RESUMEN
Inherited cerebellar ataxias (CA) are heterogeneous progressive neurological conditions associated with significant functional limitations. This study aimed to assess the implications of inherited CA on patients' self-reported quality of life (QoL) and impairments in work and activities. 129 individuals with ataxia responded to a survey focused on QoL. Health-related QoL was measured using the RAND 36-Item Short Form Survey. An adaptation of the validated Work Productivity and Activity Impairment questionnaire was used to assess the effect of health on work productivity and ability to perform activities over the past week. Nine percent of respondents were currently employed. Individuals with inherited ataxia experienced significant activity impairment, and 75% required professional or informal care. Health-related quality of life (HRQoL) was significantly worse in all areas for the individuals with inherited ataxia compared with Irish population normative values. Participants with Friedreich's ataxia (n = 56) demonstrated worse physical functioning then those with undetermined ataxia (n = 55). Female gender, younger age at symptom onset, current employment, retirement due to age or ataxia, and living in a long-term care facility were associated with higher sub-scores in different domains of HRQoL, while disease duration correlated with worse physical functioning sub-scores. This study is the first cross-sectional study on HRQoL in patients with inherited ataxia in Ireland. It highlights high rates of unemployment, difficulty with daily activities and physical functioning limitations, which is worse than comparative international studies. Given the limited therapeutic options currently available, optimising HRQoL is an important aspect of managing ataxia.
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Inherited ataxias are a heterogenous group of neurodegenerative disorders characterised by progressive impairment of balance and coordination, typically leading to permanent and progressive disability. Diagnosis and management of these disorders incurs a range of direct and indirect financial costs. The aim of this study was to collect individual ataxia-related healthcare resources in a large cohort of individuals with different subtypes of inherited ataxia and calculate the associated cost of illness in the Republic of Ireland. One hundred twenty-nine respondents completed a cross-sectional study on healthcare resource utilisation for progressive ataxia in Ireland. Costs were calculated using a prevalence-based approach and bottom-up methodology. The COI for inherited ataxia in 2016 was 59,993 per person per year. Results were similar between participants with Friedreich's ataxia (FRDA, n = 56), non-FRDA (n = 18) and those with undetermined ataxia (n = 55). Indirect costs, based on productivity losses by participants or caregivers, accounted for 52% of the cost of illness. Inherited ataxia is associated with significant health and social care costs. Further funding for inherited ataxia to ease the financial burden on patients, caregivers and healthcare system and improve standards of care compliance is warranted.
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Ataxia Cerebelosa , Ataxia de Friedreich , Degeneraciones Espinocerebelosas , Estudios Transversales , Ataxia de Friedreich/epidemiología , Ataxia de Friedreich/genética , Ataxia de Friedreich/terapia , Humanos , Irlanda/epidemiología , Degeneraciones Espinocerebelosas/diagnóstico , Degeneraciones Espinocerebelosas/epidemiología , Degeneraciones Espinocerebelosas/genéticaRESUMEN
Establishing a molecular diagnosis in patients with progressive ataxia is often challenging due to significant genetic and clinical heterogeneity and requires a methodical approach with expert clinical evaluation and investigations. We describe the 5-year experience of the National Ataxia Clinic (NAC), Ireland. All adults with ataxia attending the NAC between 2014 and 2019 were evaluated. All individuals underwent detailed clinical assessment and investigations including, where appropriate, genetic testing using next-generation sequencing. For all patients, acquired causes were ruled out. A total of 254 patients from 196 families were assessed; with growth of the clinic cohort by 82% from 133 to 242 over the 5-year period. The underlying genetic cause was identified in 128/196 probands (65.3%). The detection rate for repeat expansion disorder gene testing was 47.7% (82/172) and using NGS gene panel, a genetic diagnosis was obtained in 30/84 (35.7%). Whole exome sequencing identified the molecular diagnosis in 4/20 (20%), and whole genome sequencing provided genetic diagnosis in 1/5 (20%). The commonest diagnosis was Friedreich's ataxia (68/128, 53.1%). SPG7-associated ataxia was the second most common diagnosis (21/128, 16.4%), followed by ANO10-associated spastic ataxia, ataxia telangiectasia (AT), and other rarer phenotypes. Our results highlight that careful clinical phenotyping in a dedicated ataxia clinic is crucial for appropriate genetic testing in selected patients in a timely manner. Advanced genetic testing has significantly improved the diagnostic yield in patients with suspected genetic ataxia and should be considered in all individuals with negative repeat expansion testing.
