【作者】 朱军；

【导师】 焉传祝；

【作者基本信息】 山东大学 ， 神经病学， 2011， 硕士

【摘要】 研究背景：泛酸激酶相关的神经变性病(pantothenate kinase associated neurodegeneration, PKAN)/(Hallervorden-Spatz syndrome, HSS)是一种因编码泛酸激酶的PANK2基因突变而引起的临床以肌张力障碍、步态异常、震颤及舞蹈动作等锥体外系症状为主要特征的常染色体遗传的神经系统变性疾病,其与神经轴突营养不良(neuroaxonal dystrophy, NAD)、神经铁蛋白变性病(Neuroferritinopathy)及原血浆铜蓝蛋白缺乏症(Aceruloplasminaemia)的病理特点均为铁在大脑中的异常沉积,故这4种疾病被联合称为铁沉积性神经变性病(neurodegeneration with brain iron accumulation, NBIA)。本病的唯一致病基因为PANK2基因,于2001年被确定。颅脑磁共振成像(Magnetic resonance imaging, MRI)是临床诊断PKAN的重要辅助检查手段,确诊须经基因分析发现PANK2基因突变。目前尚未有治愈本病的方法,临床药物治疗主要以改善症状,延缓病程进展,提高患者生活质量为目的。本病病例罕见,发病率不详,迄今为止,国内外尚缺乏此疾病的流行病学资料。目的：分析2个来自同一家系的泛酸激酶相关的神经变性病患者的临床特征并对患者以及其父母进行PANK2基因的突变检测。对象与方法：收集2010年10月在齐鲁医院神经内科门诊就诊的同一家系内的以青少年起病、进行性加重的锥体外系症状为主的临床诊断为泛酸激酶相关的神经变性病的2例患者的临床资料,对其临床特征进行分析,包括突出的临床表现,实验室检查及影像学(颅脑MRI)的改变,并应用外周血DNA提取、聚合酶链反应(Polymerase Chain Reaction, PCR)、DNA直接测序技术检测2例患者及其父母的PANK2基因突变。结果：1.例1患者现41岁,女,于15岁起病,临床表现为进行性加重的步态不稳,双手静止性震颤,于40岁时出现显著的口咽肌、面肌肌张力障碍。例2患者现32岁,男,于8岁起病,表现为进行性加重的步态不稳、言语不清、右上肢震颤及智能减退。现两患者各自病程为26年和24年,但二者仍能独立行走及生活自理。2.例1患者血清铁为0.989ug/ml(参考值为1.11-1.91 ug/ml),两患者其他实验室检查如血清铁蛋白、血清铜、血清铜蓝蛋白、血常规及肝肾功均在正常范围。两患者的颅脑MRI上均有典型的“虎眼征”(eye of the tiger sign)表现。3.2例患者均检测出PANK2基因的一个新的复合杂合突变：位于第1内含子和第2外显子之间的剪切位点突变IVS1-2 A>T和第三外显子的错义突变c.258T→C,导致所编码的第86位的苯丙氨酸变为丝氨酸(Phe86Ser)。患者父母非近亲结婚,父亲为IVS1-2 A>T杂合突变,母亲为c.T258C杂合突变。结论：1.本研究中的2例患者的临床表现,包括突出症状、病程进展程度及颅脑MRI表现,符合以往国内外报道的非典型PKAN患者的临床特征,可临床诊断二者为非典型PKAN。2.两例患者的基因检测均发现有PANK2基因突变,为相同的复合杂合突变：位于第1内含子和第2外显子之间的剪切位点突变IVS1-2 A>T和第三外显子的错义突变c.258T→C。目前,国内外尚未见此突变导致PKAN的报道,故本研究报告的复合杂合突变可能为PKAN的新的致病突变。更多还原

【Abstract】 Background:Pantothenate kinase associated neurodegeneration(PKAN)/(Hallervorden-Spatz syndrome, HSS) is an autosomal recessive neurodegenerative disorder that is characterized by progressive extrapyramidal signs, such as dystonia, gait abnormalities, tremor, chorea and so on. PKAN is caused by mutations in the pantothenate kinase gene (PANK2). There are a common pathological characteristics in PKAN, neuronaxonal dystrophy(NAD), Neuroferritinopathy and Aceru oplasminaemia, that is high brain iron. So all of the four diaorders are called neurodegeneration with brain iron accumulation (NBIA). Neuroimaging technology (brian MRI) has been particularly useful in clinical diagnosis for PKAN, but a definite diagnosis should be made by identifying the mutation of PANK2 gene. There is currently no effective way to treat this disease. Pharmacologic and surgical interventions are aimed at palliation of symptoms, postponing progression and improvement of quality of life.The patients of PKAN are quite rare, so at present, there is still lack of incidence rate and epidemiological data all over the world.Objective:We sought to analyze the clinical features of two PKAN patients from a family, and investigation of the mutations in the PANK2 gene in the two patients and their parents. Object and Methods:We collected clinical data of two patients that came from the same family in October,2010 in neurological clinic of Qilu hospital, who were diagnosed PKAN based on the characteristics that were onset of adolescence, progressive predominantly extrapyramidal dysfunction. Clinical manifestations, laboratory examinations and brain MRI were analyzed, and then we analyzed the mutations in the PANK2 gene in the two patients and their parents by the method of genomic DNA extracting, PCR and DNA sequencing.Results:1.Case 1 patient is female,41 years old now, at the age of 17 years had clinical manifestations of progressive unsteady gait and resting tremor in both hands. She exhibited significant dystonia in oropharyngeal and facial muscles at the age of 40 years. Case 2 patient is male ,32 years old now, had the symptom of progressive unsteady gait ,barylalia, tremor in right upper limb and intellectual decline from 8 years old.Now the two patients have had a 26 years and 24 years disease-course respectively, but they can still walking independently and self-care.2.Serum iron level of case 1 patient was 0.989 ug/ml (reference for 1.11-1.91 ug/ml), the other laboratory tests such as serum ferrtin, serum copper, serum ceruloplasmin, blood routine, liver fuction and kidney fuction showed no abnormality.Both patients had typical performance of "eye of the tiger sign" on brain MRI.3.We identified the same compound heterozygous mutations (IVS1-2 A>T, C.T258C) in PANK2 gene of the two patients. Their parents were nonconsanguineous. The father was a heterozygote for IVS1-2 A>T mutation, and the mother was a heterozygote for C.T258C mutation.Conclusions:1.Clinical manifestations of the two patients, involving outstanding symdromes, rate of progression and performance of brain MRI, correspond with the characteristics of atypical PKAN reported previously, so the clinical diagnosis is atypical PKAN.2.At present, the compound heterozygous mutations (IVS1-2 A>T, C.T258C) which were found in this study have not been reported by others. So the compound heterozygous mutations could be a novel mutation resulting in PKAN.更多还原