RESUMEN
Ataxia-Telangiectasia (A-T) is an autosomal recessive neurodegenerative disease associated with cerebellar ataxia and extrapyramidal features. A-T has a complex and diverse phenotype with varying rates of disease progression. The development of robust natural history studies and therapeutic trials relies on the accurate recording of phenotype using relevant and validated severity of illness indexes. We compared the commonly used Scale for the Assessment and Rating of Ataxia (SARA) and the disease-specific A-T Neurological Examination Scale Toolkit (A-T NEST), in our adult A-T cohort. We found a strong correlation between A-T NEST and the established SARA score, validating the use of A-T NEST and SARA in capturing the natural history of A-T patients.
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Ataxia Telangiectasia , Ataxia Cerebelosa , Enfermedades Neurodegenerativas , Adulto , Humanos , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Índice de Severidad de la Enfermedad , Progresión de la EnfermedadRESUMEN
BACKGROUND: Telephone consultations are already employed in specific neurological settings. At Cambridge University Hospitals, the COVID-19 pandemic initially prompted almost all face-to-face appointments to be delivered by telephone, providing a uniquely unselected population to assess. OBJECTIVES: We explored patient and clinician experience of telephone consultations; and whether telephone consultations might be preferable for preidentifiable subgroups of patients after the pandemic. METHODS: Clinicians delivering neurological consultations converted to telephone between April and July 2020 were invited to complete a questionnaire following each consult (430 respondents) and the corresponding patients were subsequently surveyed (290 respondents). The questionnaires assessed clinician and patient goal achievement (and the reasons for any dissatisfaction). Clinicians also described consultation duration (in comparison to face to face) while patients detailed comparative convenience and preference. RESULTS: The majority of clinicians (335/430, 78%) and patients (227/290, 78%) achieved their consultation goals by telephone, particularly during follow-up consultations (clinicians 272/329, 83%, patients 176/216, 81%) and in some disease subgroups (eg, seizures/epilepsy (clinicians 114/122 (93%), patients 71/81 (88%)). 95% of telephone consultations were estimated to take the same or less time than an equivalent face-to-face consultation. Most patients found telephone consultations convenient (69%) with 149/211 (71%) indicating they would like telephone or video consultations to play some role in their future follow-up. CONCLUSION: Telephone consultations appear effective, convenient and popular in prespecified subgroups of neurological outpatients. Further work comparing telephone, video and face-to-face consultations across multiple centres is now needed.
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COVID-19 , Humanos , COVID-19/epidemiología , Derivación y Consulta , Pandemias , Teléfono , Evaluación del Resultado de la Atención al PacienteRESUMEN
OBJECTIVE: Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (ATM) kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant ataxia-telangiectasia and explore genotype-phenotype correlations. METHODS: Cross-sectional data were collected retrospectively. Patients were classified as variant ataxia-telangiectasia based on retained ATM kinase activity. RESULTS: The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age 10 (81%). There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands. Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset. Only one third had predominant ataxia, and 18% had a pure extrapyramidal presentation. Individuals with extrapyramidal presentations had milder neurological disease severity. There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy. Missense mutations were associated with milder neurological disease severity, but with a higher risk of malignancy, compared to leaky splice site mutations. INTERPRETATION: Individuals with variant ataxia-telangiectasia require malignancy surveillance and tailored management. However, our data suggest the condition may sometimes be mis- or underdiagnosed because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha-fetoprotein levels in some individuals. Missense mutations are associated with milder neurological presentations, but a particularly high malignancy risk, and it is important for clinicians to be aware of these phenotypes. ANN NEUROL 2019;85:170-180.
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Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/genética , Genotipo , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Niño , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
Ataxia telangiectasia is an autosomal recessive DNA repair disorder characterised by complex neurological symptoms, with an elevated risk of malignancy, immunodeficiency and other systemic complications. Patients with variant ataxia telangiectasia-with some preserved ataxia telangiectasia-mutated (ATM) kinase activity-have a milder and often atypical phenotype, which can lead to long delays in diagnosis. Clinicians need to be aware of the spectrum of clinical presentations of ataxia telangiectasia, especially given the implications for malignancy surveillance and management. Here, we review the phenotypes of ataxia telangiectasia, illustrated with case reports and videos, and discuss its pathological mechanisms, diagnosis and management.
