TTTCA repeat expansion causes familial cortical myoclonic tremor with epilepsy.

BACKGROUND AND PURPOSE: The aim was to investigate whether abnormal TTTTA and TTTCA repeat expansions in introns of SAMD12, TNRC6A and RAPGEF2 are involved in the pathogenesis of familial cortical myoclonic tremor with epilepsy (FCMTE).

METHODS: Five families diagnosed with FCMTE were included in the current genetic analysis. Whole-exome sequencing was performed in selected patients of each family. TTTTA and TTTCA expansions were examined by repeat-primed polymerase chain reaction. The clinical features of FCMTE were elicited as defined by the common genetic mechanism of 14 patients.

RESULTS: Abnormal TTTCA expansion was identified and co-segregated in all five FCMTE families, four inserted in SAMD12 and one in RAPGEF2. The insertion of expanded TTTCA was not found in 116 control alleles. TTTTA expansion in SAMD12 was detected in 90.9% (10/11) of patients or mutation carriers; TTTTA expansion in RAPGEF2 was not found. The onset age of myoclonic tremor was 27.4 ± 5.9 (19-37) and epilepsy usually presented around age 34. Focal and generalized seizures were witnessed with various origins recorded by electroencephalogram. Cognitive deficits were not common within the first 3 years after epilepsy onset. Emotional instability was reported by most patients. No patients showed any cerebellar deficits. Valproate added with clonazepam is effective in controlling seizures but cannot guarantee a complete remission of tremor. Repeat length showed intergenerational instability and was inversely correlated with age at onset of myoclonic tremor and epilepsy.

CONCLUSIONS: TTTCA expansion insertion is associated with FCMTE in Chinese families. The homogenous genetic mechanism allowed for a higher precision of FCMTE description.