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Ataxias Espinocerebelosas/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , Adolescente , Adulto , Anciano , Anoctaminas/genética , Estudios de Cohortes , Expansión de las Repeticiones de ADN , Femenino , Ataxia de Friedreich/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genoma Humano/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Irlanda , Imagen por Resonancia Magnética , Masculino , Metaloendopeptidasas/genética , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Secuenciación del Exoma , Adulto JovenRESUMEN
Ataxia pancytopenia (ATXPC) syndrome due to gain-of-function pathogenic variants in the SAMD9L gene has been described in 38 patients to date. It is characterized by variable neurological and hematological phenotypes including ataxia, pyramidal signs, cytopenias, and hematological malignancies. Peripheral neuropathy with slowing of conduction velocities has been reported in only two affected individuals. We describe a female with childhood onset neuropathy diagnosed as Charcot-Marie-Tooth disease type 1 with onset of cerebellar ataxia in her 50s. Cerebellar, pyramidal, and neuropathic features were found on examination. Additionally, she also had conjunctival telangiectasia. Nerve conduction studies confirmed a demyelinating neuropathy. MRI brain showed cerebellar atrophy with diffuse white matter hyperintensities. OCT demonstrated global thinning of the retinal nerve fiber layer (RNFL). Full blood count has always been normal. A previously described pathogenic variant in SAMD9L [c.2956C>T p.(Arg986Cys)] was identified on whole exome sequencing. This case extends the previously described phenotype to include conjunctival telangiectasia and RNFL thinning and suggests that ATXPC syndrome should be considered in the differential for inherited demyelinating neuropathies.
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Ataxia Cerebelosa/genética , Enfermedad de Charcot-Marie-Tooth/genética , Pancitopenia/genética , Proteínas Supresoras de Tumor/genética , Ataxia Cerebelosa/patología , Ataxia Cerebelosa/fisiopatología , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Femenino , Mutación con Ganancia de Función , Humanos , Persona de Mediana Edad , Polirradiculoneuropatía/genética , Polirradiculoneuropatía/patología , Polirradiculoneuropatía/fisiopatología , Síndrome , Telangiectasia/genética , Telangiectasia/patología , Telangiectasia/fisiopatologíaRESUMEN
Mutations in apoptosis-inducing factor mitochondrion-associated-1 (AIFM1) cause X-linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described. We describe a large Irish family with seven affected males. They presented with a variable age of onset, 18 months to 39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia, and pyramidal involvement. In addition, three had colour vision deficiency. Scale for the assessment and rating of ataxia ranged 2 to 23/40, while Charcot-Marie-Tooth neuropathy score 2 varied between 7 and 13/36. All individuals had normal cognitive assessment. Neurophysiology demonstrated length-dependent large-fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Four obligate female carriers were assessed clinically, two of them neurophysiologically; all were unaffected. Whole genome sequencing demonstrated a previously reported hemizygous AIFM1 mutation. Analysis for mutations in other genes associated with colour deficiency was negative. AIFM1-associated phenotype in this family demonstrated significant variability. To our knowledge, this is the first report of AIFM1-associated colour blindness. Superficial radial nerve was particularly affected neurophysiologically, which could represent a phenotypic marker towards this specific genetic diagnosis.
