[Show abstract][Hide abstract] ABSTRACT: Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.
Preview · Article · Feb 2016 · Translational Psychiatry
[Show abstract][Hide abstract] ABSTRACT: With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in approximately 1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue we studied 577 mothers-child pairs transmitting the m.11778G>A, m.3460G>A, m.8344A>G, m.8993T>G/C, and m.3243A>G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation, and ascertainment bias. We found no evidence of selection during transmission, but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T>G/C segregated significantly faster than m.11778G>A, m.8344A>G, and m.3243A>G, consistent with a tighter mtDNA genetic bottleneck in m.8993T>G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations.
Full-text · Article · Jan 2016 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial disorders are caused by mutations in nuclear DNA and mitochondrial DNA (mtDNA). Nuclear-encoded mitochondrial disorders have emerged as a major cause of inherited neurometabolic disease. As with mitochondrial DNA-encoded disorders, they characteristically affect multiple neurological systems, and also often involve other non-neurological organs and tissues. They can present at any age, from early-onset severe encephalomyopathies in children, through to late-onset, slowly progressive adult neurodegenerative disorders.Nuclear-encoded mitochondrial disorders can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive trait. The recessive forms are more common in consanguineous individuals but usually appear as isolated cases in an outbred population. This inheritance pattern contrasts with mitochondrial DNA-encoded mitochondrial disorders, which are inherited down the maternal line.Some nuclear-encoded mitochondrial disorders have the characteristic clinical phenotype, prompting early genetic testing of specific nuclear genes. However, given the overlapping spectrum for clinical phenotypes, a systematic approach is advocated in all but the most obvious cases. This should incorporate clinical investigations aimed at building a clear picture of the phenotype, and biochemical studies in an affected tissue, which guides nuclear genetic testing. The impact of exome and whole-genome sequencing will dramatically change the diagnostic approach in the near future.Current research activity is focused on providing a comprehensive molecular diagnosis to enable reliable genetic counseling and prenatal testing. Genetically defined cohorts are being assembled throughout the world, enabling the first natural history studies and treatment trials in mitochondrial disease. It is likely that new treatments will become available in the near future.
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial disease can manifest as multi-organ disorder, often with neurological dysfunction. Cerebellar ataxia in isolation or in combination with other features can result from mitochondrial disease yet genetic testing using blood DNA is not sufficient to exclude this as a cause of ataxia. Muscle biopsy is a useful diagnostic tool for patients with ataxia suspected of mitochondrial disease. Our aim was to determine specific patient selection criteria for muscle biopsy to see how frequent mitochondrial mutations are responsible for progressive ataxia. We performed a two centre retrospective review of patients with unexplained progressive ataxia who underwent muscle biopsy for suspected mitochondrial disease between 2004 and 2014 (Sheffield and Newcastle Ataxia Centres).
A total of 126 patients were identified; 26 assessed in Newcastle and 100 in Sheffield. Twenty-four patients had pure ataxia and 102 had ataxia with additional features. The total number of patients with histologically suspected and/or genetically confirmed mitochondrial disease was 29/126 (23 %).
A large proportion of patients (23 %) with progressive ataxia who underwent muscle biopsy were found to have features of mitochondrial dysfunction, with molecular confirmation in some. Muscle biopsy is a helpful diagnostic tool for mitochondrial disease in patients with progressive ataxia.
[Show abstract][Hide abstract] ABSTRACT: Ten years ago, there was an emerging view that the molecular basis for adult mitochondrial disorders was largely known and that the clinical phenotypes had been well described. Nothing could have been further from the truth. The establishment of large cohorts of patients has revealed new aspects of the clinical presentation that were not previously appreciated. Over time, this approach is starting to provide an accurate understanding of the natural history of mitochondrial disease in adults. Advances in molecular diagnostics, underpinned by next generation sequencing technology, have identified novel molecular mechanisms. Recently described mitochondrial disease phenotypes have disparate causes, and yet share common mechanistic themes. In particular, disorders of mtDNA maintenance have emerged as a major cause of mitochondrial disease in adults. Progressive mtDNA depletion and the accumulation of mtDNA mutations explain some of the clinical features, but the genetic and cellular processes responsible for the mtDNA abnormalities are not entirely clear in each instance. Unfortunately, apart from a few specific examples, treatments for adult mitochondrial disease have not been forthcoming. However, the establishment of international consortia, and the first multinational randomised controlled trial, have paved the way for major progress in the near future, underpinned by growing interest from the pharmaceutical industry. Adult mitochondrial medicine is, therefore, in its infancy, and the challenge is to harness the new understanding of its molecular and cellular basis to develop treatments of real benefit to patients.
