Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 18 de 18
Filter
1.
Cerebellum ; 22(4): 578-586, 2023 Aug.
Article in English | MEDLINE | ID: mdl-35655106

ABSTRACT

Episodic ataxia type 1 (EA1) is a rare autosomal potassium channelopathy, due to mutations in KCNA1. Patients have childhood onset of intermittent attacks of ataxia, dizziness or imbalance. In order to quantify the natural history of EA1, its effect on quality of life and in preparation for future clinical trials, we set up an international multi-centre study of EA1. We recruited thirty-three participants with EA1: twenty-three completed 1-year follow-up and eighteen completed 2-year follow-up. There was very little accumulation of disability or impairment over the course of the 2 years of the study. The outcome measures of ataxia (SARA and functional rating of ataxia) and the activities of daily living scale were largely stable over time. Self-reported health-related quality of life (SF-36) scores were lower across all domains than controls, in keeping with a chronic condition. Physical subdomain scores appeared to deteriorate over time, which seems to be driven by the female participants in the study. This is an interesting finding and warrants further study. Attacks of EA1 reported by participants in real time via an interactive voice response system showed that symptoms were not stereotyped; however, attack duration and frequency was stable between individuals. This large prospective study is the first ever completed in subjects with EA1. We document the natural history of the disorder over 2 years. These data will enable the development of outcome measures for clinical trials of treatment.


Subject(s)
Activities of Daily Living , Quality of Life , Humans , Female , Child , Prospective Studies , Kv1.1 Potassium Channel/genetics , Ataxia/diagnosis
3.
J Inherit Metab Dis ; 45(4): 796-803, 2022 07.
Article in English | MEDLINE | ID: mdl-35543492

ABSTRACT

Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease-modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively funded research designed by academics meets the core needs of people with mitochondrial disorders and their clinicians. Priority setting partnerships are an established collaborative methodology that brings patients, carers and families, charity representatives and clinicians together to try to establish the most pressing and unanswered research priorities for a particular disease. We developed a web-based questionnaire, requesting all patients affected by primary mitochondrial disease, their carers and clinicians to pose their research questions. This yielded 709 questions from 147 participants. These were grouped into overarching themes including basic biology, causation, health services, clinical management, social impacts, prognosis, prevention, symptoms, treatment and psychological impact. Following the removal of "answered questions", the process resulted in a list of 42 discrete, answerable questions. This was further refined by web-based ranking by the community to 24 questions. These were debated at a face-to-face workshop attended by a diverse range of patients, carers, charity representatives and clinicians to create a definitive "Top 10 of unanswered research questions for primary mitochondrial disorders". These Top 10 questions related to understanding biological processes, including triggers of disease onset, mechanisms underlying progression and reasons for differential symptoms between individuals with identical genetic mutations; new treatments; biomarker discovery; psychological support and optimal management of stroke-like episodes and fatigue.


Subject(s)
Biomedical Research , Mitochondrial Diseases , Caregivers , Health Priorities , Humans , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy , Surveys and Questionnaires
4.
Brain ; 143(11): 3242-3261, 2020 12 05.
Article in English | MEDLINE | ID: mdl-33150406

ABSTRACT

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.


Subject(s)
Dystonic Disorders/genetics , Histone-Lysine N-Methyltransferase/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosome Deletion , Cohort Studies , Computer Simulation , Deep Brain Stimulation , Disease Progression , Dystonic Disorders/therapy , Endocrine System Diseases/complications , Endocrine System Diseases/genetics , Female , Fetal Growth Retardation/genetics , Gait Disorders, Neurologic/etiology , Gait Disorders, Neurologic/therapy , Humans , Laryngeal Diseases/etiology , Laryngeal Diseases/therapy , Male , Mutation , Mutation, Missense , Phenotype , Quality of Life , Treatment Outcome , Young Adult
6.
Neurogenetics ; 18(1): 49-55, 2017 01.
Article in English | MEDLINE | ID: mdl-28063088

ABSTRACT

Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the MFN2 gene are the commonest cause for the axonal (CMT2) type. We describe a Caucasian 5-year old girl affected by CMT2A since the age of 2 years. She presented with unsteady gait, in-turning of the feet and progressive foot deformities. Nerve conduction studies suggested an axonal neuropathy and molecular testing identified a previously reported pathogenic variant c.1090C > T, p.(Arg364Trp) in the MFN2 gene. This variant was also detected in a mosaic state in blood and saliva by Sanger sequencing in her subjectively healthy father. Next generation sequencing showed that the level of mosaicism was 21% in blood and 24% in saliva. A high recurrence risk was given because the father had proven somatic mosaicism and an affected child implying gonadal mosaicism. The parents were referred for pre-implantation genetic diagnosis. To the best of our knowledge, this is the first reported case of somatic mosaicism for MFN2. This study has important implications for genetic counselling in families with CMT2A.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/pathology , GTP Phosphohydrolases/genetics , Mitochondrial Proteins/genetics , Mosaicism , Mutation, Missense , Adult , Child, Preschool , Father-Child Relations , Female , Humans , Male , Nuclear Family , Parents , Pedigree , Phenotype , Severity of Illness Index
7.
Brain ; 137(Pt 4): 1009-18, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24578548

ABSTRACT

Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15-65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0-40) was an average of 3.15 for all participants (range 0-14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean=50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed episodic ataxia type 1 and episodic ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed episodic ataxia type 1 (21%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.


