Fronto-striatal dysfunction in type 3 familial cortical myoclonic tremor epilepsy occurring during aging

Abstract

The aim of this work is to study the cognition, progressive gait impairment, and neuroimaging findings in two patients over 65 years old of the previously described type 3 familial cortical myoclonic tremor with epilepsy (FCMTE3). We report investigations in two of these five FCMTE3 subjects over 65 and showing progressive gait disorders. They both had a pseudo-Parkinson's way of walking and visual intolerance to bright light and brightness contrast without EEG abnormalities exacerbating cortical myoclonus or triggering seizure. Case 1 had moderate gait impairment and a severe frontal syndrome. Case 2 had severe gait impairment and diffuse cognitive disorders. Both cases had cortical hypoperfusion (predominantly in the left frontal lobe) and no cerebellar abnormality on cerebral perfusion SPECT. DAT-SPECT showed dopaminergic depletion. These data indicate fronto-striatal dysfunction associated with gait impairment and cognitive disorders appearing after several decades of disease progression. This gives clues to understanding the pathogenesis and evolution of FCMTE3. Permanent myoclonic discharges or long-term valproate treatment may cause significant toxic effects on neurons (dopaminergic and frontal neurons). Further functional and molecular analyses are required in order to better understand this pathology and the consequences of chronic cortical myoclonus.

The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism

“…In one individual the epilepsy disappeared in the adulthood. As the family described by Magnin and colleagues [25], one of our patient (II-3) also had gait disturbances, cognitive impairment, and photosensitivity that appeared during the disease progression and under treatment with valproate. The anomaly seen in the brain MRI of this patient (Figure 1D) that may explain her variable phenotype has never been described in previously reported FCMTE families [26].…”

Logopenic syndrome and corticobasal dysfunction in a “benign” type 3 familial cortical myoclonic tremor with epilepsy

“…These abnormalities were initially considered to be consequences of chronic myoclonus. However, a primitive etiological mechanism of FCMTE is not excluded [2]. In our patient and the two cases previously described, the predominantly left-sided dysfunction suggests a lateralized tropism of FCMTE3.…”

“…In addition to frontal lobe dysfunction previously described, a left posterior cortical dysfunction was also observed and can explain the logopenic syndrome [3]. Occipitoparietal and basal abnormalities can participate in the visual intolerance to the light and contrast as well [2].…”

“…Actually, no mutation has been found and the biological mechanism involved in FCMTE3 remains unclear. Fronto-striatal dysfunction, gait impairment and cognitive disorders appearing after several decades of disease progression were reported in FCMTE3 [2].…”

“…A progressive switch from VPA to levetiracetam was proposed. However, he declined because the decrease in VPA had led to a severe increase in his father's myoclonus (III-10) [2].…”