Alpers综合征的临床与病理特点及基因突变分析

Clinical and Pathological Features of Alpers Syndrome and Gene Mutational Analysis

目的探讨难治性癫患儿的病因及Alpers综合征的特点。方法对1例Alpers综合征患儿进行临床观察,神经电生理、神经影像学检查,脑脊液检查,外周神经、肌肉及脑组织活检,线粒体DNA、脱氧鸟苷激酶基因与多聚酶γ1(POLG1)基因突变分析。结果Alpers综合征患儿的临床特征为难治性癫,应用丙戊酸钠后发生急性肝衰竭、皮质盲和精神运动倒退。脑脊液蛋白与免疫指标增高。脑电图示背景节律性慢波化及双侧枕区棘慢波、快波及θ节律发放。颅脑MRI示半卵圆中心、小脑白质及枕叶皮层病变,后期有弥散性脑萎缩。腓肠肌病理活检无异常,腓肠神经病理示有髓神经纤维减少伴轴索和髓鞘病变,以轴索病变为主。左枕叶病理活检示皮层胶质细胞增生,神经元丢失,海绵样变性,白质部分脱髓鞘改变、胶质增生和空泡变性。线粒体DNA、脱氧鸟苷激酶基因未发现突变。POLG1基因发现一对新的复合杂合突变c.248T>C(p.L83P)和c.2662G>A(p.G888S),其父携带L83P突变,其母携带G888S突变。结论该例患儿临床、电生理、病理及POLG1基因突变与Alpers综合征高度一致,其突出的白质病变与脑脊液免疫指标异常为首次报道。对于应用丙戊酸钠后出现严重肝功能异常的难治性癫患儿应高度怀疑Alpers综合征。

Objective To explore the pathogenic cause of child with intractable epilepsy and the characteristic of Alpers syndrome. Methods The clinical manifestation of 1 case was observed,and eleetromyogram, video -electroencephalogram, magnetic resonance imaging lumbar puncture and biopsies of muscle, peripheral nerve and brain were performed. Gene mutational analysis of mtDNA, deoxyguanosine kinase and polymerase gamma 1 （POLG1） were conducted. Results The clinical manifestation of the patient included refractory seizures, acute liver failure after exposure to valproie acid, cortical blindness and psychomotor regression. The cerebrospinal fluid （CSF） was acellular but the protein concentration increased. The immunological studies of CSF showed that oligo - clone bands were positive, IgG synthesis rate and IgG index increased. Series of electroencephalogram showed slow activity and almost continuous spike wave over the central, parietal and occipital regions of both hemispheres. The brain MRI showed flair signals in hemioval central white matter, cerebellar white matter and occipital region. Diffused brain atrophy was revealed later. Gastrocnemius muscle biopsy was unremarkable. Sural nerve biopsy showed damaged axon and myelin. Left occipital lobe biopsy showed astrocytosis, neuronal loss and sponginess in the cortex and partial demyelination, gliosis, and vacuolization in white matter screening of mtDNA common mutations and coding exons of dexyguanosine kinase gene were negative. Two novel heterozygous missense variants, e. 248T 〉 C （ p. L83P） , e. 2662G 〉 A （p. G888S） were detected in POLG1 gene. Sequence analysis of parental blood DNA revealed that her father carried L83P and her mother carried G888S. Conclusions The characteristics of clinical manifestation, electrophysiology, pathology and POLGl gone mutation of the patient were highly consistent with Alpers syndrome. The prominent white matter change and increased immunological factors in CSF were first reported in Alpers syndrome. Alpers syndrome should be considered for those patients whose liver function were severely impaired after exposure to valproic acid.