Subject(s)
Ataxia/genetics , Ataxia/psychology , Genetic Association Studies , Myokymia/genetics , Myokymia/psychology , Quality of Life , Adolescent , Adult , Age of Onset , Aged , Ataxia/complications , Cross-Sectional Studies , Female , Humans , Kv1.1 Potassium Channel/genetics , Male , Middle Aged , Myokymia/complications , Point Mutation , Young Adult
8.
Arch Neurol ; 68(5): 653-5, 2011 May.
Article in English | MEDLINE | ID: mdl-21555642

ABSTRACT

OBJECTIVES: To highlight an unexpected clinical presentation and to review the associated polyneuropathy phenotypes of SCA3. DESIGN: Clinical follow-up. SETTING: Neurological referral center. PATIENT: Middle-aged man with no family history for SCA3. RESULTS: Presentation with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy for 6 years before developing a cerebellar syndrome prompting genetic testing for SCA3. CONCLUSION: SCA3 can present with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy.


Subject(s)
Axons , Hereditary Sensory and Motor Neuropathy/genetics , Machado-Joseph Disease/diagnosis , Machado-Joseph Disease/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Repressor Proteins/genetics , Ataxin-3 , Axons/metabolism , Diagnosis, Differential , Humans , Machado-Joseph Disease/metabolism , Male , Middle Aged , Polyneuropathies/genetics , Trinucleotide Repeat Expansion
10.
J Physiol ; 588(Pt 11): 1905-13, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20156848

ABSTRACT

Mutations in CACNA1A, which encodes the principal subunit of the P/Q calcium channel, underlie episodic ataxia type 2 (EA2). In addition, some patients with episodic ataxia complicated by epilepsy have been shown to harbour CACNA1A mutations, raising the possibility that P/Q channel dysfunction may be linked to human epilepsy. We undertook a review of all published CACNA1A EA2 cases and this showed that 7% have epilepsy--representing a sevenfold increased epilepsy risk compared to the background population risk (P<0.001). We also studied a series of 17 individuals with episodic ataxia accompanied by epilepsy and/or clearly epileptiform electroencephalograms (EEGs). We screened the entire coding region of CACNA1A for point mutations and rearrangements to determine if genetic variation in the gene is associated with the epilepsy phenotype, and measured the functional impact of all missense variations on heterologously expressed P/Q channels. We identified two large scale deletions and two new missense mutations in CACNA1A. When expressed, L621R had little detectable effect on P/Q channel function, while the other missense change, G540R, caused an approximately 30% reduction in current density. In nine patients we also identified the previously reported non-synonymous coding variants (E921D and E993V) which also resulted in impairment of P/Q channel function. Taken together, 12 of the 17 patients have genetic changes which decrease P/Q channel function. We conclude that variants in the coding region of CACNA1A that confer a loss of P/Q-type channel function are associated with episodic ataxia and epilepsy. Our data suggest that functional stratification of all variants, including common polymorphisms, rare variants and novel mutations, may provide new insights into the mechanisms of channelopathies.


Subject(s)
Ataxia/genetics , Ataxia/physiopathology , Calcium Channels/genetics , Epilepsy/genetics , Epilepsy/physiopathology , Adolescent , Adult , Ataxia/complications , Calcium Channels/physiology , Cell Line , Child , Child, Preschool , DNA/genetics , Electroencephalography , Electrophysiology , Epilepsy/complications , Female , Humans , Infant , Male , Middle Aged , Mutation/genetics , Mutation, Missense/genetics , Patch-Clamp Techniques , Point Mutation/genetics , Point Mutation/physiology , Polymorphism, Single Nucleotide , Young Adult
11.
J Neurol Sci ; 285(1-2): 238-40, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19560788

ABSTRACT

Metronidazole-induced central nervous system (CNS) toxicity causes a spectrum of neurological symptoms including ataxia, encephalopathy and peripheral neuropathy. It is associated with characteristic MRI changes of high signal intensity in the dentate nuclei. Given the increasing use of metronidazole, it is import to recognise this drug as a cause of ataxia, as it is entirely reversible on drug withdrawal.


