泛酸激酶相关性神经变性病的临床特征和分子机制

泛酸激酶相关性神经变性病( pantothenate kinase associated neurodegeneration,PKAN),又称脑内金属离子沉积性神经变性病1型,即通常所称的Hallervorden-Spatz综合征或苍白球黑质色素变性,是少见的常染色体隐性遗传性神经系统变性病.患病率(1～3)/100万.2001年Zhou等[1]报道了Hallervorden-Spatz综合征患者存在泛酸激酶2基因(pantothenate kinase 2 gene,PANK2)突变,提出了PKAN疾病命名,推动了金属离子沉积性神经变性病的研究进展.我们将PKAN的临床特征和分子机制综述如下.     

脑组织铁沉积性神经变性病遗传学研究进展

脑组织铁沉积性神经变性病是以脑组织铁代谢异常、中枢神经系统过量铁沉积为特征的神经变性病。常见临床症状为不同类型运动障碍,同时合并不同程度锥体束、小脑、周围神经系统、自主神经系统、精神认知和视觉障碍,具有高度临床异质性。目前共明确10种亚型的10种致病基因,分别为PANK2、COASY、PLA2G6、C19orf12、FA2H、WDR45、ATP13A2、FTL、CP、DCAF17。发病机制涉及线粒体功能障碍、氧化应激损伤、脂质代谢障碍、铁沉积和自噬障碍等。脑组织铁沉积性神经变性病可能与多种神经变性病如帕金森病、额颞叶痴呆、肌萎缩侧索硬化症等存在共同的发病机制。     

中英文对照名词词汇（二）

泛酸激酶2 panthothenate kinase2（PANK2） 泛酸激酶相关性神经变性疾病 pantothenate kinase—associated neurodegeneration（PKAN）     

伴周围神经损害的泛酸盐激酶相关神经变性病1例报告

正泛酸盐激酶(PANK)相关神经变性病过去也称Hallervorden-Spatz病、苍白球-黑质-红核色素变性。成人起病PANK2杂合基因突变的病例已有报道~[1],但伴有周围神经损害的病例临床少见,现报道1例如下。1病例男,45岁,因"行走不稳20年,肢体震颤伴有吞咽困难10年"于2015年12月30日入院。患者于入院前20年左右出现背重物时易向后跌倒,仍能进行日常生活,入院前     

血红素加氧酶-1在帕金森病以及阿尔茨海默病中所起的作用

在老化与神经变性疾病中引起铁沉积与线粒体破坏的机制尚不明确。血红素加氧酶-1(HO-1)属于应激蛋白超家族的一员,将血红素降解为铁离子、一氧化碳与胆绿素,以此在帕金森病以及阿尔茨海默病等神经变性疾病中发挥重要的作用。     

铁蛋白、线粒体铁蛋白与神经变性疾病的关系

正铁蛋白(Ft)是调控铁代谢的关键蛋白,是反映铁储量的临床标志,由重链(FTH)和轻链(FTL)组成,FTH含有亚铁氧化酶活性,FTL亚基主要携带铁离子~[1]。线粒体铁蛋白(FtMt)是与FTH高度同源的位于线粒体内的铁蛋白。近年来研究~[2]发现Ft和/或FtMt在神经变性疾病的病理机制中发挥着重要作用,为明确神经变性疾病与Ft和/或FtMt的关系,我     

Hallervorden-Spatz综合征的临床、磁共振成像特征及泛酸激酶2基因的突变检测

目的　研究中国人Hallervorden Spatz综合征的临床、磁共振成像 (MRI)特征与泛酸激酶 2(PANK2)基因的突变检测。方法　对 5例Hallervorden Spatz综合征患者的临床与脑MRI特征进行分析;应用聚合酶链反应(PCR)、DNA直接测序、聚合酶链反应 单链构象多态性和PCR产物酶切等技术检测 5例患者、3名家系成员及 51名健康人PANK2基因的碱基序列。结果　5例患者主要表现为锥体外系症状;头部MRIT2 加权像表现双侧苍白球、黑质等部位对称性低信号,其中 1例在苍白球低信号区的前内侧出现高信号,即“虎眼征”;检测出PANK2基因一个新的复合杂合突变:位于第三外显子 803位的A→G和第五外显子 1172位的T→A,导致所编码的氨基酸发生改变(分别为D268G和I391N)。结论　根据临床和头部MRI特征可临床诊断Hallervorden Spatz综合征,中国人Hallervorden Spatz综合征患者存在PANK2基因突变,具有PANK2基因突变的患者头部MRI表现有“虎眼征”。     

酪蛋白线粒体基质缩氨酸酶蛋白水解亚基与神经变性疾病关系的研究进展

酪蛋白线粒体基质缩氨酸酶蛋白水解亚基(ClpP)作为一种蛋白水解酶亚基,在人类细胞中,与ClpX结合成复合物ClpXP,并在线粒体异常情况下,与其它线粒体蛋白酶和线粒体分子伴侣代偿修复线粒体功能。而线粒体功能障碍是包括帕金森病、阿尔茨海默病和遗传性痉挛性截瘫在内的多种神经变性疾病的特点。ClpP基因突变和蛋白水平的变化在这些疾病中有重要作用。     

