Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described neurovascular disease affecting young to middle age individuals. The disease is caused by mutations in the Notch3 gene located in the short arm of chromosome 19. Clinically, the disease is characterized by migrainous headaches (with or without aura), mood disturbances, focal neurologic deficits, transient ischemic attacks, strokes, and dementia. Pathologically, the disease is characterized by a stereotypic degeneration of the arterial walls (especially in the intracranial compartments) with deposition in the media of a nonatheromatous, nonamyloidotic substance that under the electron microscope (EM) appears as a granular osmiophilic material (GOM), pathognomonic for the disease. The nature of the GOM is undetermined and the pathogenesis remains to be elucidated. A review of current literature in English language is presented on the clinical, radiologic, pathologic, and genetic features of CADASIL.     

High recurrence of the R1006C NOTCH3 mutation in central Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a heritable small-vessel disease caused by mutations in NOTCH3 gene and clinically characterized by recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline and dementia. Direct sequencing of NOTCH3 gene in 90 Italian patients of sixty-three unrelated families identified four heterozygous mutations (R141C and C144F in exon 4, G528C in exon 10 and R1006C in exon 19) in fifteen probands and sixteen relatives. We detected seventeen heterozygous/homozygous polymorphisms, four of them novel. Here we report the high recurrence of R1006C mutation in ten families all originate from a restricted area of central Italy, the town of Ascoli Piceno and same neighbour villages. We also developed a PCR–Restriction Fragment Length Polymorphism (RFLP) assay to analyze the R1006C mutation. Our findings might suggest, for this mutation, the presence of a common ancestor.     

A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria

Hereditary coproporphyria (HC) is an acute hepatic porphyriawith autosomal dominant inheritance caused by a deficient activityof coproporphyrinogen IX oxidase (CPX). We previously describedhardero-porphyria, a homozygous variant form of coproporphyriain three siblings, characterized by a massive excretion of harderoporphyrinand a marked decrease of coproporphyrinogen IX oxidase activity.In this kindred, the transmission of the disease was autosomalrecessive. In the present study, sequencing of cDNA and genomicDNA from these patients revealed a point mutation resultingin a lysine to glutamic acid substitution (K304E) in exon 6of the gene and the absence of the normal allele, suggestinga homozygous state for the mutation. Expression studies of normaland mutated cDNAs in E.coll demonstrated that this amino acidsubstitution was responsible for the important decrease in theenzyme activity and for the accumulation of harderoporphyrin.The Michaelis constant of the mutated enzyme was 10-fold higherthan normal suggesting that the lysine at position 304 is importantfor binding the substrate: a slightly increased sensitivityto thermal denaturation was also observed.     

Impact of MRI markers in subcortical vascular dementia: a multi-modal analysis in CADASIL

CADASIL is an arteriopathy caused by mutations of the Notch3 gene. White matter hyperintensities (WMH), lacunar lesions (LL), cerebral microhemorrhages (CM), brain atrophy and tissue microstructural changes are detected on MRI. Using an integrated multi-modal approach, we examined the relative impact of lesion burden and location of these MRI markers on cognitive impairment and disability. Multi-modal imaging was performed on 147 patients from a two-center cohort study. Volume of LL, WMH and number of CM was determined. Whole brain mean apparent diffusion coefficient (mean-ADC) and brain parenchymal fraction (BPF) were measured. In multivariate models accounting for lesion burden and location, volume of LL, mean-ADC, and BPF each had an independent influence on global cognitive function and disability. BPF explained the largest portion of the variation in cognitive and disability scores (35-38%). Brain atrophy has the strongest independent influence on clinical impairment in CADASIL when all MRI markers in the disease are considered together. The results suggest that the clinical impact of cerebral tissue loss plays a principal role in this genetic model of subcortical ischemic vascular dementia.     

伴有皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病一家系的临床及基因研究

目的 探讨伴有皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)患者的临床特征及基因诊断.方法 对1个CADASIL先证者及其家族的发病情况、遗传方式、临床表现、影像学特征、分子遗传学及治疗等方面进行研究.结果 患者均有记忆力减退、乏力、脑卒中样发作等特点,没有高血压、动脉硬化证据,有家族聚集性,头颅CT、MRI示多发性梗死灶、脑白质变性,临床符合CADASIL的诊断.存活者中基因测序显示NOTCH3基因第3、4外显子突变,可确诊为CADASIL.该家系4代中有3代10人呈临床或亚临床发病,符合常染色体显性遗传.结论 该家系的临床及分子遗传学特征符合CADASIL诊断.     

Mechanisms regulating cerebral hypoperfusion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the NOTCH3 gene mutation which leads to Notch3 ectodomain deposition and extracellular matrix aggregation around the small vessels. It further causes smooth muscle cell degeneration and small vessel arteriopathy in the central nervous system. Compromised cerebral blood flow occurs in the early stage of CADASIL and is associated with white matter hyperintensity, the typical neuroimaging pathology of CADASIL. This suggests that cerebral hypoperfusion may play an important role in the pathogenesis of CADASIL. However, the mechanistic linkage between NOTCH3 mutation and cerebral hypoperfusion remains unknown. Therefore, in this mini-review, it examines the cellular and molecular mechanisms contributing to cerebral hypoperfusion in CADASIL.     

