RESUMO
OBJECTIVE: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. METHODS: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. RESULTS: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10-7 ). Coimmunoprecipitation and mass spectroscopy studies identified ß-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. INTERPRETATION: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316-330.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Pé/fisiopatologia , Proteínas Ativadoras de GTPase/genética , Genes Modificadores/genética , Debilidade Muscular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Proteínas da Mielina/genética , Neurilemoma/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Ratos , Índice de Gravidade de Doença , Adulto JovemRESUMO
INTRODUCTION: This study evaluates carpal tunnel syndrome (CTS) symptom severity, functional status, and outcome of CTS therapies in patients with inherited neuropathies. METHODS: Validated questionnaires were used to compare symptom severity and functional status in patients with and without a diagnosis of CTS and a diagnosis of an inherited neuropathy. RESULTS: 309 patients with inherited neuropathies participated in this study. The CTS symptom severity score (SSS) was found to be the most useful tool in assessing CTS severity in patients with inherited neuropathy. Splint therapy and surgery were associated with significant improvement in carpal tunnel symptoms as measured through the SSS. DISCUSSION: This study provides insight into the assessment of CTS symptom severity and patient-reported outcomes to CTS therapy in individuals with inherited neuropathies. The SSS appears useful for evaluation of CTS symptoms and patient-reported outcomes following CTS interventions in individuals with inherited neuropathies. Muscle Nerve 57: 388-394, 2018.
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Síndrome do Túnel Carpal/diagnóstico , Doença de Charcot-Marie-Tooth/complicações , Nervo Mediano/fisiopatologia , Adulto , Idoso , Síndrome do Túnel Carpal/complicações , Síndrome do Túnel Carpal/fisiopatologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9). CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.
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Doença de Charcot-Marie-Tooth/diagnóstico , Modelos Teóricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability. OBJECTIVE: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A. METHODS: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study. RESULTS: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6â:â30773314, Pâ=â9.91×10-7, odds ratioâ=â3.288), hearing loss (lead SNP rs7720606, chr5â:â126551732, Pâ=â2.08×10-7, odds ratioâ=â3.439), decreased ability to feel (lead SNP rs17629990, chr4â:â171224046, Pâ=â1.63×10-7, odds ratioâ=â0.336), and CMT neuropathy score (lead SNP rs12137595, chr1â:â4094068, Pâ=â1.14×10-7, betaâ=â3.014). CONCLUSIONS: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.
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Doença de Charcot-Marie-Tooth/genética , Genes Modificadores/genética , Estudo de Associação Genômica Ampla , Genótipo , HumanosRESUMO
This study determines the impact of symptoms associated with Charcot-Marie-Tooth disease on quality-of-life. Charcot-Marie-Tooth patients in the Inherited Neuropathies Consortium Rare Diseases Clinical Research Network Contact Registry were surveyed. The survey inquired about 214 symptoms and 20 themes previously identified as important to Charcot-Marie-Tooth patients through patient interviews. Symptom population impact was calculated as the prevalence multiplied by the relative importance of each symptom identified. Prevalence and symptom impact were analyzed by age, symptom duration, gender, Charcot-Marie-Tooth type, and employment status. 407 participants returned the survey, identifying foot and ankle weakness (99.7%) and impaired balance (98.6%) as the most prevalent themes. Foot and ankle weakness and limitations with mobility were the themes with the highest impact. Both symptom prevalence and impact gradually increased with age and symptom duration. Several themes were more prevalent in women with Charcot-Marie-Tooth, including activity limitations, pain, fatigue, hip-thigh weakness, and gastrointestinal issues. All of the themes, except emotional or body image issues, were more prevalent among unemployed individuals. There were minimal differences in symptom prevalence between Charcot-Marie-Tooth types. There are multiple symptoms that impact Charcot-Marie-Tooth quality-of-life in adults. These symptoms have different levels of importance, are readily recognized by patients, and represent critical areas of Charcot-Marie-Tooth health.