Background And Objectives: The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most prevalent LGMD subtypes.
Methods: We reviewed the results of spirometry studies collected longitudinally in our cohort of patients in routine clinical visits from 2002 to 2020 along with additional clinical and genetic data.
Background And Objectives: Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene are increased in sCJD, potentially leading to the seeding of misfolded prion protein.
Methods: High-depth amplicon-based short read sequencing of the coding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71).
Acta Neuropathol
May 2020
The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
View Article and Find Full Text PDFActa Neuropathol
August 2019
The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls.
View Article and Find Full Text PDFApproximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.
View Article and Find Full Text PDFSomatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains.
View Article and Find Full Text PDFPurpose: To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders.
Methods: In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum.
Introduction: A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes.
Methods: We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years).
J Neurol Neurosurg Psychiatry
August 2018
Background: Several studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.
Methods: We analysed 980 neuropathologically characterised human brains with Alzheimer's disease (AD), Parkinson's disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity.
Human-to-human transmission of Creutzfeldt-Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK.
View Article and Find Full Text PDFActa Neuropathol Commun
February 2017
Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels.
View Article and Find Full Text PDFGiven the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping.
View Article and Find Full Text PDFMitochondrial dysfunction is observed in both the aging brain, and as a core feature of several neurodegenerative diseases. A central mechanism mediating this dysfunction is acquired molecular damage to mitochondrial DNA (mtDNA). In addition, inherited stable mtDNA variation (mitochondrial haplogroups), and inherited low level variants (heteroplasmy) have also been associated with the development of neurodegenerative disease and premature neural aging respectively.
View Article and Find Full Text PDFMutations in STXBP1 have recently been identified as a cause of infantile epileptic encephalopathy. The underlying mechanism of the disorder remains unclear and, recently, several case reports have described broad and progressive neurological phenotypes in addition to early-onset epilepsy. Herein, we describe a patient with early-onset epilepsy who subsequently developed a progressive neurological phenotype including parkinsonism in her early teens.
View Article and Find Full Text PDFObjective: The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA).
Methods: One series from the United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study. We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA.
Neuroferritinopathy remains the only autosomal dominant syndrome of neurodegeneration with brain iron accumulation (NBIA). While the majority of identified cases appear to be part of an extended pedigree in the northeast of England, patients are increasingly being identified across the globe. Since its discovery in 2001, there have been significant developments in our understanding of the pathological, radiological, and clinical aspects of the condition, though several key pathomechanistic questions, and crucially treatment paradigms, remain unaddressed.
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