线粒体转录因子A与神经系统疾病关系的研究进展

线粒体转录因子A(TFAM)是由核基因编码的一种多功能的线粒体mtDNA蛋白,在线粒体拟核中与mtDNA结合,广泛参与mtDNA转录,复制和损失修复,维持线粒体的稳定。线粒体功能障碍是包括帕金森病、阿尔茨海默病在内的多种神经变性疾病的特点,TFAM基因突变和蛋白水平的变化在疾病中起重要作用本文总结了国内外学者针对TFAM及与其相关的神经系统疾病最新研究进展。     

泛酸激酶2相关的神经变性病的临床特点(附1例报告)

目的探讨泛酸激酶2相关的神经变性病(PKAN)的临床特征。方法回顾性分析1例PKAN患者的临床资料。结果本例患者的主要临床表现为肌张力障碍、智能减退、言语不清及腱反射亢进。影像学检查表现为头颅MRI T2加权像和磁敏感成像呈双侧苍白球对称性低信号,其前内侧出现高信号。本例患者泛酸激酶2(PANK2)基因纯合致病突变,为c.1069 CT(p.Arg357Trp)。结论 PKAN临床表现主要为锥体外系症状,但也可伴智能减退、言语障碍及锥体束征,头颅MRI典型表现为"虎眼征"。PANK2基因c.1069CT(p.Arg357Trp)可能为中国PKAN患者一个突变热点。     

Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.     

Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) and pantothenate kinase-associated neurodegeneration.

Hallervorden Spatz syndrome (HSS), also referred to as neurodegeneration with brain iron accumulation (NBIA), is a rare inherited neurodegenerative disorder with childhood, adolescent, or adult onset. Patients with HSS/NBIA have a combination of motor symptoms in the form of dystonia, parkinsonism, choreoathetosis, corticospinal tract involvement, optic atrophy, pigmentary retinopathy, and cognitive impairment. After the recent identification of mutations in the PANK2 gene on chromosome 20p12.3-p13 in some patients with the HSS/NBIA phenotype, the term pantothenate kinase-associated neurodegeneration (PKAN) has been proposed for this group of disorders. To characterize clinically and genetically HSS/NBIA, we reviewed 34 affected individuals from 10 different families, who satisfied the inclusion criteria for NBIA. Relatives of patients who had clinical, magnetic resonance imaging (MRI), or pathological findings of NBIA were included in the study. Four patients were found to have mutations in the pantothenate kinase 2 (PANK2) gene. We compared the clinical features and MRI findings of those with and without PANK2 mutations. The presence of mutation in the PANK2 gene is associated with younger age at onset and a higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbance. Parkinsonism is seen predominantly in adult-onset patients whereas dystonia seems more frequent in the earlier-onset cases. The phenotypic heterogeneity observed in our patients supports the notion of genetic heterogeneity in the HSS/NBIA syndrome.     

Pantothenate kinase‐associated neurodegeneration is not a synucleinopathy

A. Li, R. Paudel, R. Johnson, R. Courtney, A. J. Lees, J. L. Holton, J. Hardy, T. Revesz and H. Houlden (2013) Neuropathology and Applied Neurobiology 39, 121–131 Pantothenate kinase‐associated neurodegeneration is not a synucleinopathy Aims: Mutations in the pantothenate kinase 2 gene (PANK2) are responsible for the most common type of neurodegeneration with brain iron accumulation (NBIA), known as pantothenate kinase‐associated neurodegeneration (PKAN). Historically, NBIA is considered a synucleinopathy with numerous reports of NBIA cases with Lewy bodies and Lewy neurites and some cases reporting additional abnormal tau accumulation. However, clinicopathological correlations in genetically proven PKAN cases are rare. We describe the clinical, genetic and neuropathological features of three unrelated PKAN cases. Methods: All three cases were genetically screened for the PANK2 gene mutations using standard Sanger polymerase chain reaction sequencing. A detailed neuropathological assessment of the three cases was performed using histochemical and immunohistochemical preparations. Results: All cases had classical axonal swellings and Perls' positive iron deposition in the basal ganglia. In contrast to neuroaxonal dystrophies due to mutation of the phospholipase A2, group VI (PLA2G6) gene, in which Lewy body pathology is widespread, no α‐synuclein accumulation was detected in any of our PKAN cases. In one case (20‐year‐old male) there was significant tau pathology comprising neurofibrillary tangles and neuropil threads, with very subtle tau pathology in another case. Conclusions: These findings indicate that PKAN is not a synucleinopathy and, hence the cellular pathways implicated in this disease are unlikely to be relevant for the pathomechanism of Lewy body disorders.     

The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.     

