RESUMO
BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient-reported Rasch-built interval scale on activity and participation for FSHD. METHODS: A pre-phase FSHD-Rasch-built overall disability scale (pre-FSHD-RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease-related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2-4 weeks; reliability studies). The pre-FSHD-RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. RESULTS: The pre-FSHD-RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38-inquiry (originating from 32 items; six items split) FSHD-RODS was constructed achieving Rasch model expectations. Adequate test-retest reliability and (cross-cultural and external) validity scores were obtained. CONCLUSIONS: The FSHD-RODS is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.
Assuntos
Pessoas com Deficiência , Distrofia Muscular Facioescapuloumeral , Avaliação da Deficiência , Humanos , Distrofia Muscular Facioescapuloumeral/diagnóstico , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Genetic testing strategies such as next-generation sequencing (NGS) panels and whole genome sequencing (WGS) can be applied to the hereditary cerebellar ataxias (HCAs), but their exact role in the diagnostic pathway is unclear. We aim to determine the yield from genetic testing strategies and the genetic and phenotypic spectrum of HCA in Australia by analysing real-world data. We performed a retrospective review on 87 HCA cases referred to the Neurogenetics Clinic at the Royal North Shore Hospital, Sydney, Australia. Probands underwent triplet repeat expansion testing; those that tested negative had NGS-targeted panels and WGS testing when available. In our sample, 58.6% were male (51/87), with an average age at onset of 37.1 years. Individuals with sequencing variants had a prolonged duration of illness compared to those with a triplet repeat expansion. The detection rate in probands for routine repeat expansion panels was 13.8% (11/80). NGS-targeted panels yielded a further 11 individuals (11/32, 34.4%), with WGS yielding 1 more diagnosis (1/3, 33.3%). NGS panels and WGS improved the overall diagnostic rate to 28.8% (23/80) in 14 known HCA loci. The genetic findings included novel variants in ANO10, CACNA1A, PRKCG and SPG7. Our findings highlight the genetic heterogeneity of HCAs and support the use of NGS approaches for individuals who were negative on repeat expansion testing. In comparison to repeat disorders, individuals with sequencing variants may have a prolonged duration of illness, consistent with slower progression of disease.
Assuntos
Ataxia Cerebelar/genética , Heterogeneidade Genética , Adolescente , Adulto , Idoso , Austrália , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/epidemiologia , Criança , Pré-Escolar , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sequência de DNA , Expansão das Repetições de Trinucleotídeos , Adulto JovemRESUMO
OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.
Assuntos
Cardiomiopatia Dilatada/congênito , Conectina/genética , Proteínas Musculares/genética , Músculo Esquelético/patologia , Feminino , Humanos , Masculino , Mutação/genética , Fenótipo , Isoformas de Proteínas/genéticaRESUMO
There has been increasing recognition of pre-motor manifestations of Parkinson's disease (PD) resulting from early brainstem involvement. We sought to determine whether ventilatory control is abnormal. Patients with PD without respiratory disease were recruited. Spirometry, lung volumes, diffusing capacity and respiratory muscle strength were assessed. Occlusion pressure and ventilation were measured with increasing CO(2). Arterial blood gases were taken at rest and following 20 min exposure to 15% O(2). A linear correlation assessed associations between respiratory function and indices of PD severity. 19 subjects (17 males) with mild-moderate PD were studied (mean (SD) age 66 (8) years). Respiratory flows and volumes were normal in 16/19. Maximum inspiratory and expiratory pressures were below LLN in 13/19 and 15/19 respectively. 7/15 had a reduced ventilatory response to hypercapnia and 11/15 had an abnormal occlusion pressure. There was no correlation between impairment of ventilatory response and reduction in respiratory muscle strength. Response to mild hypoxia was normal and there were no associations between disease severity and respiratory function. Our findings suggest that patients with mild-moderate PD have abnormal ventilatory control despite normal lung volumes and flows.
