition to the shown persons, 800 evaluable healthy controls underwent DNA sequencing without MFN2 436 C→T alteration identified and not reported at Web-based Human Gene Mutation Database Biobase and National Center for Biotechnology Information dbSNP. mut Indicates mutation; wt, wild type. The arrow signifies the proband; shaded squares (males) and circles (females), clinically affected by examination and history.

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