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Ataxia Telangiectasia/genética , Neurólogos , Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/diagnóstico , Encéfalo/patología , Humanos , Mutación/genética , FenotipoRESUMEN
Spinocerebellar ataxias form a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive cerebellar ataxia. Their prevalence varies among populations and ethnicities. Spinocerebellar ataxia 36 is caused by a GGCCTG repeat expansion in the first intron of the NOP56 gene and is characterized by late-onset ataxia, sensorineural hearing loss and upper and lower motor neuron signs, including tongue fasciculations. Spinocerebellar ataxia 36 has been described mainly in East Asian and Western European patients and was thought to be absent in the British population. Leveraging novel bioinformatic tools to detect repeat expansions from whole-genome sequencing, we analyse the NOP56 repeat in 1257 British patients with hereditary ataxia and in 7506 unrelated controls. We identify pathogenic repeat expansions in five families (seven patients), representing the first cohort of White British descent patients with spinocerebellar ataxia 36. Employing in silico approaches using whole-genome sequencing data, we found an 87â kb shared haplotype in among the affected individuals from five families around the NOP56 repeat region, although this block was also shared between several controls, suggesting that the repeat arises on a permissive haplotype. Clinically, the patients presented with slowly progressive cerebellar ataxia with a low rate of hearing loss and variable rates of motor neuron impairment. Our findings show that the NOP56 expansion causes ataxia in the British population and that spinocerebellar ataxia 36 can be suspected in patients with a late-onset, slowly progressive ataxia, even without the findings of hearing loss and tongue fasciculation.
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BACKGROUND AND OBJECTIVES: To systematically assess the occurrence of cerebral microbleeds (CMBs) and white matter hyperintensities (WMHs) in the largest published cohort of adults with ataxia-telangiectasia (AT). METHODS: We assessed 38 adults with AT (age range 18-55 years) including 15 classic and 23 variant AT, evaluated by two independent assessors. WMHs were quantified on T2-fluid attenuated inversion recovery images using the semiquantitative modified Scheltens and Fazekas scales and CMB on susceptibility-weighted imaging and T2*-weighted gradient echo sequences using the Brain Observer MicroBleed Scale. RESULTS: CMBs were more frequently found in classic AT compared with variant AT (66.7% vs 5.9%) predominantly in cortical and subcortical regions. WMHs were seen in 25 (73.5%) probands and CMBs in 9 (31.0%). The burden of WMHs increased with age, and WMHs were focused in periventricular and deep white matter regions. WMHs were more frequently seen in variant than classic AT. DISCUSSION: This cohort study confirms that WMHs and CMBs are a frequent finding in AT. Further longitudinal studies are required to understand how WMHs and CMBs relate to the neurodegeneration that occurs in AT and the predisposition to cerebral hemorrhage.
RESUMEN
OBJECTIVE: To describe and classify the neurologic trajectories in patients with mild neurologic forms of ataxia telangiectasia (A-T) from the Dutch A-T cohort, combined with patients reported in the literature. METHODS: Clinical, genetic, and laboratory data of 14 patients with mild neurologic phenotypes of A-T from the Dutch cohort were analyzed and combined with corresponding data from the literature. A mild neurologic phenotype was defined by a later onset, nonataxia presenting or dominant feature, or slower progression compared to the classic A-T phenotype. Neurologic trajectories were classified based on age at onset, presenting feature, and follow-up data. RESULTS: One hundred five patients were included in the study. Neurologic trajectories were categorized into 6 groups: patients with childhood-onset extrapyramidal (EP) features with cerebellar symptoms developing later (group 1; 18 patients), childhood-onset cerebellar symptoms, with EP features developing later (group 2; 35 patients), childhood- to adolescence-onset dystonia, without cerebellar symptoms (group 3; 23 patients), childhood- to adolescence-onset isolated cerebellar symptoms (group 4; 22 patients), childhood- to adult-onset prominent muscle weakness (group 5; 2 patients), and patients with adult-onset EP features, with anterior horn cell disease arising subsequently (group 6; 5 patients). CONCLUSIONS: This systematic study of the different motor abnormalities and their course over time in patients with mild phenotypes of A-T, enabled us to recognize 6 essentially different phenotypic patterns. Awareness of these different trajectories of motor abnormalities in milder forms of A-T will contribute to a reduction of diagnostic delay in this severe multisystem disorder.
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Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/diagnóstico , Trastornos del Movimiento/etiología , Adulto , Edad de Inicio , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Estudios de Cohortes , Bases de Datos Bibliográficas/estadística & datos numéricos , Femenino , Humanos , Masculino , Mutación/genética , FenotipoRESUMEN
Variation in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene plays a significant role in determining susceptibility to autoimmune thyroid disease and type 1 diabetes. Its role in multiple sclerosis is more controversial. In order to explore this logical candidate more thoroughly, we genotyped 771 multiple sclerosis trio families from the United Kingdom for the 3' untranslated region variable number tandem repeat, the CT60 single nucleotide polymorphism (SNP) and five haplotype-tagging SNPs. No individual marker or common haplotype showed evidence of association with disease. These data suggest that any effect of CTLA-4 on multiple sclerosis susceptibility is likely to be very small.