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Factor Inductor de la Apoptosis/genética , Ataxia Cerebelosa , Defectos de la Visión Cromática , Pérdida Auditiva Sensorineural , Neuropatía Hereditaria Motora y Sensorial , Adulto , Ataxia Cerebelosa/etiología , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/fisiopatología , Defectos de la Visión Cromática/etiología , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/fisiopatología , Pérdida Auditiva Sensorineural/etiología , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Neuropatía Hereditaria Motora y Sensorial/complicaciones , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Linaje , Índice de Severidad de la EnfermedadRESUMEN
The local injection of botulinum toxin is accepted as the first-line treatment of primary cervical dystonia. This approach provides adequate symptomatic relief for most patients, but up to one-third will have an unsatisfactory response. Deep brain stimulation of the globus pallidus internus has been increasingly used in dystonic syndromes that are refractory to best pharmacological approaches. Although cervical dystonia is the most common idiopathic focal dystonia, evidence for long-term responsiveness to pallidal stimulation is limited. The primary objective of this study was to prospectively collect outcome data from baseline to last clinical follow-up on patients with idiopathic cervical dystonia treated with bilateral pallidal stimulation. Blinded video assessment of examinations performed preoperatively and at last video assessment were performed. Ten patients had complete prospective clinical follow-up. Baseline total Toronto Western Spasmodic Torticollis Rating Scale score (±standard deviation) was 54.5 ± 12.4 (range, 35.0-70.3). Comparison of the blinded severity sub-score on baseline video and at last video assessment at a mean of 7.7 years postoperatively demonstrated a mean improvement of 47.6% (P = 0.002) and strong inter-observer correlation between blinded raters (Spearman r = 0.78, 95% confidence interval 0.49-0.92, P = 0.0001). All 10 patients had 5 years of open prospective follow-up, documenting a 47.4 ± 26.4% (P < 0.01) mean improvement with respect to baseline. This was maintained at a mean of 7.8 years at last follow-up after surgery (range, 4.9-10.7 years) with a 54.4 ± 27.4% mean improvement (P < 0.01). Deep brain stimulation of the globus pallidus is an effective and long-lasting second-line treatment of cervical dystonia, with benefit in some of our patients extending to >10 years. More data are needed to explain variations in individual responses and to guide individual programming parameters.
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Estimulación Encefálica Profunda , Globo Pálido , Tortícolis/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Data are limited on the frequency of 'consensus decisions' between sub-specialists attending a neurovascular multidisciplinary meeting (MDM) regarding management of patients with extracranial carotid/vertebral stenoses and post-MDM 'adherence' to such advice. METHODS: This prospective audit/quality improvement project collated prospectively-recorded data from a weekly Neurovascular/Stroke Centre MDM documenting the proportion of extracranial carotid/vertebral stenosis patients in whom 'consensus management decisions' were reached by neurologists, vascular surgeons, stroke physicians-geriatricians and neuroradiologists. Adherence to MDM advice was analysed in asymptomatic carotid stenosis (ACS), symptomatic carotid stenosis (SCS), 'indeterminate symptomatic status stenosis' (ISS) and vertebral artery stenosis (VAS) patients, including intervals between index event to MDM + / - intervention. RESULTS: One hundred fifteen patients were discussed: 108 with carotid stenosis and 7 with VAS. Consensus regarding management was noted in 96.5% (111/115): 100% with ACS and VAS, 96.2% with SCS and 92.9% with ISS. Adherence to MDM management advice was 96.4% (107/111): 100% in ACS, ISS and VAS patients; 92% (46/50) in SCS patients. The median interval from index symptoms to revascularisation in 50-99% SCS patients was 12.5 days (IQR: 9-18.3 days; N = 26), with a median interval from MDM to revascularisation of 5.5 days (IQR: 1-7 days). Thirty patients underwent revascularisation. Two out of twenty-nine patients (6.9%) with either SCS or ISS had a peri-procedural ipsilateral ischaemic stroke, with no further strokes/deaths during 3-months follow-up. CONCLUSIONS: The high frequency of inter-specialty consensus regarding management and adherence to proposed treatment supports a collaborative/multidisciplinary model of care in patients with extracranial arterial stenoses. Service development should aim to shorten times between MDM discussion-intervention and optimise prevention of stroke/death.
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Isquemia Encefálica , Estenosis Carotídea , Endarterectomía Carotidea , Accidente Cerebrovascular , Humanos , Estenosis Carotídea/cirugía , Accidente Cerebrovascular/prevención & control , Constricción Patológica/etiología , Consenso , Resultado del Tratamiento , Factores de RiesgoRESUMEN
Ocular abnormalities occur frequently in Friedreich's ataxia (FRDA), although visual symptoms are not always reported. We evaluated a cohort of patients with FRDA to characterise the clinical phenotype and optic nerve findings as detected with optical coherence tomography (OCT). A total of 48 patients from 42 unrelated families were recruited. Mean age at onset was 13.8 years (range 4-40), mean disease duration 19.5 years (range 5-43), mean disease severity as quantified with the Scale for the Assessment and Rating of Ataxia 22/40 (range 4.5-38). All patients displayed variable ataxia and two-thirds had ocular abnormalities. Statistically significant thinning of average retinal nerve fibre layer (RNFL) and thinning in all but the temporal quadrant compared to controls was demonstrated on OCT. Significant RNFL and macular thinning was documented over time in 20 individuals. Disease severity and visual acuity were correlated with RNFL and macular thickness, but no association was found with disease duration. Our results highlight that FDRA is associated with subclinical optic neuropathy. This is the largest longitudinal study of OCT findings in FRDA to date, demonstrating progressive RNFL thickness decline, suggesting that RNFL thickness as measured by OCT has the potential to become a quantifiable biomarker for the evaluation of disease progression in FRDA.