Childhood disorders of neurodegeneration with brain iron accumulation (NBIA)

Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive complex motor disorders characterized by the presence of high brain iron, particularly within the basal ganglia. A number of autosomal recessive NBIA syndromes can present in childhood, most commonly pantothenate kinase-associated neurodegeneration (PKAN; due to mutations in the PANK2 gene) and phospholipase A2 group 6-associated neurodegeneration (PLAN; associated with genetic defects in PLA2G6). Mutations in the genes that cause these two neuroaxonal dystrophies are thought to disrupt the normal cellular functions of phospholipid remodelling and fatty acid metabolism. A significant proportion of children with an NBIA phenotype have no genetic diagnosis and there are, no doubt, additional as yet undiscovered genes that account for a number of these cases. NBIA disorders can be diagnostically challenging as there is often phenotypic overlap between the different disease entities. This review aims to define the clinical, radiological, and genetic features of such disorders, providing the clinician with a stepwise approach to appropriate neurological and genetic investigation, as well as a clinical management strategy for these neurodegenerative syndromes.     

Atypical pantothenate kinase-associated neurodegeneration with PANK2 mutations : clinical description and a review of the literature

ABSTRACT

Panthothenate kinase-associated neurodegeneration (PKAN) is arare neurodegeneration caused by mutations in the pantothenate kinase (PANK2) gene, which is located on chromosome 20p13. These mutations result in iron accumulation in the brain basal ganglia leading to parkinsonism, dysarthria, spasticity, cognitive impairment, and retinopathy. Herein, we report acase of adult-onset PKAN who presented with young-onset action tremor, bradykinesia, dysarthria, and bilateral interossei atrophy. Neuroimaging demonstrated “eye-of-the-tiger signs”. Through analyzing PANK2 gene, PANK2 NM_153638:c.1133A>G (p.Asp378 Gly) and PANK2 NM_153638:c.1502 T > A (p.lle501Asn), were detected. In addition, we reviewed the clinical and genetic features and therapeutic strategies for patients with PKAN.     

Indian‐subcontinent NBIA: Unusual phenotypes,novel PANK2 mutations,and undetermined genetic forms

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase‐associated neurodegeneration (PKAN)] and 2 (PLA2G6‐associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian‐subcontinent NBIA cases are limited. We report 6 patients from the Indian‐subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA‐associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype–genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent‐onset cases. One of the four had a late‐onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye‐of‐the‐tiger sign only 10 years after onset. Two of the six presented with adult‐onset levodopa (L ‐dopa)‐responsive asymmetric re‐emergent rest tremor, developing L ‐dopa‐induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye‐of‐the‐tiger sign on MRI but were negative for known NBIA‐associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD‐like presentation. © 2010 Movement Disorder Society     

Precision medicine in pantothenate kinase-associated neurodegeneration

Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas,mainly the basal ganglia.The predominant clinical symptoms include spasticity,progressive dystonia,Parkinson's disease-like symptoms,neuropsychiatric alterations,and retinal degeneration.Among the neurodegeneration with brain iron accumulation disorders,the most frequent subtype is pantothenate kinase-associated neurodegeneration(PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2(PANK2)which catalyzed the first reaction of the coenzyme A biosynthesis pathway.Currently there is no effective treatment to prevent the inexorable course of these disorders.The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN.Recently,we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules,mitochondrial dysfunction and a pronounced increase of markers of oxidative stress.In addition,PKAN fibroblasts showed a morphological senescence-like phenotype.Interestingly,pantothenate supplementation,the substrate of the PANK2 enzyme,corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression.However,pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein.The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts.Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations.Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment.The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate.The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available,and monitoring its effect on the pathophysiological changes,can help for a better therapeutic strategy.In addition,these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.     

Genetic heterogeneity in patients with pantothenate kinase-associated neurodegeneration and classic magnetic resonance imaging eye-of-the-tiger pattern.

We performed a detailed molecular study in two unrelated families with pantothenate kinase-associated neurodegeneration (PKAN) and the specific magnetic resonance imaging (MRI) eye-of-the-tiger pattern. In the first family with classic PKAN, linkage analysis using polymorphic markers from the PANK2 region ruled out linkage with this locus, and no mutation of the PANK2 gene was found. In the second family with atypical PKAN, we identified a novel homozygous C-to-T transition at nucleotide 1069 of the PANK2 gene, which resulted in an arginine to tryptophane substitution at codon 357. As far as we are aware, this is the first case of classic PKAN with the specific MRI eye-of-the-tiger pattern not carrying a PANK2 mutation. Therefore, the present observation reinforces the notion of the phenotypic and genetic heterogeneity in PKAN.     

Novel PANK2 gene mutations in two Chinese siblings with atypical pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive disorder characterized by neurodegeneration and iron accumulation in the brain. Classic and atypical PKAN are distinguished on the basis of age at onset and disease progression. PANK2, localized on chromosome20p13, is confirmed as the responsible gene. We report two Chinese siblings with atypical PKAN, who had a 26- and 24-year disease course, respectively. Brain MRI scans of the two siblings showed the specific “eye of the tiger” sign. Genetic analysis identified novel compound heterozygous mutations (IVS1-2 A>T, c.T1130C) in PANK2 gene, which were confirmed to be deleterious. We verify the clinical heterogeneity even in siblings with identical genotype and expand the gene mutation pool for PKAN.