Pontocerebellar hypoplasia type 1 Clinical spectrum and relevance of EXOSC3 mutations
Pontocerebellar hypoplasia type 1 Clinical spectrum and relevance of EXOSC3 mutations
复制标题
DOI：
10.1212/wnl.0b013e31827f0f66
复制
发表时间：
2013-01-01
期刊：
影响因子：
9.9
通讯作者：
Zerres, Klaus
中科院分区：
文献类型：
--
作者：
Rudnik-Schoeneborn, Sabine;Senderek, Jan;Zerres, Klaus
目的：桥小脑发育不全伴脊髓性肌萎缩症，又称PCH1，是一组常染色体隐性遗传病，以全身性肌肉无力和全身性发育迟缓为特征，常导致早期死亡。基因缺陷只在单个患者中被发现，直到最近在几个PCH1病程相对较轻的家系中发现了EXOSC3突变。我们的目标是在一个大的和明确的队列中对受试者进行基因分层，以确定临床谱和基因-表型相关性。方法：我们记录了来自27个PCH1家系的37名受试者的临床、神经影像和形态学数据。结果：27个家系中有10个(37%)检测到EXOSC3双等位基因突变。所有种族中最常见的突变是C.395A>；C，p.D132a，占20个突变等位基因中的11个(55%)，起源于祖先。突变阳性的受试者通常表现为正常妊娠，正常的出生尺寸，以及脑干和皮质结构的相对保存。精神运动发育迟缓在所有患者中都很严重，但寿命各不相同，有3名受试者活过了十几岁。在存活超过一年的患者中，通常观察到眼球运动功能异常。以前报道的PCH1的主要临床特征，包括宫内异常、出生后呼吸不足和喂养困难、关节痉挛和新生儿死亡，在突变阳性的婴儿中很少被观察到，但在突变阴性的受试者中是典型的。结论：在PCH1患者中，EXOSC3突变占30%-40%，其生存和临床严重程度与基因相关。神经病学(R)2013；80：438-446
Objectives: Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype-phenotype correlation.Methods: We documented clinical, neuroimaging, and morphologic data of 37 subjects from 27 families with PCH1. EXOSC3 gene sequencing was performed in 27 unrelated index patients of mixed ethnicity.Results: Biallelic mutations in EXOSC3 were detected in 10 of 27 families (37%). The most common mutation among all ethnic groups was c.395A>C, p.D132A, responsible for 11 (55%) of the 20 mutated alleles and ancestral in origin. The mutation-positive subjects typically presented with normal pregnancy, normal birth measurements, and relative preservation of brainstem and cortical structures. Psychomotor retardation was profound in all patients but lifespan was variable, with 3 subjects surviving beyond the late teens. Abnormal oculomotor function was commonly observed in patients surviving beyond the first year. Major clinical features previously reported in PCH1, including intrauterine abnormalities, postnatal hypoventilation and feeding difficulties, joint contractures, and neonatal death, were rarely observed inmutation-positive infants but were typical among themutation-negative subjects.Conclusion: EXOSC3 mutations account for 30%-40% of patients with PCH1 with variability in survival and clinical severity that is correlated with the genotype. Neurology (R) 2013;80:438-446