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Ataxia de Friedreich , Enfermedades del Nervio Óptico , Ataxia de Friedreich/complicaciones , Ataxia de Friedreich/diagnóstico por imagen , Humanos , Estudios Longitudinales , Enfermedades del Nervio Óptico/complicaciones , Enfermedades del Nervio Óptico/diagnóstico , Tomografía de Coherencia Óptica/métodos , Agudeza VisualRESUMEN
BACKGROUND: Mutations in SPG7 are increasingly identified as a common cause of spastic ataxia. We describe a cohort of Irish patients with recessive SPG7-associated phenotype. METHODS: Comprehensive phenotyping was performed with documentation of clinical, neurophysiological, optical coherence tomography (OCT) and genetic data from individuals with SPG7 attending two academic neurology units in Dublin, including the National Ataxia Clinic. RESULTS: Thirty-two symptomatic individuals from 25 families were identified. Mean age at onset was 39.1 years (range 12-61), mean disease duration 17.8 years (range 5-45), mean disease severity as quantified with the scale for the assessment and rating of ataxia 9/40 (range 3-29). All individuals displayed variable ataxia and spasticity within a spastic-ataxic phenotype, and additional ocular abnormalities. Two had spasmodic dysphonia and three had colour vision deficiency. Brain imaging consistently revealed cerebellar atrophy (n = 29); neurophysiology demonstrated a length-dependent large-fibre axonal neuropathy in 2/27 studied. The commonest variant was c.1529C > T (p.Ala510Val), present in 21 families. Five novel variants were identified. No significant thinning of average retinal nerve fibre layer (RNFL) was demonstrated on OCT (p = 0.61), but temporal quadrant reduction was evident compared to controls (p < 0.05), with significant average and temporal RNFL decline over time. Disease duration, severity and visual acuity were not correlated with RNFL thickness. CONCLUSIONS: Our results highlight that recessive SPG7 mutations may account for spastic ataxia with peripheral neuropathy in only a small proportion of patients. RNFL abnormalities with predominant temporal RNFL reduction are common and OCT should be considered part of the routine assessment in spastic ataxia.
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Espasticidad Muscular , Paraplejía Espástica Hereditaria , ATPasas Asociadas con Actividades Celulares Diversas/genética , Adolescente , Adulto , Niño , Preescolar , Humanos , Discapacidad Intelectual , Metaloendopeptidasas/genética , Persona de Mediana Edad , Espasticidad Muscular/diagnóstico por imagen , Espasticidad Muscular/genética , Neurofisiología , Atrofia Óptica , Fenotipo , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Paraplejía Espástica Hereditaria/genética , Ataxias Espinocerebelosas , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
The relationship between plaque morphology, cerebral micro-embolic signals (MES) and platelet biomarkers in carotid stenosis patients warrants investigation.We combined data from two prospective, observational studies to assess carotid plaque morphology and relationship with cerebral MES and platelet biomarkers in patients with recently symptomatic (≤4 weeks of transient ischaemic attack (TIA)/ischaemic stroke) versus asymptomatic carotid stenosis. Plaque morphology on ultrasound was graded with Grey-Scale Median (GSM) and Gray-Weale (GW) scoring. Bilateral transcranial Doppler ultrasound classified patients as 'MES+ve' or 'MES-ve'. Full blood counts were analysed and flow cytometry quantified CD62P and CD63 expression, leucocyte-platelet complexes and reticulated platelets.Data from 42 recently symptomatic carotid stenosis patients were compared with those from 36 asymptomatic patients. There were no differences in median GSM scores between symptomatic and asymptomatic patients (25 vs. 30; P = 0.31) or between MES+ve vs. MES-ve symptomatic patients (36 vs. 25; P = 0.09). Symptomatic patients with GSM-echodense plaques (GSM ≥25) had higher platelet counts (228 vs. 191 × 109/L), neutrophil-platelet (3.3 vs. 2.7%), monocyte-platelet (6.3 vs. 4.55%) and lymphocyte-platelet complexes (2.91 vs. 2.53%) than 'asymptomatic patients with GSM-echodense plaques' (P ≤ 0.03).Recently, symptomatic carotid stenosis patients with 'GSM-echodense plaques' have enhanced platelet production/secretion/activation compared with their asymptomatic counterparts. Simultaneous assessment with neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis.
