家族性脑动脉瘤研究进展

家族性脑动脉瘤具有不同的临床特征和生物学特征,病因及发病机制尚不清楚,环境和遗传因素可能发挥着主要作用,导致动脉壁的薄弱及遗传缺陷,目前基因水平的研究已发现一些可能与之相关的基因。因其家族聚集性高且动脉瘤破裂后预后差,对无症状亲属可以进行筛选以便治疗。     

原发性家族性脑钙化研究进展

原发性家族性脑钙化是一组以双侧对称性基底节区及其他脑区钙化为影像学特点的神经变性病,可伴多种神经精神症状,具有高度临床和遗传异质性。目前已知的4种致病基因(SLC20A2、PDGFRB、PDGFB、XPR1)及其相关功能研究提示原发性家族性脑钙化可能与细胞内外无机磷转运障碍和血-脑屏障损害相关。本文拟对近年原发性家族性脑钙化诊断标准、分子遗传学机制、基因型与临床表型相关性、治疗等方面研究进展进行概述。     

家族性特发性基底节钙化研究进展

两侧对称性大脑基底节钙化可由病理、生理多种原因造成,可伴有(无)神经病学和精神病学异常,是一种临床综合征。其中特发性两侧对称性基底节钙化由Fahr于1930年首次报道,故也称Fahr病。国内1983年由蒋雨平首次报道[1],目前头颅CT显示双侧基底节对称性钙化为本病重要诊断依据。Fahr病属罕见病,呈散发或家族性发病。本文就近年来家族性特发性基底节钙化研究进展进行综述。     

家族性帕金森病分子遗传学研究进展

帕金森病 (Parkinson’sdisease ,PD)是一种常见的神经系统变性疾病 ,临床上主要表现为静止性震颤、肌强直、运动迟缓及姿势反射障碍等。主要病理改变是中脑黑质多巴胺能神经元进行性变性坏死 ,残存神经元中出现Lewy小体。近几年来 ,在一些呈明显单基因遗传方式的家族性帕金森病中 ,已经成功定位并克隆了该病的致病基因 ,这是帕金森病病因与发病机理研究的重大突破。本文就家族性帕金森病的致病基因定位与克隆情况综述如下。1　PARK1 α 突触核蛋白 (α Synuclein)基因1997年Polymeropoulos等对一个意大利Contursi家系进行研究 ,患者主…     

脑海绵状血管瘤分子遗传学研究进展

脑海绵状血管瘤(CCM)是先天性脑血管畸形的一种,从遗传学角度可分为散发性和家族遗传性两种类型。目前脑海绵状血管瘤分子遗传学研究取得了突破性进展,已有3个致病基因被克隆,包括CCM1/KRIT1、CCM2/MGC4607和CCM3/PDCD10。由于病灶组织内体细胞基因突变的发现认为"二次打击"机制学说参与了脑海绵状血管瘤的发病机制,其导致表达于病灶毛细血管腔内皮细胞的致病基因所编码的蛋白完全失去功能。上述研究为阐明脑海绵状血管瘤的发病机制提供了重要线索。     

家族性偏瘫性偏头痛的分子遗传学研究进展

偏头痛是神经系统的常见病,发病机制未明,但遗传因素无疑参与了偏头痛的发病。近年来,许多学者认为遗传因素最明显的偏头痛亚型——家族性偏瘫性偏头痛(FHM)可以作为研究偏头痛遗传机制的一个模型。本文对近年来FHM的分子遗传学研究进展及相关的偏头痛发病机制的认识加以综述。     

家族性特发性基底节钙化一家系报告

1病例报告 病例1：患者女，73岁。因“突发头痛、头晕5h，头CT提示蛛网膜下腔出血”入院。既往有原发性高血压病史近50年。神经系统查体：BP190／100mmHg，神清语利，记忆力、定向力、理解力完全。双侧瞳孔等大等圆，对光反射灵敏，眼动充分，视野无缺损，眼震（-）。伸舌示齿居中。颈软无抵抗感，凯尔尼格征、布鲁津斯基征均阴性。     

8个家族性特发性基底节钙化家系患者的临床研究

目的探讨8个家族性特发性基底节钙化(familial idiopathic basal ganglia calcification,FIBGC)家系患者的临床特点。方法收集8个FIBGC家系患者的临床资料,分析患者的临床检验结果、头颅CT及MRI改变、发病年龄、临床表现与患者基底节钙化体积(the volume of basal ganglia calcification,VBGC)的关系。结果家系患者和健康成员血清钙、铝、砷、钴、镁、磷、铁、甲状旁腺激素和降钙素的值比较均无显著性差异(P0.05)。8个家系包括两个近亲结婚的家系均呈现常染色体显性遗传;运动受损患者的病情严重程度与基底节区钙化的病灶大小相关;精神症状的患者有无症状与VBGC的大小无关;运动受损与精神症状的患者间发表年龄(43.954±2.473 vs.31.319±10.156 y,t=4.438,P=0.001)和VBGC(1.748±0.622 vs.0.392±0.276 cm3,t=2.518,P=0.028)比较有统计学差异。结论 8个FIBGC家系患者呈现常染色体显性遗传的特点,运动受损的患者基底节区钙化的病灶大,发病年龄较晚;精神症状的患者基底节区钙化的病灶小,发病年龄较早。     

家族性基底节钙化2例临床报告

家族性基底节钙化(familial basal ganglia calcification)又称Fahr病，特发性家庭性脑血管亚铁钙沉着症，是一种以精神发育迟滞、锥体外系统损害、抽搐、锥体束征为主要表现的临床综合征，为一种较为罕见的疾病。现将我院诊断的同一家系Fahr病2例报道如下。     

Anticipation in a family with primary familial brain calcification caused by an SLC20A2 variant

Aim of the study

To describe a family with primary familial brain calcification (PFBC) due to SLC20A2 variant showing possible genetic anticipation.

