RESUMO
BACKGROUND: The non-genetic factors predisposing to trigger finger (TF) have mostly been characterised in small studies from individual institutions. Here, we aimed to provide a more complete picture of TF and its associations. METHODOLOGY: This case-control study used cross-sectional data from the UK Biobank population-based cohort to identify and determine the strength of associations of phenotypic variables with TF. We performed multivariable logistic regression of a multitude of phenotypic factors associated with TF. RESULTS: We identified 2250 individuals with medical and surgical diagnostic codes for TF, and 398,495 controls. TF was found to be significantly associated with age (OR 1.04, 95% CI 1.03-1.04, P < 2.23×10-308), female sex (OR 1.22, 95% CI 1.08-1.39, P = 2.35×10-3), body mass index (OR 1.10, 95% CI 1.04-1.16, P = 5.52×10-4), carpal tunnel syndrome (OR 9.59, 95% CI 8.68-10.59, P < 2.23×10-308), Dupuytren's disease (OR 4.89, 95% CI 4.06-5.89, P < 2.23×10-308), diabetes mellitus without complications (OR 1.35, 95% CI 1.15-1.58, P = 2.03×10-4) and with complications (OR 2.46, 95% CI 1.90-3.17, P = 4.98×10-12), HbA1c (OR 1.01, 95% CI 1.01-1.02, P = 8.99×10-9), hypothyroidism (OR 1.24, 95% CI 1.07-1.43, P = 4.75×10-3) and rheumatoid arthritis (OR 1.33, 95% CI 1.06-1.68, P = 0.014). CONCLUSION: Our results provide evidence supporting the well-known risk factors such as diabetes mellitus, carpal tunnel syndrome, age and female sex. Furthermore, we can confirm putative associations such as hypothyroidism, obesity and rheumatoid arthritis, while providing evidence against others such as hypertension and hyperlipidaemia. A novel finding arising from this study is the strong association with Dupuytren's disease. Our study design allowed us to identify these associations as being independent from carpal tunnel syndrome, thereby indicating a shared pathophysiology between this disease and TF.
Assuntos
Dedo em Gatilho , Humanos , Dedo em Gatilho/genética , Dedo em Gatilho/epidemiologia , Feminino , Masculino , Estudos de Casos e Controles , Pessoa de Meia-Idade , Estudos Transversais , Fatores de Risco , Reino Unido/epidemiologia , Idoso , Fatores Sexuais , Adulto , Fatores Etários , Índice de Massa Corporal , Síndrome do Túnel Carpal/genética , Contratura de Dupuytren/genética , Contratura de Dupuytren/epidemiologiaRESUMO
OBJECTIVE: To evaluate the association of carpal tunnel syndrome (CTS) with incident heart failure and incident amyloidosis and to assess the risk of CTS in pathogenic TTR genetic variant carriers. METHODS: This prospective cohort study included multiethnic US adults 18 years of age and older without prevalent heart failure and amyloidosis with available genotypic data from the All of Us Research Program. The primary outcomes were incident heart failure and incident amyloidosis. The association of incident heart failure and incident amyloidosis with CTS was assessed using multivariable adjusted Cox models accounting for age, sex, race and ethnicity, obesity, hypertension, diabetes, statin use, and smoking status. RESULTS: Of the 166,987 individuals included, the median age was 54 (38 to 66) years; 105,279 (63.0%) were female, and 92,780 (55.6%) were non-Hispanic White individuals; CTS was identified in 12,407 (7.4%) individuals. Compared with individuals without CTS, the adjusted hazard ratio for incident heart failure was 1.13 (95% CI, 1.02 to 1.26) in individuals with CTS. The risk of amyloidosis was â¼3-fold higher (adjusted hazard ratio, 2.86; 95% CI, 1.71 to 4.77) in individuals with CTS compared with those without CTS. Individuals carrying a pathogenic TTR variant had an approximately 40% higher risk (adjusted hazard ratio, 1.38; 95% CI, 1.16 to 1.65) for development of CTS compared with noncarriers. CONCLUSION: Cardiac amyloidosis screening programs may use CTS as a sentinel event and use genetic testing to identify individuals at a higher risk of TTR amyloidosis.
