Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families.

AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.

Description of clinical and genetic features of 122 patients included in the Spanish Pompe registry.

Pompe disease is a rare genetic disorder with an estimated prevalence of 1:60.000. The two main phenotypes are Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). There is no published data from Spain regarding the existing number of cases, regional distribution, clinical features or, access and response to the treatment. We created a registry to collect all these data from patients with Pompe in Spain. Here, we report the data of the 122 patients registered including nine IOPD and 113 LOPD patients. There was a high variability in how the diagnosis was obtained and how the follow-up was performed among different centres. Seven IOPD patients were still alive being all treated with enzymatic replacement therapy (ERT) at last visit. Ninety four of the 113 LOPD patients had muscle weakness of which 81 were receiving ERT. We observed a progressive decline in the results of muscle function tests during follow-up. Overall, the Spanish Pompe Registry is a valuable resource for understanding the demographics, patient's journey and clinical characteristics of patients in Spain. Our data supports the development of agreed guidelines to ensure that the care provided to the patients is standardized across the country.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

[Medical emergency card for Steinert's disease: an unmet need]. / Tarjeta de emergencias médicas para la enfermedad de Steinert: una necesidad desatendida.

INTRODUCTION: Myotonic dystrophy type 1 (DM1) or Steinert's disease (ORPHA 273; OMIM #160900) is a rare disorder of genetic origin with muscular manifestations (muscle weakness and myotonia), early-onset cataracts (before 50 years of age) and systemic manifestations (cerebral, endocrine, cardiac, gastrointestinal tract, uterus, skin and immune system). Its clinical expressivity is highly variable and ranges from lethal forms in infancy to mild late-onset disease. Its low frequency prevents emergency medical professionals from becoming familiar with the essential precautions for its treatment. In order to alleviate this lack of information, those affected by DM1 have, in the countries of our environment, a medical emergency card (Tarjeta de Emergencias Medicas, TEM) that the patient should always carry with him/her and give to the physician before receiving emergency care. OBJECTIVES: To define the TEM. To describe the TEM for DM1 already implemented. To list the advantages for patients and professionals of their use. MATERIAL AND METHODS: Some of the TEM for DM1 currently in use in France and the United Kingdom are described. RESULTS: The arguments justifying their implantation in our setting are presented in detail. CONCLUSIONS: The TEM for DM1 managed by a physician can improve the emergency medical care of patients affected by Steinert's disease.

TITLE: Tarjeta de emergencias médicas para la enfermedad de Steinert: una necesidad desatendida.Introducción. La distrofia miotónica de tipo 1 (DM1), o enfermedad de Steinert (ORPHA 273; OMIM #160900), es un trastorno de origen genético poco frecuente con manifestaciones musculares (debilidad muscular y miotonía), cataratas de inicio temprano (antes de los 50 años) y manifestaciones sistémicas (cerebral, endocrina, cardíaca, del tubo digestivo, del útero, de la piel y del sistema inmunitario). Su expresividad clínica es muy variable y se extiende desde formas letales en la lactancia hasta una enfermedad leve de aparición tardía. Su baja frecuencia impide que los profesionales de urgencias médicas se familiaricen con las precauciones imprescindibles para su tratamiento. Con el propósito de paliar esta falta de información, los afectados por DM1 disponen, en los países de nuestro entorno, de una tarjeta de emergencia médica (TEM) que el paciente siempre debe llevar consigo y entregar al facultativo antes de recibir asistencia urgente. Objetivos. Definir la TEM, describir las TEM para la DM1 ya implantadas y enumerar las ventajas para pacientes y profesionales que supone su utilización. Material y métodos. Se describen algunas de las TEM para la DM1 actualmente en uso en Francia y el Reino Unido. Resultados. Se exponen pormenorizadamente los argumentos que justifican su implantación en nuestro medio. Conclusiones. La TEM para la DM1 gestionada por un facultativo puede mejorar la asistencia en emergencias médicas de los pacientes afectados por la enfermedad de Steinert.

[Cognitive impairment in myotonic dystrophy type 1 (Steinert's disease)]. / Alteración cognitiva en la distrofia miotónica tipo 1 (enfermedad de Steinert).

Traditionally, it has been recognized that patients with myotonic dystrophy type 1 (MD-1) - also known as Steinert disease -, they show a specific behaviour, not including those who suffer from mental or neurodevelopmental diseases. The neurological substrate of this behaviour is described. The aim of this text has two purposes. The first intention is that clinical staff, when faced with a patient with MD-1, always consider the cognitive aspects of the disease. On the other hand, it is intended to combat preconceived ideas about the particular behaviour of these patients.

[From in-person didactic sessions to videoconferencing during the COVID-19 pandemic: satisfaction survey among participants]. / Cambio de sesiones docentes presenciales a virtuales durante la pandemia de COVID-19 en un servicio de neurología: descripción del proceso y satisfacción de los usuarios.

INTRODUCTION AND AIM: COVID-19 pandemic has disturbed many hospital activities, including medical education. We describe the switch from in-person didactic sessions to videoconferencing in a Neurology department. We analyse the opinions and satisfaction of participants. MATERIAL AND METHODS: Narrative description of the adopted measures; Online survey among participants. RESULTS: One of the three weekly sessions was cancelled, and two switched to videoconferencing. There were more participants online than in the conference hall. 49 users answered the survey, 51% women, mean age 40.5 years (range 25-65). Satisfaction was higher for previous face-to-face meetings (8.68) than for videoconferencing (8.12) (p=0.006). There was a significant inverse correlation between age and satisfaction with virtual sessions (r=-0.37; p=0.01), that was not found for in-person attendance. Most users (75.5%) would prefer to continue with online sessions when the pandemic is over, and 87.8% support inter-hospital remote meetings, but the safety of web platforms is a concern (53.1%). CONCLUSIONS: The change from in-person to virtual sessions is an easy measure to implement in a neurology department, with a good degree of satisfaction among users. There are some unsolved problems with the use of commercial web platforms and inter-hospital connection. Most users recommend leadership and support from educational and health authorities.