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Biomarcadores/sangre , Plaquetas/metabolismo , Estenosis Carotídea/sangre , Estenosis Carotídea/diagnóstico , Embolia Intracraneal/diagnóstico , Embolia Intracraneal/etiología , Placa Aterosclerótica/patología , Anciano , Enfermedades Asintomáticas , Estenosis Carotídea/complicaciones , Comorbilidad , Manejo de la Enfermedad , Femenino , Humanos , Embolia Intracraneal/tratamiento farmacológico , Embolia Intracraneal/prevención & control , Ataque Isquémico Transitorio , Masculino , Persona de Mediana Edad , Fenotipo , Placa Aterosclerótica/diagnóstico por imagen , Inhibidores de Agregación Plaquetaria/uso terapéutico , Índice de Severidad de la Enfermedad , Evaluación de Síntomas , Ultrasonografía Doppler TranscranealRESUMEN
INTRODUCTION: Cerebral micro-embolic signals (MES) predict risk of stroke in carotid stenosis patients. However, MES-negative 'recently symptomatic patients' also have a higher stroke risk than 'asymptomatic patients'. Differences in platelet activation status may contribute to this disparity in risk. METHODS: This prospective, observational study assessed platelet biomarkers and their relationship with MES in asymptomatic versus symptomatic moderate (≥50-69%) or severe (≥70-99%) carotid stenosis patients. Full blood count parameters were measured and whole-blood flow cytometry was used to quantify platelet surface CD62P and CD63 expression and leucocyte-platelet complex formation. Bilateral simultaneous transcranial Doppler ultrasound of the middle cerebral arteries classified patients as 'MES positive' or 'MES negative'. RESULTS: Data from 34 asymptomatic patients were compared with those from 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 of these symptomatic patients in the 'late phase' (≥ 3 months) after transient ischaemic attack/ischaemic stroke. There were no differences in %CD62P or %CD63 expression between early or late symptomatic and asymptomatic patients overall (p > 0.05). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic patients (2.8 vs. 2.16%; p < 0.001). MES were more commonly observed in early symptomatic (31.4%; p = 0.027) but not in late symptomatic (6.7%; p = 0.996) versus asymptomatic patients (7.1%). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic MES-negative patients (2.7 vs. 2.17%; p = 0.02). CONCLUSION: These data add to the evidence that leucocyte-platelet complex formation/platelet activation is increased in recently symptomatic versus asymptomatic patients, and may contribute to the pathogenesis of first and subsequent strokes in carotid stenosis patients, including those who are MES negative.
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Plaquetas/fisiología , Estenosis Carotídea/diagnóstico , Embolia Intracraneal/diagnóstico , Leucocitos/fisiología , Anciano , Enfermedades Asintomáticas , Comunicación Celular , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Activación Plaquetaria , Pronóstico , Estudios ProspectivosRESUMEN
BACKGROUND: Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqalpha protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy. METHODS AND RESULTS: To test this hypothesis, we generated transgenic (DGKzeta-TG) mice with cardiac-specific overexpression of DGKzeta. There were no differences in heart size and heart weight between DGKzeta-TG and wild-type littermate mice. The left ventricular function was normal in DGKzeta-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKzeta-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKzeta-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKzeta-TG mouse hearts, suggesting that DGKzeta regulated PKC activity by controlling cellular diacylglycerol levels. CONCLUSIONS: These results demonstrated the first evidence that DGKzeta negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.