Assuntos
Neuropatias Amiloides Familiares , Síndrome do Túnel Carpal , Insuficiência Cardíaca , Humanos , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/complicações , Estudos Prospectivos , Estados Unidos/epidemiologia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/etiologia , Idoso , Adulto , Incidência , Pré-Albumina/genética , Fatores de RiscoRESUMO
BACKGROUND: Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions. METHODS: In the UK Biobank's unrelated European cohort (N = 379â708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren's disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. RESULTS: Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 [95% confidence interval (CI), 1.20-1.88], Dupuytren's disease: OR = 1.17 (95% CI, 1.01-1.35), trigger finger: OR = 1.30 (95% CI, 1.09-1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09-1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93-17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50-5.44) but not Dupuytren's disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10-1.16) and associated negatively with Dupuytren's disease: OR = 0.94 (95% CI, 0.90-0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42-2.69) P = 3.6e-05) and carpal tunnel syndrome [OR 1.63 (95% CI, 1.36-1.95) P = 8.5e-08] are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat. CONCLUSIONS: Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications.
Assuntos
Bursite , Síndrome do Túnel Carpal , Diabetes Mellitus , Contratura de Dupuytren , Hiperglicemia , Doenças Musculoesqueléticas , Dedo em Gatilho , Humanos , Contratura de Dupuytren/epidemiologia , Contratura de Dupuytren/genética , Contratura de Dupuytren/complicações , Síndrome do Túnel Carpal/epidemiologia , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/complicações , Dedo em Gatilho/complicações , Hiperglicemia/complicações , Hiperglicemia/epidemiologia , Hiperglicemia/genética , Extremidade Superior , Doenças Musculoesqueléticas/complicações , Fatores de Risco , Bursite/complicações , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genéticaRESUMO
PURPOSE: To investigate the health-related factors and analyze the expression of epigenetic related genes and inflammatory genes in metabolic syndrome Trigger Finger (TF) and smoker TF. METHODS: Samples from patients' fingers with symptomatic TF were collected. There were seven groups: healthy control group, carpal tunnel syndrome (as a control for gene expression analysis), TF, diabetic TF, hypertensive TF, dyslipidemic TF and smoker TF. The expression levels of epigenetic related genes and inflammatory genes in metabolic syndrome TF and smoker TF were evaluated by the reverse transcription-polymerase chain reaction (RT-PCR) technique. The Perceived Stress Scale (PSS), Pittsburgh Sleep Quality Index (PSQI) questionnaires, disability of the arm, shoulder and hand (DASH) and numeric pain rating scale were given to the participants to fill out. RESULTS: There was a significant increase in hand dysfunction in the metabolic TF groups and smoker group compared to the TF group (p < 0.0001). The stress levels of the smoker TF group and TF with hypertension group were significantly increased compared with those in the TF group (p < 0.03) and (p < 0.021), respectively. On the other hand, there was a significant increase in the COL-I, COL-II and TNF-α gene expression of the metabolic TF groups and smoker group (p < 0.0001). CONCLUSIONS: Health-related factors in the TF tendons was highly associated with the level of inflammation and genetic alteration in TF metabolic syndromes and smoker TF patients. Therefore, further investigation is required to examine the combination of occupational therapy, gene expression, and health-related factors as a promising method of managing TF.
Assuntos
Síndrome do Túnel Carpal , Síndrome Metabólica , Dedo em Gatilho , Humanos , Dedo em Gatilho/genética , Síndrome Metabólica/genética , Síndrome Metabólica/complicações , Fumantes , Tendões , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/complicações , Epigênese Genética/genéticaRESUMO
INTRODUCTION: Hereditary gelsolin (AGel) amyloidosis is a systemic disease that is characterised by neurologic, ophthalmologic, dermatologic, and other organ involvements. We describe the clinical features with a focus on neurological manifestations in a cohort of patients with AGel amyloidosis referred to the Amyloidosis Centre in the United States. METHODS: Fifteen patients with AGel amyloidosis were included in the study between 2005 and 2022 with the permission of the Institutional Review Board. Data were collected from the prospectively maintained clinical database, electronic medical records and telephone interviews. RESULTS: Neurologic manifestations were featured in 15 patients: cranial neuropathy in 93%, peripheral and autonomic neuropathy in 57% and bilateral carpal tunnel syndrome in 73% of cases. A novel p.Y474H gelsolin variant featured a unique clinical phenotype that differed from the one associated with the most common variant of AGel amyloidosis. DISCUSSION: We report high rates of cranial and peripheral neuropathy, carpal tunnel syndrome and autonomic dysfunction in patients with systemic AGel amyloidosis. The awareness of these features will enable earlier diagnosis and timely screening for end-organ dysfunction. The characterisation of pathophysiology will assist the development of therapeutic options in AGel amyloidosis.
