Large kindred evaluation of mitofusin 2 novel mutation, extremes of neurologic presentations, and preserved nerve mitochondria

Christopher Jon Klein, Grace W. Kimmel, Sean J Pittock, JaNean E. Engelstad, Julie M Cunningham, Yanhong Wu, Peter J Dyck

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 thenerve 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.

Original languageEnglish (US)
Pages (from-to)1295-1302
Number of pages8
JournalArchives of Neurology
Volume68
Issue number10
DOIs
StatePublished - Oct 2011

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Nervous System
Mitochondria
Optic Atrophy
Mutation
Phenotype
Multiple Sclerosis
Tooth
Magnetic Resonance Imaging
Mitochondrial Dynamics
Biopsy
Early Ambulation
Sural Nerve
North American Indians
GTP Phosphohydrolases
Mitochondrial Proteins
Genetic Counseling
Brain
Mitochondrial Membranes
Nerve Fibers
Age of Onset

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Large kindred evaluation of mitofusin 2 novel mutation, extremes of neurologic presentations, and preserved nerve mitochondria. / Klein, Christopher Jon; Kimmel, Grace W.; Pittock, Sean J; Engelstad, JaNean E.; Cunningham, Julie M; Wu, Yanhong; Dyck, Peter J.

In: Archives of Neurology, Vol. 68, No. 10, 10.2011, p. 1295-1302.

Research output: Contribution to journalArticle

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AB - 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 thenerve 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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