No preview · Article · Nov 2015 · EMBO Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation.
Preview · Article · Nov 2015 · The American Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: There is a growing body of evidence linking mitochondrial dysfunction, mediated either through inherited mtDNA variation or mitochondrial proteomic deficit, to Parkinson’s disease (PD). Yet despite this, the role of somatic mtDNA point mutations and specifically point-mutational burden in PD is poorly understood. Here we take advantage of recent technical and methodological advances to examine the role of age-related and acquired mtDNA mutation in the largest study of mtDNA in post-mortem PD tissue to date.
Full-text · Article · Nov 2015 · Neurobiology of Aging
[Show abstract][Hide abstract] ABSTRACT: Mutations in PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17 cause neurodegeneration with brain iron accumulation (NBIA), but the genetic etiology remains undefined in many patients. We report the second patient with sterol carrier protein x (SCPx) deficiency presenting with adult-onset spinocerebellar ataxia and brain MRI characteristic of NBIA.
[Show abstract][Hide abstract] ABSTRACT: Background:
Behr's syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties.
Here we describe 4 patients with the classical Behr's syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the C12orf65 gene encoding a protein involved in mitochondrial translation.
Whole exome sequencing was performed in genomic DNA and oxygen consumption was measured in patient cell lines.
We detected 2 different homozygous C12orf65 nonsense mutations in 4 patients with a homogeneous clinical presentation matching the historical description of Behr's syndrome. The first symptom in all patients was childhood-onset optic atrophy, followed by spastic paraparesis, distal weakness, motor neuropathy and ophthalmoparesis.
We think that C12orf65 mutations are more frequent than previously suggested and screening of this gene should be considered not only in patients with mitochondrial respiratory chain deficiencies, but also in inherited peripheral neuropathies, spastic paraplegias and ataxias, especially with pre-existing optic atrophy.
[Show abstract][Hide abstract] ABSTRACT: The identification of cell-free circulating mitochondrial DNA (ccf-mtDNA) in early stage Alzheimer's disease (AD) raised the possibility that the same neurodegenerative effect could be seen in Parkinson's disease (PD). Here and for the first time, we investigated the role of ccf-mtDNA in PD, identifying a significant reduction of ccf-mtDNA in PD patient cerebrospinal fluid (CSF) when compared to controls. Our data demonstrates that CSF ccf-mtDNA is not only a powerful biomarker for PD but, given that the effect is also seen in AD, is likely a biomarker for neurodegeneration. This article is protected by copyright. All rights reserved.
No preview · Article · Sep 2015 · Annals of Neurology
[Show abstract][Hide abstract] ABSTRACT: Common genetic variants of mitochondrial DNA (mtDNA) increase the risk of developing several of the major health issues facing the western world, including neurodegenerative diseases. In this Review, we consider how these mtDNA variants arose and how they spread from their origin on one single molecule in a single cell to be present at high levels throughout a specific organ and, ultimately, to contribute to the population risk of common age-related disorders. mtDNA persists in all aerobic eukaryotes, despite a high substitution rate, clonal propagation and little evidence of recombination. Recent studies have found that de novo mtDNA mutations are suppressed in the female germ line; despite this, mtDNA heteroplasmy is remarkably common. The demonstration of a mammalian mtDNA genetic bottleneck explains how new germline variants can increase to high levels within a generation, and the ultimate fixation of less-severe mutations that escape germline selection explains how they can contribute to the risk
[Show abstract][Hide abstract] ABSTRACT: Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10–41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262–1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial diseases are inherited disorders of oxidative phosphorylation that present with a multitude of clinical features in different combinations and with various inheritance patterns. To complicate the issue further, the clinical features of mitochondrial disorders overlap with common neurological and non-neurological diseases. This presents a diagnostic challenge: when is a rare mitochondrial disease responsible for a more 'common or garden' neurological presentation, and how often are neurologists missing them in routine clinical practice? Here, we briefly review some common clinical features associated with mitochondrial disease, and provide some clues as to how patients with these mitochondrial disorders might be identified. We discuss both 'chameleons'-mitochondrial disorders that may look like something else, and 'mimics'-other conditions that may clinically resemble mitochondrial disease. The diagnosis sometimes needs highly specialised tests, but the advent of 'next generation' sequencing will simplify the clinical approach over the next few years.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
No preview · Article · Jul 2015 · Practical Neurology