Assuntos
Neuropatias Amiloides Familiares , Síndrome do Túnel Carpal , Amiloidose de Cadeia Leve de Imunoglobulina , Doenças do Sistema Nervoso , Disautonomias Primárias , Humanos , Gelsolina/genética , Gelsolina/metabolismo , Síndrome do Túnel Carpal/genética , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/genética , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/genéticaRESUMO
BACKGROUND: The recent availability of disease-modifying therapies for hereditary transthyretin amyloid (ATTRv) amyloidosis warrants urgency for earlier diagnosis and timely identification of active disease state among genetic carriers. METHODS: We reviewed clinical neurological data of all patients with ATTRv amyloidosis with initial visits at our amyloidosis centre between January 2016 and December 2018. We abstracted the signs and symptoms of neurological manifestations, as well as rates and patterns of diagnostic testing. RESULTS: Of 92 patients with 19 different transthyretin (TTR) mutations, 66 and 36% had symptoms attributed to large-fibre and small-fibre neuropathy, respectively, compared to 75 and 66% with corresponding examination findings. Thirty-six patients with V122I ATTR mutation had asymptomatic polyneuropathy identified on neurological examination, eight without concurrent cardiac disease. Seventy-three percent of patients had symptoms of carpal tunnel syndrome (CTS), while 26% had dysautonomia. The average delays between the onset of symptoms of large fibre neuropathy (LFN) or CTS to ATTRv amyloidosis diagnosis were 2.9 and 6.7 years, respectively. DISCUSSION: Our study found higher rates of polyneuropathy by examination than patient-reported symptoms, especially among those with V122I TTR amyloidosis, signalling asymptomatic polyneuropathy. Our findings suggest the need for routine neurological examinations and other testing for genetic carriers to achieve earlier identification of active disease state.
Assuntos
Neuropatias Amiloides Familiares , Síndrome do Túnel Carpal , Polineuropatias , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Síndrome do Túnel Carpal/genética , Diagnóstico Tardio , Humanos , Pré-Albumina/genéticaRESUMO
BACKGROUND: Carpal tunnel steroid injection is a nonoperative intervention for the treatment for idiopathic carpal tunnel syndrome (CTS). The antifibrotic, anti-inflammatory, and antiedematous properties of steroids account for their therapeutic effects in the context of CTS; however, their relative contribution has not been clarified. METHODS: Fibroblasts from subsynovial connective tissues (SSCT) were intraoperatively collected from patients with idiopathic CTS and were incubated with or without the steroid triamcinolone acetonide (TA) for 1, 3, and 7 days; the expression of fibrosis-related genes and inflammatory cytokines was evaluated using quantitative reverse transcription-polymerase chain reaction. A clinical prospective study was conducted with patients who received carpal tunnel TA injections. We performed clinical and electrophysiological evaluations before and 1, 3, and 5 months after TA injection; and we compared the median nerve, flexor tendon, and SSCT areas and the median nerve flattening ratio before and 1 month after TA injection using 3-T magnetic resonance imaging (MRI). RESULTS: TA induced downregulation of the fibrosis-related genes Col1A1 (collagen type I alpha 1 chain), Col1A2, and Col3A1 but not the inflammation-related genes. The nerve flattening ratio did not change after TA injection according to the MRI-based observation of the median nerve, flexor tendon, and SSCT areas. CONCLUSIONS: The therapeutic effects of injected TA are apparently mediated by its antifibrotic rather than its anti-inflammatory and antiedematous properties. TA probably alters the properties but not the morphology of SSCT. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
Assuntos
Antifibróticos/administração & dosagem , Síndrome do Túnel Carpal/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Triancinolona Acetonida/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antifibróticos/farmacologia , Síndrome do Túnel Carpal/genética , Células Cultivadas , Feminino , Fibrose/tratamento farmacológico , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Membrana Sinovial/efeitos dos fármacos , Triancinolona Acetonida/farmacologiaRESUMO
