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1.
J Med Genet ; 61(9): 856-860, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-38925914

RESUMO

OBJECTIVES: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed. METHODS: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed. RESULTS: 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1-related schwannomatosis and SMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2. CONCLUSIONS: This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.


Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromatose 2 , Neurofibromina 2 , Proteína SMARCB1 , Neoplasias Cutâneas , Humanos , Neurilemoma/genética , Neurilemoma/epidemiologia , Neurilemoma/patologia , Neurofibromatoses/genética , Neurofibromatoses/epidemiologia , Neurofibromatoses/patologia , Neurofibromatose 2/genética , Neurofibromatose 2/epidemiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Masculino , Feminino , Proteína SMARCB1/genética , Neurofibromina 2/genética , Fatores de Transcrição/genética , Prevalência , Adulto , Mutação/genética , Pessoa de Meia-Idade , Predisposição Genética para Doença , Adolescente
2.
J Peripher Nerv Syst ; 27(4): 302-310, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36190435

RESUMO

Patient-reported outcome measures engage patients in disease severity measurement and the metrics reported can be meaningful to their lives. The Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes syndrome (POEMS) is a complex multisystem disorder with disabling neuropathy which is distinct from other acquired inflammatory neuropathies. No current POEMS-specific validated disability scales exist. To address this, we have produced a Rasch-built overall disability scale (RODS) specific to POEMS. A 146-item preliminary questionnaire containing relevant activity and participation items for neuropathic disability was applied to 49 clinically stable patients with POEMS from the UK national POEMS cohort. A total of 123 items not fulfilling Rasch model expectations were sequentially removed. The final 23-item POEMS-RODS fulfilled Rasch model expectations and showed acceptable test-retest reliability. The 23-item POEMS-RODS is a disease-specific patient-reported outcome measure able to detect activity limitations within the range of ability demonstrated by the UK POEMS cohort. Larger international studies are needed to confirm the broader applicability and responsiveness of this scale in other countries.


Assuntos
Pessoas com Deficiência , Síndrome POEMS , Humanos , Síndrome POEMS/diagnóstico , Reprodutibilidade dos Testes , Inquéritos e Questionários , Índice de Gravidade de Doença
3.
Brain ; 144(2): 584-600, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33559681

RESUMO

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.


Assuntos
Proteínas da Matriz Extracelular/genética , Neuropatia Hereditária Motora e Sensorial/genética , Adulto , Idoso , Animais , Comportamento Animal/fisiologia , Criança , Feminino , Neuropatia Hereditária Motora e Sensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Mutação , Linhagem , Adulto Jovem , Peixe-Zebra
4.
Brain ; 144(2): 682-693, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33313649

RESUMO

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.


Assuntos
COVID-19/epidemiologia , Síndrome de Guillain-Barré/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , SARS-CoV-2 , Reino Unido/epidemiologia , Adulto Jovem
5.
Pract Neurol ; 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35850979

RESUMO

In clinical neurology practice, there are few sensitive, specific and responsive serological biomarkers reflecting pathological processes affecting the peripheral nervous system. Instead, we rely on surrogate multimodality biomarkers for diagnosis and management. Correct use and interpretation of the available tests is essential to ensure that appropriate treatments are used and adjusted in a timely fashion. The incorrect application or interpretation of biomarkers can result in misdiagnosis and delays in appropriate treatment. Here, we discuss the uses and limitations of such biomarkers and discuss possible future developments.

7.
Disabil Rehabil ; 43(17): 2502-2510, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-31838877

RESUMO

AIM: Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome is a rare condition with an estimated prevalence rate of 0.3 per 100,000 people. Patient perspectives on healthcare experiences and quality of life have not yet been studied in depth. This novel study aimed to explore one person's lived experience of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome, taking into consideration healthcare experiences in relation to diagnosis and treatment. METHOD: A mixed-method design was used; one participant completed a semi-structured interview and three self-report measures: Hospital Anxiety and Depression Scale; World Health Organisation Quality of Life Scale (brief); Brief Illness Perception Questionnaire. RESULTS: Three qualitative themes appeared to influence the participant's healthcare experiences and quality of life: (1) Diagnosis and treatment, (2) identity and adjustment, and (3) recovery. Diagnosis and treatment summarised the patient's journey to receiving her diagnosis and the difficulties with treatment for this condition. Identity and adjustment included pre and post-diagnosis identity, frustrations and coping strategies. Recovery included experiences of progression and decline and service provision. CONCLUSION: All Multidisciplinary Team (MDT) interventions for Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome should be person-centred and focus on identity and personal strengths. Further research and service development should be completed to increase awareness and understanding of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome, promote patient wellbeing, reduce psychological distress, and facilitate engagement in neurorehabilitation.Implications for rehabilitationPolyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome is a rare condition and incorrect diagnoses and treatment have a significant impact on patients' physical and psychological wellbeing.Patients and families require support through person-centred care and good communication and continuity of care between multiple services.Multi-disciplinary interventions which focus on identity and strengths were beneficial for the participant in this case study.Further research and education are needed to increase knowledge on patient experiences of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes (POEMS) Syndrome and continue to improve service provision.


Assuntos
Síndrome POEMS , Paraproteinemias , Atenção à Saúde , Feminino , Humanos , Síndrome POEMS/diagnóstico , Síndrome POEMS/terapia , Qualidade de Vida
8.
J Neurol ; 268(4): 1485-1490, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33608795

RESUMO

INTRODUCTION: Individualized dosing is an established approach in intravenous immunoglobulin (IVIg) treatment for inflammatory neuropathies. There is less experience in effective dosing strategies for subcutaneous (SC) immunoglobulin. METHODS: We conducted a retrospective cohort study of patients with inflammatory neuropathies transferring from IVIg to SCIg in two UK peripheral nerve services. I-RODS and grip strength were used to measure outcome. Dose and clinical progress were documented at 1 year and at last review. RESULTS: 44/56 patients remained on maintenance SCIg beyond 1 year (mean 3.3 years, range 1-9 years) with stable clinical outcomes. Clinical deteriorations were corrected by small increases in SCIg dose in 20 patients at 1 year, a further 9 requiring subsequent further up-titrations. Sixteen tolerated dose reduction. Mean dose change was + 2.4% from baseline. Two patients required IVIg bolus rescue (2 g/kg). Three patients successfully discontinued Ig therapy. Nine patients returned to IVIg due to clinical relapse or patient preference. Overall tolerance was good. DISCUSSION: Dose titration to clinical response is an effective approach in SCIg maintenance therapy.


Assuntos
Neurite (Inflamação) , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Infusões Intravenosas , Infusões Subcutâneas , Injeções Subcutâneas , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Estudos Retrospectivos
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