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Mutations in the MFN2 gene, encoding mitofusin2, cause autosomal dominant axonal Charcot-Marie-Tooth type 2 (CMT2A, MIM: 608507).1 MFN2 mutations are also found in CMT2 subjects with optic atrophy2 or cognitive impairment.3 The sibship we studied comprised 3 affected and 3 apparently healthy individuals (figure e-1 on the Neurology® Web site at www.neurology.org).
Standard protocol approvals, registrations, and patient consents.
The study was approved by the institutional ethics committee. Written informed consent was obtained from all participants in the study.
Clinical cases and results.
For more information, see e-Methods. A 48-year-old woman presented with a 10-year history of progressive leg weakness, foot drop, hypotrophy, areflexia, intact sensation, and cognition. Neurophysiology (table e-1) revealed a severe axonal polyneuropathy. The sural nerve biopsy (figure e-2, A and B) showed reduced fiber densities, loss of large myelinated fibers, and marginal Wallerian degeneration. Teased fibers were thin, with shortened internodes, some ongoing remyelination, and no demyelination. She was wheelchair-bound within 1 year. At age 50, after colectomy, she developed a progressive brainstem syndrome with vomiting, nystagmus, chorea, clouded consciousness, and dysautonomia (hyperthermia, breathing irregularities). MRI showed diffuse T2 hyperintensities in the upper brainstem and periaqueductal gray (figure 1A). Blood and CSF examinations were unremarkable. The patient progressively worsened in spite of aggressive management, including thiamine supplementation, and died 7 days later. Brain pathology revealed symmetric vasculonecrotic lesions in the brainstem and the periaqueductal gray with small hemorrhagic component (figure e-2, C and D).
Figure 1 Neuroimaging and molecular data of index case
(A) Fluid-attenuated inversion recovery axial (a) and coronal (b) images of case II-7 2 days after onset of the encephalopathic symptoms. Symmetric high signal intensity alterations surround the aqueduct, involve the medial thalami, the mammillary bodies, and the tegmental area. (B) Sequence of the wild-type (WT) and mutated (Mut) MFN2 …
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