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Antígenos de Diferenciación/genética , Esclerosis Múltiple/genética , Polimorfismo Genético/genética , Regiones no Traducidas 3'/fisiología , Adulto , Antígenos CD , Antígeno CTLA-4 , Distribución de Chi-Cuadrado , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Repeticiones de Minisatélite/genética , Esclerosis Múltiple/epidemiologíaRESUMEN
The hereditary spastic paraplegias (HSPs) are a group of genetic conditions in which spastic paralysis of the legs is the principal clinical feature. This is caused by a relatively selective distal axonal degeneration involving the longest axons of the corticospinal tracts. Consequently, these conditions provide an opportunity to identify genes, proteins and cellular pathways that are critical for axonal health. In this review, we will provide a brief overview of the classification, clinical features and genetics of HSP, highlighting selected HSP subtypes (i.e. those associated with thin corpus callosum or cerebellar ataxia) that are of particular clinical interest. We will then discuss appropriate investigation strategies for HSPs, suggesting how these might evolve with the introduction of next-generation sequencing technology. Finally, we will discuss the management of HSP, an area somewhat neglected by HSP research.
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Análisis de Secuencia de ADN/métodos , Paraplejía Espástica Hereditaria , Cuerpo Calloso/patología , Humanos , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/terapiaRESUMEN
Individual genotyping of the 10 most promising markers identified in our previously reported screen for linkage disequilibrium (LD) in multiple sclerosis identified a number of effects which confound the analysis and are of general importance in the interpretation of results obtained using microsatellite markers typed in pooled DNA. In order to identify and characterise these effects, we individually genotyped 529 promising markers in 16 trio families. We then devised adapting factors, which were designed to correct for these confounders. This more extensive analysis of the previously published UK data set and the repeat analyses incorporating these adaptations led to the identification of two novel markers that may be associated with multiple sclerosis in this population, providing a close correlation between the results of pooled analysis and individual typing.
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Pruebas Genéticas/métodos , Genoma Humano , Desequilibrio de Ligamiento , Esclerosis Múltiple/genética , Repeticiones de Dinucleótido , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Pruebas Genéticas/estadística & datos numéricos , Genotipo , Prueba de Histocompatibilidad/estadística & datos numéricos , Humanos , Repeticiones de Microsatélite , Esclerosis Múltiple/epidemiología , Repeticiones de Trinucleótidos , Reino Unido/epidemiologíaRESUMEN
We report on a genome-wide screen for association with multiple sclerosis (MS) in the German population performed using 6000 microsatellite markers. These markers were typed in four DNA pools consisting of 234 MS patients (cases), 209 unrelated controls, 68 index patients from trio families and their 136 parents (related controls). Stringent analysis identified 11 markers showing apparent evidence for association. Five from regions previously identified in linkage studies and two from the MHC region on chromosome 6p21. These MHC markers are known to be in linkage disequilibrium with HLA class II alleles influencing susceptibility to MS. The identification of these markers serves as an important positive control.
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Pruebas Genéticas/métodos , Genoma Humano , Desequilibrio de Ligamiento , Esclerosis Múltiple/genética , Adulto , Alelos , Femenino , Frecuencia de los Genes , Alemania/epidemiología , Humanos , Cooperación Internacional , Masculino , Repeticiones de Microsatélite , Esclerosis Múltiple/epidemiologíaRESUMEN
Genome-wide screens for linkage in multiplex families with multiple sclerosis (MS) from United Kingdom, Sardinia, Italy and the Nordic countries (Denmark, Finland, Norway and Sweden) have each shown suggestive or potential linkage on chromosome 10. The partially overlapping regions identified by these studies encompass around 60 cM of the chromosome. In order to explore this region further, we typed 13 microsatellite markers in the same 449 families originally studied in the individual screens. This additional genotyping increased the information extraction in the region from 52% to 79% and revealed increased support for linkage (MLS 2.5) peaking at 10p15.
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Cromosomas Humanos Par 10/genética , Ligamiento Genético , Esclerosis Múltiple/genética , Hermanos , Alelos , Finlandia/epidemiología , Pruebas Genéticas/métodos , Genotipo , Humanos , Cooperación Internacional , Italia/epidemiología , Repeticiones de Microsatélite/genética , Esclerosis Múltiple/epidemiología , Países Escandinavos y Nórdicos/epidemiología , Programas InformáticosRESUMEN
Recent years have witnessed considerable advances in our understanding of monogenic neurodegenerative diseases, such as hereditary motor sensory neuropathy and Huntington's Chorea. Progress has been slower in the genetic dissection of other more common neurological diseases with a complex mode of inheritance. The identification of relevant genes in some, such as Alzheimer's disease (AD) or Parkinson's disease (PD), has been facilitated by characteristic pathological findings and autosomal dominant inheritance in a proportion of early onset families. Attempts to identify relevant genes for multiple sclerosis have highlighted the role of the major histocompatibility complex, but so far failed to unequivocally implicate other immunologic or structural candidate genes. Six linkage-based whole genome screens have been completed in multiple sclerosis and several regions of interest have been identified. As technology and progress in the human genome project advance, it has become clear that future studies of common neurological diseases will depend critically on the availability of large sample sizes and will have to address issues of disease heterogeneity.
