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Título

Late-onset Charcot-Marie-Tooth disease with leukoencephalopathy due to MFN2 gene variant

RESUMO

Case Presentation: A 73-year-old Austrian man presented with a long-standing clinical course of 20 years of slowly progressive unsteady gait, imbalance, tingling in the legs and hands, and complained about difficulty in speech and hand tremors for 5 years and the need of unilateral support for ambulation for 2 years. Medical history disclosed: bilateral cataracts and glaucoma surgery; chronic migraine with aura; left sinusectomy at age 35; chronic allergic rhinitis; three episodes of motor aphasia lasting about 30 minutes; generalized tonic-clonic seizures at 46 and 56 years; progressive hearing loss since age 58 years; chronic diarrhea; moderate hepatic steatosis. Family history was unremarkable. Examination disclosed diffuse palatal tremor, thoracic hyperkyphotic posture, slight saccades decomposition at horizontal and conjugate gaze, reduced deep tendon reflexes, flaccid quadriparesis (predominantly distal); hypopalesthesia, painful hypoesthesia, and distal-proximal thermal gradient in the lower limbs. Electroneuromyography disclosed signs of severe axonal sensorimotor polyneuropathy, predominantly sensory, distal. Brain MR imaging disclosed diffuse leukoencephalopathy. Muscle biopsy showed chronic nonspecific neurogenic amyotrophy (10% of COX-negative muscle fibers). Cerebrospinal fluid analysis was unremarkable. Audiometry showed moderate bilateral sensorineural hearing loss. Genetic testing for Fabry’s disease was negative. NGS-based multigene panel for neuropathies disclosed the definitely pathogenic missense variant c.2119C>T (p.Arg707Trp) in single heterozygosity in the MFN2 gene.
Discussion: MFN2 (mitofusin 2) gene (1p36.22) is associated with mediating mitochondrial fusion and fission. MFN2 variants are the most common cause of axonal CMT, generally presenting with optic atrophy, hearing loss, vocal cord paralysis, severe early-onset axonal neuropathy (SEOAN) and even spasticity. Most cases have onset during the infancy, childhood, adolescence, or early adulthood, however our patient presented with late-onset compromise, as well as with palatal tremor, kyphosis, seizures, and leukoencephalopathy, which are not the most typical signs associated with MFN2 pathogenic variants.
Final comments: Genetic screening for MFN2 variants in late-onset neuropathies with complex clinical pictures is important in the diagnostic work-up, including cases with marked leukoencephalopathy.

Palavras Chave

Charcot-Marie-Tooth; MFN2 gen; leukoencephalopathy; CMT