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Cardiomegalia/prevención & control , Diacilglicerol Quinasa/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Proteínas de Unión al GTP Heterotriméricas/agonistas , Miocardio/metabolismo , Angiotensina II/farmacología , Animales , Diacilglicerol Quinasa/genética , Diglicéridos/metabolismo , Ratones , Ratones Transgénicos , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Fenilefrina/farmacología , Regiones Promotoras Genéticas , Proteína Quinasa C/metabolismo , ARN Mensajero/análisis , Ratas , Transducción de Señal/efectos de los fármacos , Miosinas Ventriculares/genéticaRESUMEN
The autosomal recessive cerebellar ataxias are a heterogeneous group of neurodegenerative disorders. Mutations in the anoctamin 10 gene (ANO10) recently have been identified as a cause of autosomal recessive spinocerebellar ataxia type 10. Comprehensive phenotypic data are provided on 3 siblings with homozygous ANO10 mutations, including detailed ocular and cognitive assessments and bladder involvement not previously described in the literature. Data also are provided on unblinded therapy with coenzyme Q10, previously reported as a possible therapy in ANO10-related ataxia. A genetic diagnosis in this family was obtained through next-generation sequencing techniques after over 10 years of expensive sequencing of individual genes using the traditional Sanger approach. Greater commercial availability of gene panels will improve the ability to obtain a genetic diagnosis in the uncommon "non-Friedreich's" recessive ataxias. Clinical recognition of these recessive ataxic syndromes will also inevitably improve as the full phenotypic spectrum is identified.
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BACKGROUND: Pelvic symptoms are distressing symptoms experienced by patients with Friedreich's Ataxia (FRDA). The aim of this study was to describe the prevalence of lower urinary tract symptoms (LUTS), bowel and sexual symptoms in FRDA. METHODS: Questionnaire scores measuring LUTS, bowel and sexual symptoms were analysed with descriptive statistics as a cohort and as subgroups (Early/Late-onset and Early/Late-stage FRDA) They were also correlated with validated measures of disease severity including those of ataxia severity, non-ataxic symptoms and activities of daily living. RESULTS: 80% (n = 46/56) of patients reported LUTS, 64% (n = 38/59) reported bowel symptoms and 83% (n = 30/36) reported sexual symptoms. Urinary and bowel or sexual symptoms were significantly likely to co-exist among patients. Late-onset FRDA patients were also more likely to report LUTS than early-onset ones. Patients with a longer disease duration reported higher LUTS scores and poorer quality of life scores related to urinary symptoms. CONCLUSIONS: A high proportion of FRDA have symptoms suggestive of LUTS, bowel and sexual dysfunction. This is more marked with greater disease duration and later disease onset. These symptoms need to be addressed by clinicians as they can have a detrimental effect on patients.
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Ataxia de Friedreich/complicaciones , Enfermedades Intestinales/etiología , Conducta Sexual , Enfermedades Urológicas/etiología , Adolescente , Adulto , Anciano , Recolección de Datos , Femenino , Ataxia de Friedreich/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Adulto JovenRESUMEN
BACKGROUND: Myocyte apoptosis plays an important role in pathological cardiac remodeling and the progression of heart failure. cAMP signaling is crucial in the regulation of myocyte apoptosis and cardiac remodeling. Multiple cAMP-hydrolyzing phosphodiesterases (PDEs), such as PDE3 and PDE4, coexist in cardiomyocytes and elicit differential temporal/spatial regulation of cAMP signaling. However, the role of PDE3 and PDE4 in the regulation of cardiomyocyte apoptosis remains unclear. Although chronic treatment with PDE3 inhibitors increases mortality in patients with heart failure, the contribution of PDE3 expression/activity in heart failure is not well known. METHODS AND RESULTS: In this study we report that PDE3A expression and activity were significantly reduced in human failing hearts as well as mouse hearts with chronic pressure overload. In primary cultured cardiomyocytes, chronic inhibition of PDE3 but not PDE4 activity by pharmacological agents or adenovirus-delivered antisense PDE3A promoted cardiomyocyte apoptosis. Both angiotensin II (Ang II) and the beta-adrenergic receptor agonist isoproterenol selectively induced a sustained downregulation of PDE3A expression and induced cardiomyocyte apoptosis. Restoring PDE3A via adenovirus-delivered expression of wild-type PDE3A1 completely blocked Ang II- and isoproterenol-induced cardiomyocyte apoptosis, suggesting the critical role of PDE3A reduction in cardiomyocyte apoptosis. Moreover, we defined a crucial role for inducible cAMP early repressor expression in PDE3A reduction-mediated cardiomyocyte apoptosis. CONCLUSIONS: Our results suggest that PDE3A reduction and consequent inducible cAMP early repressor induction are critical events in Ang II- and isoproterenol-induced cardiomyocyte apoptosis and may contribute to the development of heart failure. Drugs that maintain PDE3A function may represent an attractive therapeutic approach to treat heart failure.