Inflammatory glial activation in the brain of a patient with hereditary sensory neuropathy type 1 with deafness and dementia

The brain of a patient with hereditary sensory neuropathy type 1 (HSN-1) associated with sensorineural deafness and early-onset dementia was neuropathologically investigated. Widespread neuronal degeneration in cerebral neocortex, hippocampus and basal ganglia was revealed, accounting for the clinical features. Loss of neurons with ballooning of residual neurons was remarkable in the hippocampus and frontal, parietal, and occipital lobes. Neuronal degeneration in these regions was accompanied by axonal dystrophy and glial reactions such as microgliosis and astrocytosis, however, only glial responses were prominent in the basal ganglia, brain-stem and cerebellum with mild neuronal loss. These results indicate that the widespread neuronal degeneration may be accelerated by inflammatory processes including glial activation in the brain of a patient with HSN-1 associated with deafness and dementia.     

Biochemical characterization of a neuroserpin variant associated with hereditary dementia

Neuroserpin isolated from inclusion bodies in the brain of a patient with a neurodegenerative disease was characterized biochemically. The protein consisted of residues 20 to 410 of the neuroserpin precursor deduced from its cDNA sequence indicating the entire molecule was deposited. A minor amount started with residue 19 of the precursor, and the carboxyl terminus was heterogeneous ending at residues 405, 407, 409, and 410. Arg was present at position 52. No normal Ser52 was found indicating that only mutant neuroserpin was present in the inclusion bodies. The three potential Asn glycosylation sites all contained carbohydrate. DNA sequence analysis of exons 2 to 9 of the neuroserpin gene in the proband showed the published normal neuroserpin sequence except for the presence of both adenine and cytosine at the first position of codon 52, that indicates heterozygosity for both the normal Ser(AGT) and variant Arg(CGT) at this position in the expressed protein. Restriction fragment length polymorphism analysis of a polymerase chain reaction product from exon 2 revealed the propositus and his affected sibling both were heterozygous for the mutation whereas 100 unaffected controls were negative. Chemical characterization of the variant neuroserpin will significantly enhance the understanding of this protein in both normal physiology and neurodegenerative diseases.     

The neuropathology of neurodegenerative diseases causing dementia

The dementia syndrome is increasing in prevalence throughout the developed world as the population ages. For example, in the United States it is estimated that between 2000 and 2020, the number of people living to 100 years or more will increase by over 200%, and the number of people surviving to 90–95 years will double. Based on these and other epidemiologic data, the prevalence of diseases causing the dementia syndrome has and will continue to increase dramatically over the next several decades. Considering Alzheimer's disease alone, the most common cause of dementia in the elderly, there are currently 5.5 million persons affected in the United States, and that prevalence will increase to 16 million by the first half of this century. This review will focus on the histopathology of important neurodegenerative diseases of the brain that cause dementia, including Alzheimer's disease, frontotemporal lobar degenerations, and dementia with Lewy bodies. In addition, a less common but extraordinarily interesting condition, chronic traumatic encephalopathy, will be reviewed.     

Evidence for a common mutation in hereditary pancreatitis.

Hereditary pancreatitis is an autosomal dominant disorder with incomplete penetrance. It is characterised by recurring episodes of severe abdominal pain and often presents in childhood. Recently, a mutation in the cationic trypsinogen gene was identified in this disease. Previously, only one mutation at residue 117 of the trypsinogen gene has been found in the five separate hereditary pancreatitis families, four from the USA and one from Italy. Alteration of the Arg117 site is believed to disrupt a fail-safe mechanism for the inactivation of trypsin, leading to autodigestion of the pancreas under certain conditions. Molecular analysis of the trypsinogen gene was carried out on a hereditary pancreatitis family from the UK. The same G to A mutation at residue 117 was identified in this family, suggesting that this is a common mutation in hereditary pancreatitis.     

Familial cosegregation of manic-depressive illness and a form of hereditary cerebellar ataxia

We report on a Spanish family with cooccurrence of manic-depression and a form of hereditary cerebellar ataxia. All affected individuals in the second generation showed cerebellar ataxia and manic-depression simultaneously. Since anticipation has been described in both disorders and the pattern of segregation may be autosomal as well as X-linked, we have searched for a possible involvement of two candidate genes which are located either on an autosome (SCA1) or on the X-chromosome (GABRA3). We concluded that expansion of trinucleotide repeats at SCA1 gene cannot be considered as a disease-causing mutation, and this gene should be initially discarded. © 1995 Wiley-Liss, Inc.     

SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors

Defects in complex II of the mitochondrial respiratory chain are a rare cause of mitochondrial disorders. Underlying autosomal-recessive genetic defects are found in most of the ‘SDHx'' genes encoding complex II (SDHA, SDHB, SDHC, and SDHD) and its assembly factors. Interestingly, SDHx genes also function as tumor suppressor genes in hereditary paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors. In these cases, the affected patients are carrier of a heterozygeous SDHx germline mutation. Until now, mutations in SDHx associated with mitochondrial disease have not been reported in association with hereditary tumors and vice versa. Here, we characterize four patients with isolated complex II deficiency caused by mutations in SDHA presenting with multisystem mitochondrial disease including Leigh syndrome (LS) and/or leukodystrophy. Molecular genetic analysis revealed three novel mutations in SDHA. Two mutations (c.64-2A>G and c.1065-3C>A) affect mRNA splicing and result in loss of protein expression. These are the first mutations described affecting SDHA splicing. For the third new mutation, c.565T>G, we show that it severely affects enzyme activity. Its pathogenicity was confirmed by lentiviral complementation experiments on the fibroblasts of patients carrying this mutation. It is of special interest that one of our LS patients harbored the c.91C>T (p.Arg31*) mutation that was previously only reported in association with paragangliomas and pheochromocytomas, tightening the gap between these two rare disorders. As tumor screening is recommended for SDHx mutation carriers, this should also be considered for patients with mitochondrial disorders and their family members.     

多发梗塞性痴呆和阿尔采默氏痴呆的脑 CT 改变及认知障碍对比研究

本文对28例多发梗塞性痴呆(MID)患者和25例阿尔采默氏痴呆(DAT)患者的脑CT 改变及认知障碍特点进行了对比研究。结果发现,MID 患者脑室周围低密度改变的比率(82%)显著高于 DAT 组患者(36%)。而 DAT 组患者的脑沟较 MID 组的显著增宽。MID 组患者第三脑室扩大与智能损害严重程度呈显著正相关。MID 患者的智能损害不完全,可保留某方面的能力致疾病严重阶段。     

Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder caused by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. We performed molecular characterization in clinically affected probands of 31 HHT families and detected a total of 28 different mutations in the two genes, including four shared by more than one family. Twelve mutations were identified in the ENG gene, six of which were novel and comprised two nonsense mutations in exons 6 and 8, deletions in exons 5 and 11, and splice site mutations in exon 12 and intron 8. Eleven of sixteen mutations identified in the ALK1 gene were novel single base pair substitutions in exons 4, 7, 8, and 9. We also describe the first de novo ALK1 mutation that causes a previously unreported c.1133C>A substitution of a highly conserved residue (p.P378H). The proband and his two daughters, who also carried the familial mutation, all suffered from gastrointestinal (GI) bleeding. In addition, we report seven newly identified polymorphisms and summarize all known ones in both genes.     

Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer's disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI.     

An unusual form of proliferative arteriopathy in macaque monkeys (Macacca sps)

A hitherto unreported arteriopathy of macaque monkeys is described, mainly affecting the medium-sized muscular arteries of the kidneys. Lesions were characterized chiefly by eccentric swellings of the tunica media, where normal smooth muscle was replaced by irregularly proliferating cells. The condition was first observed in the course of toxicity studies on cromolyn sodium, but subsequently it has been seen in other laboratories where cromolyn had not been used. No causal relationship between the arteriopathy and any experimental treatment has been established. The literature on comparable lesions in other animal species and man is reviewed. The condition appears to be a distinct entity confined to the genus Macacca and different from any of the arteriopathies described in other animal species and man. Its cause is obscure although the evidence suggests that a single exposure to an infectious or toxic factor may be involved.     

Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized adult-onset autosomal dominant vascular dementia, caused by highly stereotyped mutations in the Notch3 receptor. CADASIL is a widespread angiopathy characterized by a degeneration of vascular smooth muscle cells (VSMCs) and the abnormal accumulation of electron-dense granular material called GOM and Notch3 protein, because of an impaired clearance. Evidence that VSMCs are the primary target of the pathogenic process is supported by the restricted expression of Notch3 in these cells but mechanisms of their degeneration remain essentially unknown. We generated transgenic mice in which the SM22alpha promoter drove, in VSMCs, the expression of a full-length human Notch3 carrying the Arg90Cys mutation, a CADASIL archetypal mutation. Transgenic mice showed no evidence of prominent brain parenchyma damage but demonstrated the two hallmarks of the CADASIL angiopathy, GOM deposits and Notch3 accumulation, within both the cerebral and peripheral arteries. Of interest, arteries of the tail were more severely affected with prominent signs of VSMC degeneration. Time-course analysis of vessel changes revealed that disruption of normal VSMC anchorage to adjacent extracellular matrix and cells, VSMC cytoskeleton changes as well as starting signs of VSMC degeneration, which were detected around 10 months of age, preceded Notch3 and GOM accumulation appearance, which were observed only by 14 to 16 months of age. In conclusion, we have generated transgenic mice that recapitulate the characteristic vascular lesions observed in CADASIL. Our results indicate that Notch3 or GOM accumulation are unlikely to be the prerequisites for the induction of VSMC degeneration and suggest that degeneration of VSMCs may rather be triggered by the disruption of their normal anchorage, based on the important role of adhesion for cell survival.