BACKGROUND AND AIMS: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. METHODS: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007-2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. RESULTS: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (ageâ<â50 years) with the following variants: ATTR-V30M (p.Val50Met), ATTR-G47A (p.Gly67Ala), ATTR-S50I (p.Ser70Ile) and ATTR-A97S (p.Ala117Ser); one patient with ATTR-A97S (p.Ala117Ser) had isolated unilateral carpal tunnel syndrome with amyloid deposits identified on histological examination of the transverse carpal ligament. All early-onset patients had a positive parental history; two patients, with ATTR-S50I (p.Ser70Ile) and ATTR-Ala97Ser (p.Ala117Ser) respectively, demonstrated anticipation with mother-to-daughter inheritance. Amongst the 24 patients with late-onset disease (age≥50 years), two patients had novel variants, ATTR-G66D (p.Glu86Asp) and ATTR-A81V (p.Ala101Val) that were confirmed to be pathogenic based on the histological identification of transthyretin amyloid. Other identified variants included ATTR-V30M (p.Val50Met), ATTR-R34T (p.Arg54Thr), ATTR-S50I (p.Ser70Ile), ATTR-H88R (p.His108Arg) and ATTR-A97S (p.Ala117Ser). CONCLUSION: Our study further expands the genotypic and phenotypic knowledge regarding ATTRv amyloidosis.
Assuntos
Neuropatias Amiloides Familiares/genética , Adulto , Idoso , Sudeste Asiático , Síndrome do Túnel Carpal/genética , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , SingapuraRESUMO
BACKGROUND: Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers. METHODS: Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers. RESULTS: Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p < 0.01), in the subgroup of TTR-CTS subjects (16 subjects, 5 with bilateral CTS) CSA did not significantly correlate with CTS severity (r = - 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p < 0.001). CONCLUSIONS: The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).
Assuntos
Síndrome do Túnel Carpal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuropatias Amiloides Familiares , Biomarcadores , Síndrome do Túnel Carpal/diagnóstico por imagem , Síndrome do Túnel Carpal/genética , Diagnóstico Tardio , Itália , Nervo Mediano/diagnóstico por imagemRESUMO
Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, affecting a large proportion of the general population. Genetic susceptibility has been implicated in CTS, but the causative genes remain elusive. Here, we report the identification of two mutations in cartilage oligomeric matrix protein (COMP) that segregate with CTS in two large families with or without multiple epiphyseal dysplasia (MED). Both mutations impair the secretion of COMP by tenocytes, but the mutation associated with MED also perturbs its secretion in chondrocytes. Further functional characterization of the CTS-specific mutation reveals similar histological and molecular changes of tendons/ligaments in patients' biopsies and the mouse models. The mutant COMP fails to oligomerize properly and is trapped in the ER, resulting in ER stress-induced unfolded protein response and cell death, leading to inflammation, progressive fibrosis and cell composition change in tendons/ligaments. The extracellular matrix (ECM) organization is also altered. Our studies uncover a previously unrecognized mechanism in CTS pathogenesis.
Assuntos
Síndrome do Túnel Carpal , Proteína de Matriz Oligomérica de Cartilagem , Animais , Síndrome do Túnel Carpal/etiologia , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/metabolismo , Síndrome do Túnel Carpal/patologia , Proteína de Matriz Oligomérica de Cartilagem/genética , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Condrócitos/patologia , Estresse do Retículo Endoplasmático/fisiologia , Matriz Extracelular/patologia , Humanos , Inflamação , Ligamentos/citologia , Ligamentos/patologia , Mutação , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Tendões/citologia , Tendões/patologia , Tenócitos/patologiaRESUMO
Sarcoidosis is a multisystemic disease that may lead to neurologic complications in 10% of the patients. Carpal tunnel syndrome is very rare in sarcoidosis. We present two identical twin sarcoidosis patients with carpal tunnel syndrome. A number of factors may cause carpal tunnel syndrome like wrist anatomy, occupation, diabetes, rheumatoid arthritis, pregnancy and renal failure. Although the above factors do not directly cause carpal tunnel syndrome, they may increase your chances of developing or aggravate median nerve damage as it is in sarcoidosis. Sarcoidosis relevant neuropathy and granulomas may be the primary mechanism of sarcoidosis associated carpal tunnel syndrome. Although rare, carpal tunnel syndrome may be a feature of sarcoidosis that may lead to irreversible damage in cases of delayed diagnosis. The presence of this syndrome in identical twin patients may shed light into the pathogenesis and the genetic transmission of sarcoidosis with the associated carpal tunnel syndrome.
