Objective: To evaluate for the presence of ataxia and cerebellar atrophy in a cohort of Charcot-Marie-Tooth neuropathy type 4C (CMT4C) patients. Two of these patients were previously diagnosed with Friedreich ataxia.

Background: Establishing the etiology of hereditary ataxias is still challenging despite the use of mass sequencing. Ataxia can be a feature in complex syndromes such as hereditary spastic paraparesis and hereditary neuropathies. Charcot-Marie-Tooth neuropathies are a heterogeneous group of hereditary diseases that follow different patterns of inheritance. Ataxia can occur in some of the CMT neuropathies but has not been described for autosomal recessive Charcot-Marie-Tooth neuropathy type 4C (CMT4C).

Methods: We evaluated 6 unrelated CMT4C patients using standard motor scales and neurophysiological studies. Five of them went through neuroimaging and targeted gene panel analyses. In one case mass sequencing was applied.

Results: A Swedish 80-year-old woman who as a child was diagnosed with FA on clinical grounds was re-evaluated at our center. At pre-school age tip toe walking and general clumsiness were noticed. Slowly, she developed drop feet and impaired mobility. At age 60 she became confined to a wheel-chair. She also has scoliosis, restrictive pulmonary dysfunction, macular degeneration and hearing loss but no evidence of cardiomyopathy. Striking features upon examination are nystagmus, broken smooth pursuit, myokymias, dysarthria and dysmetria in the upper limbs. A severe axonal and demyelinating sensory-motor polyneuropathy was found on neurography. Neuroimaging revealed atrophy of the cerebellar hemispheres and the frontoparietal regions (Figure 1). Screening with MoCA yielded 26 points. FA and other ataxias associated with pathological nucleotide expansions were ruled out, as well as duplication/deletion in PMP-22. Mass sequencing revealed a homozygous R954X mutation in SH3TC2. The same mutation was found in the other 5 CMT4C patients (age range 32-80, all of European ancestry), none of them displayed cerebellar signs or atrophy. Another patient in this cohort was also diagnosed with FA during childhood.

Conclusions: This is the first time ataxia and cerebellar atrophy are described in CMT4C. Based on our findings we propose CMT4C as a differential diagnosis in autosomal recessive ataxia. The early stages of CMT4C can mimic FA, however, very slow progression, type of polyneuropathy and the presence of nystagmus differentiate FA and CMT4C. Since nystagmus is a cerebellar feature previously reported in two CMT4C cases, we raise the possibility that ataxia may have been overseen in those cases.

References: J. Senderek et al, AJHG, 73; 2003. J. Baets et al, Brain, 134, 2011. H Azzedine et al, Gene reviews, 2015.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ataxia-and-cerebellar-atrophy-in-charcot-marie-tooth-neuropathy-type-4c/