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Esclerosis Múltiple/genética , Enfermedades del Sistema Nervioso/genética , Predisposición Genética a la Enfermedad , Genoma Humano , HumanosRESUMEN
OBJECTIVES: To report our approach to the surgical management of vestibular schwannomas (VSs) and hearing rehabilitation in neurofibromatosis Type 2 (NF2). DESIGN: Retrospective cohort study. SETTING: Tertiary referral NF2 unit. PATIENTS: Between 1981 and 2011, seventy-five patients were managed in our NF2 unit, of which, 58 patients are under current review. MAIN OUTCOME MEASURES: Patients who underwent VS excision were evaluated for tumor size, surgical approach, and outcomes of hearing and facial nerve function. All current patients were evaluated for NF2 mutation, hearing, and auditory implantation outcomes. RESULTS: Forty-four patients underwent resection of 50 VS in our unit, of which, 14% had facial neuroma excision and reinnervation during the same operation. At 12 months after surgery, facial nerve outcomes were House-Brackmann (HB) 1 in 33%, HB2 in 21%, and HB3 in 30%. Total VS resection was achieved in 78% of patients using a translabyrinthine approach. Seventy-two percent of the current patients have American Association of Otolaryngology-Head and Neck Surgery class A to C hearing (maximum speech discrimination score over 50%) in the better hearing ear, and a further 14% are full-time users of cochlear implants or auditory brainstem implants. The remaining patients have been assessed for auditory implantation. CONCLUSION: By following a policy of treating VS in NF2 patients where tumor growth is observed, complete tumor resection can be achieved through a translabyrinthine approach while achieving comparable facial nerve outcomes to published series. We advocate proactive hearing rehabilitation in all patients with timely assessment for auditory implantation to maintain quality of life.
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Pérdida Auditiva/rehabilitación , Neurofibromatosis 2/rehabilitación , Neurofibromatosis 2/cirugía , Neuroma Acústico/rehabilitación , Neuroma Acústico/cirugía , Procedimientos Quirúrgicos Otológicos/métodos , Adolescente , Adulto , Anciano , Audiometría de Tonos Puros , Implantes Auditivos de Tronco Encefálico , Niño , Preescolar , Implantación Coclear , Implantes Cocleares , Estudios de Cohortes , Nervio Facial/fisiología , Femenino , Estudios de Seguimiento , Genes de la Neurofibromatosis 2 , Genotipo , Audición/fisiología , Pruebas Auditivas , Humanos , Lactante , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación/fisiología , Neurofibromatosis 2/complicaciones , Neuroma Acústico/etiología , Procedimientos Quirúrgicos Otológicos/efectos adversos , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenAsunto(s)
Botulismo/complicaciones , Botulismo/diagnóstico , Dependencia de Heroína/complicaciones , Oftalmoplejía/etiología , Trastornos del Habla/etiología , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Dependencia de Heroína/microbiología , Humanos , Intubación Intratraqueal , Masculino , Examen Neurológico , Oftalmoplejía/microbiología , Trastornos del Habla/microbiología , Abuso de Sustancias por Vía Intravenosa/microbiología , Heridas y Lesiones/microbiologíaRESUMEN
Linkage analysis in multiplex families has provisionally identified several genomic regions where genes influencing susceptibility to multiple sclerosis are likely to be located. It is anticipated that association mapping will provide a higher degree of resolution, but this more powerful approach is limited by the substantial genotyping effort required. Here, we describe the first use of DNA pooling to screen the whole genome for association in multiple sclerosis based on a 0.5 cM map of microsatellite markers and using four DNA pools derived from cases (n = 216), controls (n = 219) and trio families (n = 745 affected individuals and their 1490 parents). The 10 markers showing the greatest evidence for association with multiple sclerosis that emerge from this analysis include three from the HLA region on chromosome 6p (D6S1615, D6S2444 and TNFa), providing a positive control for the method, four from regions previously identified by linkage analysis in UK multiplex families (two mapping to chromosome 17q GCT6E11 and D17S1535; one to chromosome 1p GGAA30B06; and one to 19q D19S585), and three from novel sites with respect to linkage analysis (D1S1590 at 1q; D2S2739 at 2p; and D4S416 at 4q). Our results thus provide further supporting evidence for the candidature of 6p, 17q, 19q and 1p as regions encoding susceptibililty genes for multiple sclerosis. The protocol used in this UK-based study is now being extended to 18 additional sites in Europe in order to search for susceptibility genes shared between populations of common ancestry, as well as those that exert ethnically more restricted effects.