Assuntos
Síndrome do Túnel Carpal/complicações , Síndrome do Túnel Carpal/genética , Cadeias HLA-DRB1/genética , Sarcoidose/complicações , Sarcoidose/genética , Adulto , Alelos , Feminino , Humanos , Polimorfismo Genético , Gêmeos Monozigóticos/genéticaRESUMO
We report the clinical features of a patient with hereditary transthyretin (ATTR) amyloidosis associated with a novel mutation (Y114S, p.Y134S). A 65-year-old Japanese man was admitted to our hospital after a 3-year history of progressive dyspnea on exertion. Five years previously, he presented dysesthesia in both hands caused by carpal tunnel syndrome. A genetic analysis revealed a base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C). The clinical characteristics were progressive cardiomyopathy with a poor vital prognosis, late onset, sporadic case, bilateral carpal tunnel syndrome, hypothyroidism, and small fiber neuropathy.
Assuntos
Neuropatias Amiloides Familiares/genética , Cardiomiopatias/genética , Pré-Albumina/genética , Idoso , Neuropatias Amiloides Familiares/fisiopatologia , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/fisiopatologia , Éxons , Testes Genéticos , Humanos , Hipotireoidismo/genética , Masculino , Mutação , Condução NervosaRESUMO
DESIGN: Randomized clinical trial. OBJECTIVE: To investigate the association of the Val158Met polymorphism with pain and function outcomes in women with carpal tunnel syndrome (CTS) who received surgery or manual therapy including desensitization manoeuvres of the central nervous system. METHODS: A pre-planned secondary analysis of a randomized controlled trial investigating the efficacy of manual therapy including desensitization manoeuvres of the central nervous system vs. surgery in 120 women with CTS was conducted. Women were randomized to receive 3 sessions of manual therapy (n = 60) or decompression of the carpal tunnel (n = 60). The primary outcome was intensity of pain (mean pain and the worst pain), and secondary outcomes included function and symptoms severity subscales of the Boston Carpal Tunnel Questionnaire. Outcomes were assessed at baseline, and 1, 3, 6, and 12 months after the intervention. Rs4680 genotypes were determined after amplifying the Val158Met polymorphism by polymerase chain reactions. We classified subjects according to their Val158Met polymorphism: Val/Val, Val/Met, or Met/Met. The primary aim (treatment group*Val158Met*time) was examined with repeated measures ANCOVA with intention-to-treat analysis. RESULTS: At 12 months, 111 (92%) women completed the follow-up. No interaction was observed between the Val158Met genotype and any outcome: mean pain intensity (F = 0.60; P = 0.69), worst pain intensity (F = 0.49; P = 0.61), function (F = 0.12; P = 0.88) or symptom severity (F = 0.01; P = 0.98). CONCLUSION: The current clinical trial did not show an association between the Val158Met polymorphism and changes in pain and function outcomes after either surgery or physical therapy in women with CTS.
Assuntos
Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/terapia , Catecol O-Metiltransferase/genética , Polimorfismo de Nucleotídeo Único , Descompressão Cirúrgica , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Manejo da Dor , Modalidades de Fisioterapia , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
Fibrosis of the subsynovial connective tissue (SSCT) is a characteristic finding in patients with idiopathic carpal tunnel syndrome (CTS). Idiopathic CTS frequently occurs in postmenopausal women; therefore, female steroid hormones, especially estrogens, may be involved in its development. In this study, we evaluated the effect of the estradiol on the expression of genes and proteins related to fibrosis of SSCT fibroblasts from patients with idiopathic CTS. This study included 10 postmenopausal women (mean age 76 years). Fibroblasts derived from SSCT were treated with estradiol (10-4 -10-12 M), and the expression levels of TGF-ß-responsive genes were evaluated. The relationships between the expression of untreated estrogen receptor α (ERα) and ERß and changes in gene expression due to estradiol treatment were examined by quantitative real-time polymerase chain reaction. The effects of 10-4 M estradiol on collagen type I (Col1) and collagen type III (Col3) protein expression levels were also evaluated by fluorescent staining. The relationships between ERα/ß and Col1/3 expression were evaluated by immunohistochemical staining. The reduction in Col1A1 mRNA expression due to estradiol treatment was positively correlated with ERα expression (r = 0.903, p < 0.01). At the protein level, expression of Col1 and Col3 were down-regulated. These results indicated that ERα-mediated signaling may be involved in the regulation of Col1A1, and its regulatory effect may be dependent on the ERα expression level. The accurate evaluation of ERα expression level in the SSCT of individual patients with idiopathic CTS might guide the effective use of new estrogen replacement therapy.
