Histopathologic Features and Molecular Genetics of Charcot-Marie-Tooth Patients of Korean Origin

Abstract

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group. By virtue of rapid advances of molecular genetics, a wide number of genes associated with CMT and related neuropathies have been identified. However, the exact function of many genes and the underlying pathogenic mechanism has not been established so far. The objective of this study is to analyze the histopathologic features of 27 Korean CMT patients and investigate a correlation between phenotypic and pathologic features. Nerve conduction studies were performed following the standard methods. To identify their causative mutations, their blood samples were prescreened for 17p12 duplication and sequencing was determined for major genes including MPZ, GJB1 and MFN2. Whole exome sequencing was performed for functionally significant variants and rare mutations. For histopathological studies, the distal sural nerve of them was biopsied. This study enrolled 27 unrelated patients with various types of CMT neuropathy. A total of 17 responsible genes were found. They were classified into CMT1 (11 cases), CMT2 (13 cases) and intermediate (3 cases) groups, based on their phenotype. Categorized by the histopathologic charactistics, 6 cases with PMP22 point mutation, SBF1 or PRX mutations were included in a group with demyelinating histopathology, 12 cases with OPA1, TFG, GARS, PLEKHG5, HSPB8, TUBB3, DGAT2 or MPV17 mutations in a group of axonal histopathology and 9 cases with MFN2, GDAP1, GJB1, HADHB, BSCL2 or MPZ mutations in a group with axonal and demyelinating histopathology. In view of the correlation between phenotypic and histopathological findings, the two characteristics of phenotype and histopathology matched in only 63% patients. This study shows that the phenotype of CMT neuropathy does not necessarily concur with the histopathological characteristics. This discrepancy might result from the location and function of causative genes, as well as clinical and genetic heterogeneity of CMT neuropathy. In-depth research into the molecular function and localization of CMT-relevant genes could contribute to advancing our understanding of underlying pathogenic mechanism of CMT neuropathies.;샤르코-마리-투스병(이하 CMT)은 임상적으로, 유전학적으로 매우 다양한 질환군이다. 분자유전학의 빠른 발전으로 CMT병과 관련된 많은 유전자들이 발견되고 있다. 그러나, 그 중 많은 유전자들의 정확한 기능과 병리적 기전은 아직까지 밝혀지지 않았다. 이 논문의 목적은 27명의 CMT병 환자들의 조직병리학적 특징을 분석하고 표현형의 특징과 병리학적 특징 간의 연관성을 밝히고자 함이다. 총 27명의 CMT병 환자들을 대상으로 연구를 진행하였다. 조직병리학적 특징으로 분류하였을 때, PMP22의 점돌연변이, SBF1 또는 PRX 돌연변이가 확인된 6 증례가 탈수초군에 속하였고, OPA1, TFG, GARS, PLEKHG5, HSPB8, TUBB3, DGAT2, MPV17 돌연변이가 확인된 9 증례는 축삭군에 속하였다. 그 외 MFN2, GDAP1, GJB1, HADHB, BSCL2, MPZ 돌연변이가 확인된 8 증례는 혼합형 병리학적 특징을 보였다. 표현형과 조직병리학적 소견의 연관성을 고려할 때, 63%의 증례에서만 표현형과 조직병리학적 특징이 상응되는 것이 확인되었다. 이 연구 결과는 CMT병의 표현형과 조직병리학적 특징이 항상 일치하지 않는다는 것을 보여주었다. 이러한 불일치는 CMT의 임상적, 유전학적 다양성에 의해서뿐 아니라, 원인이 되는 유전자의 위치 및 기능에 의해서 영향을 받기 때문일 것이다. 그러므로, CMT병에 관련된 유전자의 분자학적 기능과 위치에 대한 심도 깊은 연구를 통해 이러한 표현형-조직병리학적 연관성의 이해를 넓힐 수 있을 것으로 생각한다.