Subject(s)
Anti-Infective Agents/adverse effects , Ataxia/chemically induced , Metronidazole/adverse effects , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Ataxia/pathology , Brain/drug effects , Brain/pathology , Follow-Up Studies , Humans , Kidney Transplantation , Magnetic Resonance Imaging , Male , Metronidazole/pharmacology , Metronidazole/therapeutic use , Middle Aged , Pancreas Transplantation
12.
Neurobiol Dis ; 32(1): 10-5, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18606230

ABSTRACT

Premature stop codons in CACNA1A, which encodes the alpha(1A) subunit of neuronal P/Q-type (Ca(V)2.1) Ca(2+) channels, cause episodic ataxia type 2 (EA2). CACNA1A undergoes extensive alternative splicing, which contributes to the pharmacological and kinetic heterogeneity of Ca(V)2.1-mediated Ca(2+) currents. We identified three novel heterozygous stop codon mutations associated with EA2 in an alternately spliced exon (37A), which encodes part of an EF-hand motif required for Ca(2+)-dependent facilitation. One family had a C to G transversion (Y1854X). A dinucleotide deletion results in the same premature stop codon in a second family, and a further single nucleotide change leads to a different truncation (R1858X) in a de novo case of EA2. Expression studies of the Y1854X mutation revealed loss of Ca(V)2.1-mediated current. Because these mutations do not affect the alternate exon 37B, these findings reveal unexpected dependence of cerebellar function on intact exon 37A-containing Ca(V)2.1 channels.


Subject(s)
Alternative Splicing/genetics , Calcium Channels, N-Type/genetics , Codon, Nonsense/genetics , EF Hand Motifs/genetics , Frameshift Mutation/genetics , Protein Isoforms/genetics , Spinocerebellar Ataxias/genetics , Adult , Animals , Cerebellum/chemistry , Cerebellum/physiopathology , Codon, Nonsense/chemistry , Exons/genetics , Female , Genetic Variation/genetics , Humans , Male , Pedigree , Protein Isoforms/chemistry , Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/physiopathology , Xenopus laevis
14.
Epilepsy Curr ; 8(2): 37-8, 2008.
Article in English | MEDLINE | ID: mdl-18330464
15.
Lancet Neurol ; 6(11): 970-80, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17913586

ABSTRACT

BACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.


Subject(s)
Chromosome Mapping , Epilepsy/genetics , Seizures/genetics , Adult , Case-Control Studies , Cohort Studies , Genetic Predisposition to Disease , Genetic Variation , Genotype , Humans , Kv1.3 Potassium Channel/genetics , Large-Conductance Calcium-Activated Potassium Channel beta Subunits/genetics , Nerve Tissue Proteins/genetics , Phenotype , Polymorphism, Single Nucleotide , Receptors, GABA-A , Receptors, GABA-B/genetics , Succinate-Semialdehyde Dehydrogenase/genetics , Synapsins/genetics , Syndrome
16.
Neurology ; 65(2): 308-10, 2005 Jul 26.
Article in English | MEDLINE | ID: mdl-16043807

ABSTRACT

Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy characterized by paroxysmal cerebellar ataxia. Previous studies suggest that most EA2 cases are associated with mutations in the alpha1A subunit of the P/Q-type voltage-gated calcium channel gene CACNA1A. In a UK national study, the authors analyzed 15 index cases with typical EA2 and identified two unreported intronic mutations that predict aberrant splicing.


Subject(s)
Alternative Splicing/genetics , Calcium Channels/genetics , Cerebellar Ataxia/genetics , Mutation/genetics , RNA/genetics , Adolescent , Adult , Cerebellar Ataxia/metabolism , Cerebellar Ataxia/physiopathology , Child , Child, Preschool , Chromosome Mapping , Chromosomes, Human, Pair 19/genetics , DNA Mutational Analysis , Female , Genes, Dominant , Genetic Markers/genetics , Genetic Predisposition to Disease/genetics , Genetic Testing , Humans , Infant , Introns/genetics , Male , Pedigree , Polymorphism, Genetic/genetics , Protein Subunits/genetics , RNA Splice Sites/genetics , United Kingdom
18.
Ann Thorac Surg ; 74(1): 261-3, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12118781

ABSTRACT

We discuss the case of a young man with mediastinal tuberculosis who presented with pericarditis, thymic involvement, and respiratory failure because of upper airway obstruction. Although mediastinal tuberculosis is not uncommon, the simultaneous occurrence of these complications is exceedingly rare and in this patient resulted in an acute life-threatening illness. The diagnosis and treatment of this condition can be complex, and these aspects of the patient's care are discussed.


Subject(s)
Airway Obstruction/etiology , Pericardial Effusion/etiology , Respiratory Insufficiency/etiology , Thymus Gland , Tuberculosis, Lymph Node/complications , Adult , Airway Obstruction/therapy , Humans , Male , Respiration, Artificial , Respiratory Insufficiency/therapy , Tuberculosis, Lymph Node/diagnosis
SELECTION OF CITATIONS
SEARCH DETAIL
...