Assuntos
Síndrome do Túnel Carpal/tratamento farmacológico , Colágeno Tipo I/genética , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Fibrose/genética , Idoso , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/fisiopatologia , Cadeia alfa 1 do Colágeno Tipo I , Colágeno Tipo III/genética , Receptor beta de Estrogênio/genética , Feminino , Fibroblastos/efeitos dos fármacos , Fibrose/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/crescimento & desenvolvimento , Membrana Sinovial/patologia , Fator de Crescimento Transformador beta/genéticaRESUMO
Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) is an autosomal-dominant, adult-onset, rare systemic disorder predominantly characterized by irreversible, progressive, and persistent peripheral nerve damage. TTR gene mutations (e.g. replacement of valine with methionine at position 30 [Val30Met (p.Val50Met)]) lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, which form amyloid fibrils that deposit in peripheral nerves and various organs, giving rise to peripheral and autonomic neuropathy and several non-disease specific symptoms.Phenotypic and genetic variability and non-disease-specific symptoms often delay diagnosis and lead to misdiagnosis. Red-flag symptom clusters simplify diagnosis globally. However, in Japan, types of TTR variants, age of onset, penetrance, and clinical symptoms of Val30Met are more varied than in other countries. Hence, development of a Japan-specific red-flag symptom cluster is warranted. Presence of progressive peripheral sensory-motor polyneuropathy and ≥1 red-flag sign/symptom (e.g. family history, autonomic dysfunction, cardiac involvement, carpal tunnel syndrome, gastrointestinal disturbances, unexplained weight loss, and immunotherapy resistance) suggests ATTR-FAP. Outside of Japan, pharmacotherapeutic options are first-line therapy. However, because of positive outcomes (better life expectancy and higher survival rates) with living donor transplant in Japan, liver transplantation remains first-line treatment, necessitating a Japan-specific treatment algorithm.Herein, we present a consolidated review of the ATTR-FAP Val30Met landscape in Japan and summarize findings from a medical advisory board meeting held in Tokyo on 18th August 2016, at which a Japan-specific ATTR-FAP red-flag symptom cluster and treatment algorithm was developed. Beside liver transplantation, a TTR-stabilizing agent (e.g. tafamidis) is a treatment option. Early diagnosis and timely treatment using the Japan-specific red-flag symptom cluster and treatment algorithm might help guide clinicians regarding apt and judicious use of available treatment modalities.
Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/terapia , Algoritmos , Neuropatias Amiloides Familiares/genética , Benzoxazóis/uso terapêutico , Síndrome do Túnel Carpal/genética , Humanos , Japão , Transplante de Fígado , Metionina/química , Metionina/genética , Mutação/genética , Valina/química , Valina/genéticaRESUMO
Fibrosis of the subsynovial connective tissue (SSCT) is a pathognomonic change in carpal tunnel syndrome (CTS). Identification of molecular targets and anti-fibrotic therapies could provide new treatment strategies for CTS. The contribution of SSCT cells to fibrosis and the signaling pathways that initiate and aggravate fibrosis in CTS remain unknown. Here we report that platelet-derived growth factor receptor alpha (PDGFRα) positive ( + ) cells accumulate in CTS SSCT and that the presence of fibrotic growth factor, PDGF-AA, results in increased proliferation of PDGFRα+ cells via PI3K/Akt signaling pathway. Although PI3K inhibition decreased proliferation, there was no change in fibrosis-related gene expression. Indeed, protein levels of fibrosis signaling mediator TGF-ß remained the same and the second messenger, Smad2/3, accumulated in the nucleus. In contrast AMP-activated protein kinase (AMPK) activation, which can be induced with metformin and AICAR inhibited proliferation, TGF-ß expression, and altered cell morphology in SSCT cells. Further we show that AMPK activation by metformin reduced collagen III levels and the ratio of Collagen I to Collagen III. Both AICAR and metformin reduced F-actin and significantly reduced the fiber cross alignment. Our results suggest that PDGFRa signaling may be an important fibrosis target and that activators of AMPK, may be an important therapeutic approach for treating CTS.
