Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population.

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093-4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375-4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype.

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival.

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Factors predicting survival in amyotrophic lateral sclerosis patients on non-invasive ventilation.

OBJECTIVE: Non invasive ventilation (NIV) improves quality of life and extends survival in amyotrophic lateral sclerosis (ALS) patients. However, few data exist about the factors related to survival. We intended to assess the predictive factors that influence survival in patients after NIV initiation. METHODS: Patients who started NIV from 2000 to 2014 and were tolerant (compliance ≥ 4 hours) were included; demographic, disease related and respiratory variables at NIV initiation were analysed. Statistical analysis was performed using the Kaplan-Meier test and Cox proportional hazard models. RESULTS: 213 patients were included with median survival from NIV initiation of 13.5 months. In univariate analysis, the identified risk factors for mortality were severity of bulbar involvement (HR 2), Forced Vital Capacity (FVC) % (HR 0.99) and ALSFRS-R (HR 0.97). Multivariate analysis showed that bulbar involvement (HR 1.92) and ALSFRS-R (HR 0.97) were independent predictive factors of survival in patients on NIV. CONCLUSIONS: In our study, the two prognostic factors in ALS patients following NIV were the severity of bulbar involvement and ALSFRS-R at the time on NIV initiation. A better assessment of bulbar involvement, including evaluation of the upper airway, and a careful titration on NIV are necessary to optimize treatment efficacy.

Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review.

Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X-linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene.

[The patient's opinion matters: experience in the nutritional care in an ALS multidisciplinary team]. / La opinión del paciente cuenta: Experiencia en la atención nutricional en un equipo multidisciplinar de ELA.

UNLABELLED: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease which has no cure, so the treatment will be symptomatic in a Multidisciplinary Unit. It is composed of professionals, experts in patient care, with an interdisciplinary vision in order to act in a coordinated manner depending on the different situations which may arise over the course of the disease. There are several studies showing improved survival in patients treated within the framework of a multidisciplinary team compared to treatment by isolated specialties. An ALS Multidisciplinary Unit was created in 2004 in the University Hospital of Bellvitge (HUB). It is composed of a neurologist, pulmonologist, nutritionist, endocrinologist, rehabilitation, physical therapist, psychologist, social worker, nurse manager, speech therapist and an administrative worker. To assess the impact of the multidisciplinary care of our program 418 patients diagnosed with ALS were evaluated, 84 patients who had been treated by general neurology and 334 who had been treated under a model of multidisciplinary care. Patients who were treated in the unit of multidisciplinary care had a median survival of 1246 days (IC 1109-1382), 104 days above the median 1148 days of those followed by a general neurology consultation (CI 998-1297). This difference was statistically significant (log-rank 10,8; p= 0.008). This benefit was independent of having received treatment with riluzole, non-invasive mechanical ventilation or percutaneous gastrostomy. Nutritional assessment was performed on the first visit and all subsequent controls. It is important to do anthropometric measurements and detect unintentional weight loss and its possible precipitating causes in order to establish the appropriate nutritional treatment. The exploration of dysphagia allows a determination of the appropriate dietary advice, the introduction of thickeners to adjust the texture of food or nutritional supplementation with high-calorie formulas to prevent or correct weight loss. If these measures are not sufficient or there is the risk of failure of respiratory function, early gastrostomy placement will be indicated. The analysis of 140 ALS patients (92 controls and 48 with radiologic percutaneous gastrostomy) showed no difference in mean survival time between groups (32 vs 33.9 months, log Rank 1.86 p=0.39). Any patient had major complications. Despite not find changes in survival, the use of gastrostomy should be understood as a treatment to improve the quality of life and well-being of the patient. Psychosocial support of the person and the family environment is essential to integrate all the changes and situations that arise in the course of the disease. This should start from diagnosis as early intervention contributes to improved training, preventing situations of deterioration and helping coping with the dependency process. It is also possible to use technology and social media to complement the classic care model. In the case of the HUB ALS Multidisciplinary Unit, affected individuals and their families have the resources of the Aula Paciente and ALS blog, created with the objective of providing opportunities for dialogue between patients, families and caregivers. The satisfaction degree of the patients with the care provided by the ALS Multidisciplinary Unit on service accessibility, information received and the quality of care was assessed globally as good in 52.8% or very good in 29, 2% of patients. CONCLUSION: Attention for the ALS affected person must be considered within the framework of a multidisciplinary team made up of all the professionals who go to intervene throughout the disease process in order to provide increased survival with the best care and quality of life.