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Doença de Parkinson/fisiopatologia , Ventilação Pulmonar/fisiologia , Respiração , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/fisiopatologia , Testes de Função RespiratóriaRESUMO
Gait disturbance and cognitive changes are common with ageing. The cerebellum contributes to motor coordination and participates in various aspects of cognition. However, no research has investigated the possible cerebellar contribution to gait and cognition in non-demented very old individuals. The current study aimed to determine the associations between indices of cerebellar size (vermal area and total volume) and measures of motor and cognitive integrity, as well as the role of variables known to impact on cerebellar size (alcohol consumption and chronological age) in a sample of 111 community dwellers (mean age: 85 years; range: 81-97 years). A marginally significant association was present between age and total vermal area. Significant correlations between current daily alcohol intake and some vermal areas were observed. These associations were more pronounced in men, particularly after controlling for cerebrum size. Multiple linear regression models revealed limited unique contributions of cerebellar predictors to neurological and cognitive measures. In summary, the results indicate that the cerebellum may be susceptible to alcohol-related shrinkage in non-demented very old individuals, more so in men, even at low dose. It also appears that the observed changes in cerebellum size in this population contribute little to neurological and cognitive changes.
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Consumo de Bebidas Alcoólicas/efeitos adversos , Cerebelo/patologia , Transtornos Cognitivos/etiologia , Marcha Atáxica/etiologia , Fatores Etários , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Atrofia , Transtornos Cognitivos/diagnóstico , Diagnóstico Diferencial , Feminino , Seguimentos , Marcha Atáxica/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Exame Neurológico , Testes Neuropsicológicos , Valores de Referência , Fatores de Risco , Estatística como Assunto , Telencéfalo/patologiaRESUMO
OBJECTIVES: To identify the clinical correlates of functional incapacity in the community living "old-old." DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: One hundred six nondemented people aged 80 to 94. MEASUREMENTS: Participants were medically and cognitively assessed, underwent magnetic resonance imaging scanning (MRI), and were interviewed regarding their functional status: activities of daily living (ADLs), instrumental ADLs (IADLs), and the complex IADL functions of reading, hobbies, and socializing. RESULTS: Dependency in IADLs, but not ADLs, was present. After controlling for age, sex, and education, extrapyramidal (EP) signs were significantly associated with two of the three IADLs, with EP signs comprising a composite score of 10 EP signs (e.g., resting tremor) and a 5-meter timed walk. Cognitive test performance on a range of tests was also associated with functional status. A hierarchical model confirmed the association between the EP signs and cognitive test performance and functional scores, but no "pattern" of cognitive association emerged. Hippocampal volume was associated with socializing. CONCLUSION: This study has shown that many nondemented very old people living in the community are losing capacity to perform IADL functions and that areas of incapacity are associated with the presence of EP signs and impaired cognition. These results highlight the need for health workers to include an assessment of EP and cognitive status in their evaluation of older persons living in the community, even in the context of a lack of dementia diagnosis. Furthermore, it signifies the need to directly evaluate IADL function to identify need for intervention and support if required. This group of old-old individuals may now be considered the "survivors" of their cohort, and early detection of the difficulties they are experiencing will enable clinicians to respond appropriately, thus providing them a higher quality of life for their years to come.
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Idoso de 80 Anos ou mais/fisiologia , Idoso de 80 Anos ou mais/psicologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Cognição/fisiologia , Atividade Motora/fisiologia , Atividades Cotidianas , Austrália , Estudos de Coortes , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Imageamento por Ressonância Magnética , Masculino , Recreação , Características de Residência , Comportamento SocialRESUMO
OBJECTIVES: To identify predictors of activity of daily living (ADL) and instrumental activity of daily living (IADL) decline in a population with subcortical vascular dementia (SVD) and to evaluate potential mechanism of decline. DESIGN: Longitudinal. SETTING: Hospital-based. PARTICIPANTS: Computed tomographic (CT) scanning identified 77 participants as having subcortical infarction. MEASUREMENTS: Participants were neurologically, neuropsychologically, behaviorally, and functionally assessed four times over 5.82 years. Baseline data were grouped into four modules: basic demographic and risk factor, CT scan, neurological and other clinical, and neuropsychological and behavioral. Multivariate analysis determined predictors of decline in ADLs and IADLs. RESULTS: Predictors of ADL decline were age, alcohol consumption, coordination, snout reflex, and performance on a neuropsychological test (Block Design). Predictors of IADL decline were predominantly cognitive and included the presence of paratonia and performance on the two neuropsychological tests (attention and memory tasks). CONCLUSION: These findings suggest that cognitive impairments are most likely to have an effect on IADL function, because the skills involved are complex and involve integrative activity, whereas physical and cognitive impairments combined are likely to compromise ADL function, given the more basic and physical nature of the functions involved. These findings indicate that in people with SVD, both ADL and IADL status should be monitored, because, for many, decline in function over time is likely, and thus the provision of appropriate support required.