Assuntos
Síndrome do Túnel Carpal/metabolismo , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Síndrome do Túnel Carpal/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteína Oncogênica v-akt/genética , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
INTRODUCTION: Carpal tunnel syndrome (CTS) is a nonspecific manifestation of hereditary ATTR amyloidosis (ATTRm). Amyloid deposition of wild-type TTR (WT-ATTR) has been found in transverse carpal ligament (TCL) in idiopathic CTS. We retrospectively studied a group of patients with ATTRm and CTS submitted to carpal tunnel release surgery (CTRS). METHODS: From the nerve conduction studies performed in our Clinical Unit dedicated to hereditary amyloidosis between July 2009 and October 2013, we selected patients who fulfilled neurophysiological criteria for CTS, had been submitted to CTRS and whose TCL was available for pathology. Clinical registries were reviewed and amyloid detection in the ligaments was performed using Congo-red staining. RESULTS: We included 16 patients: three males (18.8%), mean age = 46.1 years old, all with V30M mutation. At the time of surgery, four patients were considered asymptomatic and 12 symptomatic carriers, five of them late-onset ATTRm (onset age >50 years old). In all but one patient, the CTS preceded the polyneuropathy. Amyloid detection in the TCL was positive in 14 patients (87.5%). DISCUSSION/CONCLUSIONS: In most patients, CTS preceded or was contemporary to the polyneuropathy and amyloid detection in TCL was positive. The detection of amyloid in TCL may add specificity to CTS as an early manifestation of the disease but more studies are needed.
Assuntos
Amiloide/metabolismo , Amiloidose Familiar/metabolismo , Síndrome do Túnel Carpal/metabolismo , Ligamentos/metabolismo , Adulto , Idoso , Amiloide/genética , Amiloidose Familiar/genética , Amiloidose Familiar/patologia , Amiloidose Familiar/cirurgia , Síndrome do Túnel Carpal/genética , Síndrome do Túnel Carpal/patologia , Síndrome do Túnel Carpal/cirurgia , Feminino , Humanos , Ligamentos/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: The direct causes of idiopathic carpal tunnel syndrome (CTS) are still unknown. It is suggested that pathology of the tendons and other connective tissue structures within the carpal tunnel may play a role in its aetiology. Variants in genes encoding connective tissue proteins, such as type V collagen, have previously been associated with CTS. Since variants within other collagen genes, such as type I, XI and XII collagen, have previously been associated with modulating the risk of musculoskeletal soft tissue injuries, the aim of this study was to determine whether variants within COL1A1, COL11A1, COL11A2 and COL12A1 were associated with CTS. METHODS: Self-reported Coloured South African participants, with a history of carpal tunnel release surgery (CTS, n=103) and matched control (CON, n=150) participants without any reported history of CTS symptoms were genotyped for COL1A1 rs1800012 (G/T), COL11A1 rs3753841 (T/C), COL11A1 rs1676486 (C/T), COL11A2 rs1799907 (T/A) and COL12A1 rs970547 (A/G). RESULTS: The TT genotype of COL11A1 rs3753841 was significantly over-represented in the CTS group (21.4%) compared to CON group (7.9%, p=0.004). Furthermore, a trend for the T minor allele to be over-represented in the CTS group (p=0.055) with a significant association when only female participants (p=0.036) were investigated was observed. Constructed inferred pseudo-haplotypes including a previously investigated COL5A1 variant, rs71746744 (-/AGGG), suggest gene-gene interactions between COL5A1 and COL11A1 modulate the risk of CTS. DISCUSSION: These findings provide further information of the role of the genetic risk factors and the possible role of variations in collagen fibril composition in the aetiology of CTS. Genetic factors could potential be included in models developed to identify indivisuals at risk of CTS. Strategies that target modifiable risk factors to mitigate the effect of non-modifiable risk factors, such as the genetic risk, could be also developed to reduce incidence and morbidity of CTS.