First pediatric case with primary familial brain calcification due to a novel variant on the MYORG gene and review of the literature

Variants in the myogenesis-regulating glycosidase (MYORG) gene which is known as the first autosomal recessive gene that has been associated with primary familial brain calcification (AR-PFBC). Although adult patients have been reported, no pediatric case has been reported until now. Herein, we review the clinical and radiological features of all AR- PFBC patients with biallelic variants in the MYORG gene who were reported until now, and we report the youngest patient who has a novel homozygous variant. Since the first identification of the MYORG gene in 2018, 74cases of MYORG variants related to AR-PFBC were evaluated. The ages of symptom onset of the patients ranged between 7.5 and 87 years. The most frequent clinical courses were speech impairment, movement disorder and cerebellar signs. All patients showed basal ganglia calcification usually bilaterally with different severities. Conclusion; herein, we reported the first pediatric patient in the literature who had a novel homozygous variant in the MYORG gene with mild clinic findings.     

A heterozygous deletion of PDGFB gene causes paroxysmal kinesigenic dyskinesia with primary familial brain calcification

BackgroundPrimary familial brain calcification (PFBC) is a neurodegenerative disease characterized with calcium deposition in multiple brain regions. Mutations in PDGFB have been discovered in sporadic and familial PFBC cases. While several known variants displayed loss-of function, no complete deletion of platelet-derived growth factor B (PDGFB) has been reported.MethodsFor the diagnostic purpose, brain computerized tomography or magnetic resonance imaging scanning and whole-genome sequencing were performed on the proband and family members in the pedigree.ResultsWe identified a heterozygous PDGFB complete deletion in a Chinese pedigree. The proband presented with paroxysmal kinesigenic dyskinesia (PKD), a rare symptom in PFBC. The proband's mother carrying the same mutation was asymptomatic.ConclusionsFor the first time, we reported a PFBC with a heterozygous deletion of PDGFB, and provided evidence of haploinsufficiency in the pathogenesis of PFBC.     

Biallelic XPR1 mutation associated with primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia with infantile convulsions

BackgroundMutations in the XPR1 gene are associated with primary familial brain calcifications (PFBC). All reported mutations are missense and inherited as an autosomal dominant trait. PFBC patients exhibited movement disorders, neuropsychiatric symptoms, and other associated symptoms with diverse severity, even within the same family.Materials and methodsWe identified and enrolled a patient with PFBC. Clinical data were comprehensively collected, including the age of onset, seizure types and frequency, trigger factors of paroxysmal dyskinesia, response to drugs, and general and neurological examination results. Whole-exome sequencing (WES) was performed to detect pathogenic variants. We further systematically reviewed the phenotypic and genetic features of patients with XPR1 mutations.ResultsThe patient showed bilateral calcification involving basal ganglia and cerebellar dentate. Clinically, he presented as paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) with favorable outcome. We identified a compound heterozygous XPR1 mutation (c.786_789delTAGA/p.D262Efs*6, c.1342C>T/p.R448W), which were inherited from unaffected parents respectively. Further literature review shows a wide range of clinical manifestations of patients with XPR1 mutations, with movement disorders being the most common.ConclusionsThis is the first report of biallelic mutations in XPR1. The findings suggest for the first time a possible link between PKD/IC and XPR1 mutations.     

Primary familial brain calcification: update on molecular genetics

Primary familial brain calcification is a neuropsychiatric disorder with calcium deposits in the brain, especially in basal ganglia, cerebellum and subcortical white matter. The disease is characterized by a clinical heterogeneity, with a various combination of symptoms that include movement disorders and psychiatric disturbances; asymptomatic patients have been also reported. To date, three causative genes have been found: SLC20A2, PDGFRB and PDGFB. SLC20A2 gene codes for the ‘sodium-dependent phosphate transporter 2’ (PiT-2), a cell membrane transporters of inorganic phosphate, involved in Pi uptake by cells and maintenance of Pi body levels. Over 40 pathogenic variants of SLC20A2 have been reported, affecting the regulation of Pi homeostasis. It was hypothesized that SLC20A2 mutations cause brain calcification most likely through haploinsufficiency. PDGFRB encodes for the platelet-derived growth factor receptor-β (PDGFRβ), a cell-surface tyrosine-kinase (RTK) receptor that regulates cell proliferation, migration, survival and differentiation. PDGFB encodes for the ‘platelet-derived growth factor beta’ (PDGFβ), the ligand of PDGFRβ. The loss of function of PDGFRβ and PDGFβ could lead to the impairment of the pericytes function and blood brain barrier integrity, causing vascular and perivascular calcium accumulation. SLC20A2 accounts for about 40 % of familial form and 14 % of sporadic cases, while PDGFRB and PDGFB mutations are likely rare. However, approximately 50 % of patients are not genetically defined and there should be at least another causative gene.     

Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes

IntroductionThere are now a number genes, known to be associated with familial primary brain calcification (PFBC), causing the so called ‘Fahr's’ disease or syndrome. These are SCL20A2, PDGFB, PDGFRB and XPR1. In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined.MethodsWe performed a Medline search, from 1st Jan 2012 through to 7th November 2016, for publications with confirmed mutations of SCL20A2, PDGFB, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases.ResultsSLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism.ConclusionWe combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and brain calcification.