Enfermedad de Kennedy y resistencia parcial androgénica. Descripción de 4 casos y revisión de la literatura / Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review

La enfermedad de Kennedy o atrofia muscular espino-bulbar es un trastorno neurodegenerativo raro de herencia recesiva ligada al cromosoma X que afecta a varones en la edad adulta. Está causado por la expansión repetida de la secuencia citosina-adenosina-guanina en el exón 1 del gen del receptor androgénico localizado en el cromosoma Xq11-12, y se caracteriza por la degeneración progresiva de las neuronas motoras espinales. Desde el punto de vista endocrinológico es común encontrar en estos pacientes datos de hipogonadismo englobados en el síndrome de resistencia androgénica, particularmente la forma parcial. Se describen 4 casos con presentación clínica neurológica típica de la enfermedad, con debilidad muscular generalizada lentamente progresiva con atrofia y afectación de musculatura bulbar; entre las manifestaciones endocrinológicas observadas la ginecomastia fue la más frecuente. El estudio molecular mostró una expansión anormal del triplete citosina-adenosina-guanina en el gen del receptor androgénico en todos los casos

Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X -linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene

La opinión del paciente cuenta: Experiencia en la atención nutricional en un equipo multidisciplinar de ELA / The patient’s opinion matters: experience in the nutritional care in an ALS multidisciplinary team

La Esclerosis Lateral Amiotrófica (ELA) es una enfermedad neurodegenerativa que carece de tratamiento curativo por lo que el tratamiento será sintomático en Unidades Multidisciplinares. Éstas estarán compuestas por los profesionales expertos necesarios para la atención del enfermo con una visión interdisciplinar que actúe de una forma coordinada ante las diferentes situaciones que puedan surgir a lo largo de la evolución de la enfermedad. En este sentido existen diferentes estudios que demuestran una mayor supervivencia en los pacientes tratados en el marco de un equipo multidisciplinar comparado con el tratamiento por especialidades aisladas. En el Hospital Universitario de Bellvitge desde 2004 se ha creado una Unidad Multidisciplinar de ELA que integra neurólogo, neumólogo, nutricionista, endocrinólogo, rehabilitador, fisioterapeuta, psicólogo, trabajador social, enfermera gestora, logopeda, administrativo. Para evaluar el impacto de la atención multidisciplinar de nuestro programa se evaluaron 418 pacientes diagnosticados de ELA, 84 pacientes habían recibido atención por consultas de neurología general y 334 tratados bajo un modelo de atención multidisciplinar. Los pacientes que fueron tratados en la unidad de atención multidisciplinar tuvieron una mediana de supervivencia de 1246 días (IC 1109 - 1382), 104 días superior a la mediana de 1148 días de aquellos seguidos en la consulta de neurología general (IC 998 - 1297). Esta diferencia fue estadísticamente significativa (log-rank10,8, p 0,008). Este beneficio fue independiente del hecho de haber recibido tratamiento con riluzole, ventilación mecánica no invasiva o gastrostomía percutánea. La valoración nutricional se realizará desde la primera visita y en todos los controles posteriores. Es importante realizar las medidas antropométricas y detectar la pérdida de peso involuntaria y las posibles causas desencadenantes para establecer el tratamiento nutricional adecuado. La exploración de la disfagia permite establecer el consejo dietético adecuado, la introducción de espesantes para adecuar la textura de los alimentos o la suplementación nutricional con fórmulas hipercalóricas para evitar o corregir la pérdida de peso. En el caso que estas medidas no sean suficientes o bien existe el riesgo de fracaso de la función respiratoria se indicará la colocación precoz de gastrostomía. El análisis de 140 pacientes con ELA (92 controles y 48 con gastrostomía radiológica percutánea), no mostró diferencias en el tiempo de supervivencia media entre los grupos (32 vs 33,9 meses, log Rank 1,86 p= 0,39). Ningún paciente presentó complicaciones mayores. A pesar de no evidenciar cambios en la supervivencia, el uso de la gastrostomía debe ser entendido como un tratamiento destinado a mejorar la calidad de vida y el bienestar del paciente. El apoyo psicosocial a la persona y al entorno familiar es fundamental para poder integrar todos los cambios y situaciones que surgirán en la evolución de la enfermedad. Debe iniciarse desde el diagnóstico ya que la atención temprana contribuye a su mejor formación, prevenir situaciones de deterioro y afrontar el proceso de dependencia. Además existe la posibilidad de utilizar la tecnología y las redes sociales para complementar el modelo asistencial clásico. En el caso concreto de la Unidad Funcional de ELA del HUB, las personas afectadas y sus familias cuentan con los recursos del Aula Paciente y el blog ELA, creados con el objetivo de ofrecer espacios de diálogo entre pacientes, familiares y cuidadores. El grado de satisfacción del paciente con la atención recibida por la Unidad Multidisciplinar de ELA sobre la accesibilidad al servicio, la información recibida y la calidad de la atención, globalmente fue valorada cómo buena en el 52,8% o muy buena en el 29,2 % de los pacientes. Conclusión: La atención a la persona afectada de ELA debe ser contemplada en el marco de un equipo multidisciplinar integrado por todos los profesionales que vayan a intervenir a lo largo del proceso de su enfermedad para ofrecer una mayor supervivencia con la mejor atención y calidad de vida (AU)

No disponible