The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C

Abstract

Background: Friedreich ataxia (FRDA) is the most common familial ataxia syndrome in Central and Southern Europe but rare in Scandinavia. Biallelic mutations in SH3 domain and tetratricopeptide repeats 2 (SH3TC2) cause Charcot-Marie-Tooth disease type 4C (CMT4C), one of the most common autosomal recessive polyneuropathies associated with early onset, slow disease progression and scoliosis. Beyond nystagmus reported in some patients, neither ataxia nor cerebellar atrophy has been documented as part of the CMT4C phenotype.

Methods: Here we describe a single centre CMT4C cohort. All patients underwent a comprehensive characterization that included physical examination, neurophysiological studies, neuroimaging and genetic testing. In a patient with cerebellar features, an evaluation of the vestibular system was performed.

Results: All five patients in this cohort harbored the R954X mutation in SH3TC2 suggesting a founder effect. Two patients had been diagnosed as FRDA. One of them, an 80-year-old woman had onset of unsteadiness during childhood leading to gradual loss of mobility. She also had scoliosis and hearing loss. On examination she had generalized muscle atrophy, leg flaccidity, pes cavus, facial myokymia, limb dysmetria, dysarthria and gaze-evoked nystagmus. She exhibited bilateral vestibular areflexia. Neuroimaging demonstrated atrophy in the frontoparietal regions and cerebellar hemispheres.

Conclusions: CMTC4A may present with a cerebellar phenotype and mimic a flaccid-ataxic form of FRDA. Absence of cardiomyopathy or endocrine abnormalities and lack of pathological dentate iron accumulation in CMT4C distinguish it from FRDA.

Keywords: Ataxia; Charcot-Marie-tooth neuropathy type 4C; Friedreich-like ataxia; SH3TC2; VEMP; vHIT.

Fig. 1

Coronal T1-weighted (a), mid-sagittal T2-weighted (b) of patient 5 at age 76. Note atrophy in the bi-parietal brain regions (thick arrows) as well as lateral hemispheres and superior vermis of the cerebellum (notched arrows)

Fig. 2

Calorigram for the right irrigations (on the top) and left irrigations (on the bottom). The two overlapping traces for each side correspond to the videooculography recording after cold and warm irrigation, in terms of instantaneous eye angular velocity: ⁰ (Y-axis) over time in seconds (X-axis). The two traces for each side configure an irregular eye motility in darkness in the absence of a consistent caloric nystagmus pattern. This pattern is typical for bilateral vestibular failure

Fig. 3

cVEMP evoked by submaximal air conducted 500 Hz tone bursts, delivered at the right ear (left panel) and left ear (right panel). Responses recorded at the ipsilateral sternocleidomastoideus muscle under controlled contraction. The two traces per side represent the averaged response of 120 sweeps. The classical positive-negative EMG deflection within 12–25 ms after stimuli is not identifiable on either a side with responses configuring EMG noise only

Fig. 4

Summary of findings on vHIT. Test conducted with the system Synapsis vHIT Ulmer 2. The canalogram at the center shows a general VOR gain depression for all the tested canals bilaterally. Selected responses (corresponding to the larger spots on the canalogram) are shown in panels, with the eye position (dotted lines) traced in contrast with the head position (green lines) over time (ms). VOR gains are given for the specific trials on the top of the panels