Clinical Characteristics Analysis And Genetic Studies In A Familial Cortical Myoclonic Tremor With Epilepsy Family

BackgroundFamilial cortical myoclonic tremor with epilepsy(FCMTE) is a rare, autosomal dominant genetic disease, which presents cortical tremors, distal limb clonus and infrequent epileptic seizures, a non-progressive course and large somatosensory-evoked potentials(SEP). A few cases have been identified in adolescents. There is no significant correlation between FCMTE prevalence and subject gender. To date, more than 100 families with FCMTE have been reported worldwide. Japan and Italy have the most reported cases, with more than 60 found in Japan alone.However,the genetic causes and disease pathogenesis of FCMTE are still unclear.So far,FCMTE has been mapped to chromosomal locations 8q23.3-q24.1,2p11.1-q12.1, 5p15.31-p15.1, and 3q26.32-3q28, in Japanese, Italian, Thai, and French pedigrees respectively. Many neurologist grops conducted genetic study on some genes,such as DRPLA gene, ACMSD gene,CSMD3 gene. Pathogenic gene is still unclear.The mechanism of this disease, however, remains unclear. It has previously been suggested that FCMTE may be associated with ion channel defects.Others believe that dysfunction GABA-receptor signaling in the cerebellar-thalamo-cortical projection loop,leading to increased cortical excitability,may be responsible. The number of reported FCTME cases in China is apparently small. Study on the pathogenic gene and gene location is rare.AimIn this study,we had the Investigation of clinical characteristics and genetic features of the FCTME family.We aimed to establish the pathogenic gene loci in thisFamilial cortical myoclonic tremor with epilepsy(FCMTE) pedigree. This study helps us to investigate the pathogenesis and the disease genes. It show us how to adjust and intervent lifestyle and environmental factors in the risk population.It is helpful to guide the clinical treatment of the disease.MethodsAfter the family members signed the informed consent, clinical information was obtained on the Chinese family members. We invested the pedigrees members history, physical examination and auxiliary examination, clinical characteristics, at the same time drawed the pedigree analysis and summarized the characteristics of the genetic pedigree. Peripheral blood was obtained from FCMTE patients, suspected cases and control individuals. Our study performed linkage analysis across these loci to identify and further characterize the pathogenic gene locus underlying FCMTE in Chinese patients. Using polymerase chain reaction(PCR) and purification of PCR products for sequencing to detect the existence of mutations gene BASP1, gene SEMA5 A and gene CTNND2.The resulting product was subjected to agarose gel electrophoresis and a gel imaging system,then the PCR amplification products were sequenced.ResultsThe clinical features of affected individuals were consistent with FCMTE diagnotic standards: Disease incidence across three generations; adult onset with both genders affected; and autosomal dominant inheritance; Primary disease manifestations include distal limb tremors and seizures; some patients present with comprehensive tonic seizures after light stimulation, emotional stimuli or startle; Symptoms are non-progressive and effectively managed with oral phenobarbital; and Somatosensory evoked potentials support a cortical source for tremors. In our present study, we selected STR polymorphism markers from the 5 chromosomal segments reported athome and abroad, and performed linkage analysis. Multiple STR linkage analysis of 8q23.3-q24.1, 2p11.1-q12.2, 3q26.32-3q28, and 10p15 didn’t support linkage to these regions, indicating that the pathogenic gene contained in the pedigree we studied is not in these 4 chromosome segments. Linkage analysis of 5p15.31-p15 using 12 STRs shows potential linkage to D5S1957 and D5S2095, with θ=0.0, and LOD values of 2.16 and 1.34. In this paper, the LOD scores of 2.16 and 1.34 may be attributed to regional and ethnic differences. As these LODs were >1, the experimental results support the pedigree as containing a site of linkage, and suggest that the pathogenic gene is within the 5p15.31-p15 chromosome segment. In the study of pathogenic genes, gene BASP1 did not produce the corresponding product by PCR.We neither found any DNA sequence variation nor disease-related mutations in gene BASP1 and gene SEMA5 A.ConclusionGenetic analysis of a Chinese family provides further evidence for linkage of Familial Cortical Myoclonic Tremor with Epilepsy to 5p15.31-p15. No mutation was observed in gene SEMA5 A and gene CTNND2 at present in this pedigree. We need to further find the disease genes and the mutations of in this family.