Research and treatment of hereditary neuropathy

Charcot-Marie-Tooth病(CMT)是一种最常见的遗传性神经病，是一种遗传异质性疾病。许多致病基因已经被确定，然而，在许多日本患者中还没有发现致病突变。为此，我们建立了变性高效液相色谱(DHPLC)和多重连接依赖的探针扩增(MLPA)方法来筛选主要致病基因。我们研究了许多无CMT1A重复的日本患者，用DHPLC方法检测到脱髓鞘CMT中MPZ突变15例，GJB1突变18例，PMP22突变6例，EGR2突变1例，Prx突变4例。对于轴突CMT，DHPLC筛查发现MPZ突变3例，GJB1突变2例，Mfn2突变10例。此外，DHPLC筛查发现2例远端遗传性运动神经病HSP27突变。除CMT1A(PMP22)重复外，MLPA筛查未检测到基因拷贝数的变化。9例发现CMT1A重复，其中3例经Southern印迹杂交或FISH方法未发现。我们的研究证实，除PMP22外，基因拷贝数的改变不是CMT的原因，MLPA对检测CMT1A重复比Southern杂交或FISH方法更敏感。

Charcot-Marie-Tooth disease (CMT) is a most common hereditary neuropathy and is a genetically heterogeneous disease. Many responsible genes have been identified, however, disease-causing mutations had not been identified in many Japanese patients. So we established denaturing high performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) methods for screening of major disease-causing genes. We studied many Japanese patients with no CMT1A duplication and detected 15 cases with MPZ mutations, 18 cases with GJB1 mutations, 6 cases with PMP22, 1 case with EGR2 mutations and 4 cases with PRX mutations in demyelinating CMT using DHPLC method. As for axonal CMT, DHPLC screening detected 3 cases with MPZ mutations, 2 cases with GJB1 mutations and 10 cases with MFN2 mutations. In addition, DHPLC screening detected 2 cases with HSP27 mutations in distal hereditary motor neuropathy. MLPA screening did not detect a change in gene copy numbers except for CMT1A (PMP22) duplication. Nine cases were found to have CMT1A duplications and 3 of them had not been found by Southern blot hybridization or FISH methods. Our study confirmed that a change in gene copy numbers except for PMP22 is not a cause of CMT and MLPA is more sensitive to detect CMT1A duplication than Southern blot hybridization or FISH methods.