TITLE: Cambio de sesiones docentes presenciales a virtuales durante la pandemia de COVID-19 en un servicio de neurología: descripción del proceso y satisfacción de los usuarios.Introducción y objetivo. La pandemia de COVID-19 ha trastornado la actividad hospitalaria, incluyendo la docente. Se describe el cambio de un sistema presencial a otro de sesiones en línea en un servicio de neurología, y se analizan la satisfacción y las opiniones de los usuarios. Material y métodos. Exposición de las medidas adoptadas para pasar a modalidad en línea y análisis de una encuesta entre los participantes. Resultados. Se pasó de tres a dos sesiones semanales, con restricción del público presencial. El público virtual superó al presencial. Contestaron la encuesta 49 participantes, un 51% mujeres, con una media de 40,5 años (rango: 25-65). La satisfacción de los asistentes fue mayor para las sesiones presenciales (8,68) que para las en línea (8,12) (p = 0,006). Existía una correlación inversa significativa entre la edad y la satisfacción con las sesiones en línea (r = ­0,37; p = 0,01) que no se daba para las sesiones presenciales. El 75,5% fue partidario de mantener las sesiones virtuales cuando se eliminaran las restricciones de aforo. Una mayoría (87,8%) apoyó sesiones interhospitalarias y recomienda que las autoridades sanitarias faciliten aplicaciones informáticas seguras (53,1%). Conclusiones. La introducción de sesiones virtuales es una medida fácil de implementar en un servicio de neurología, con un alto grado de satisfacción de los usuarios, aunque menor que con las sesiones presenciales. Existen problemas no resueltos respecto al uso de plataformas comerciales y conexión interhospitalaria. Sería recomendable que las autoridades sanitarias y educativas desarrollaran aplicaciones seguras y fomentaran la educación médica en línea.

[Myotonic dystrophy type 1: a series of 107 patients]. / Distrofia miotónica de tipo 1: una serie de 107 pacientes.

INTRODUCTION: Myotonic dystrophy type 1 is the most common muscular dystrophy in adults. It is a genetic disorder of autosomal dominant inheritance and one of its most striking features is its multi-systemic involvement with a wide clinical phenotype. PATIENTS AND METHODS: Data from 107 patients with a genetically confirmed diagnosis of the disease were retrospectively analysed from the database of a national reference division for neuromuscular diseases. Demographic and clinical data were collected over a 7-year period. RESULTS: The most frequent age of symptom onset was adulthood (66.4%). 35% showed exclusive distal weakness and a majority (63.6%) had clinical myotonia. Only 10 patients lacked neuromuscular symptoms at diagnosis and up to 9.5% were restricted to a wheelchair. The implantation of a pacemaker or cardioverter-defibrillator was conducted in 16 patients but no sudden cardiac death was detected. A venous thromboembolic disease incidence rate of 5.6 cases per 1000 patient-year was identified. More than half of the patients (54%) in the series developed respiratory failure. 13 patients died during the follow-up period, with respiratory failure being the main cause of death. CONCLUSIONS: The follow-up and clinical management of patients with DM1 should be multidisciplinary. In our series, the main cause of morbidity and mortality was respiratory disorders, whereas the incidence of cardiac disorders was lower. In addition, there is a notable frequency of complications derived from falls, which can have serious consequences. Finally, a higher than expected incidence of thromboembolic events was identified, which deserves further study in other cohorts of patients.

TITLE: Distrofia miotónica de tipo 1: una serie de 107 pacientes.Introducción. La distrofia miotónica de tipo 1 (DM1) es la distrofia muscular más frecuente en adultos, aunque puede comenzar a cualquier edad. Genéticamente determinada y de transmisión dominante, se caracteriza por la afectación constante, aunque variable, de múltiples sistemas. Pacientes y métodos. Se analizaron retrospectivamente datos de 107 pacientes con diagnóstico genético de DM1 en seguimiento en una unidad de referencia nacional en enfermedades neuromusculares raras. Se recopilaron datos demográficos y clínicos de un período de seguimiento de siete años. Resultados. El 66,4% de los pacientes comenzó en la edad adulta. El 35,5% tenía debilidad distal exclusiva y la mayoría (63,6%) presentaba miotonía clínica. Sólo 10 pacientes no tenían síntomas neuromusculares en el diagnóstico. En un 8,6%, las caídas ocasionaron complicaciones graves y hasta un 9,5% perdió la deambulación autónoma. Se implantó un dispositivo cardíaco en 16 pacientes y no se registró ninguna muerte súbita de origen cardíaco. Se identificó una tasa de incidencia de enfermedad tromboembólica venosa de 5,6 casos/1.000 pacientes-año. Un 54% de los pacientes desarrolló insuficiencia respiratoria. Durante el seguimiento fallecieron 13 pacientes y la insuficiencia respiratoria fue la principal causa de muerte (38,5%). Conclusiones. El manejo clínico y el seguimiento de los pacientes con DM1 debe ser multidisciplinar. En nuestra serie, la principal causa de morbimortalidad fueron los trastornos respiratorios, mientras que la incidencia de complicaciones cardiológicas graves fue baja. Destacan, además, las complicaciones derivadas de las caídas, que pueden tener consecuencias graves. Finalmente, se identificó una incidencia mayor de la esperada de eventos tromboembólicos, que merece ser estudiada en mayor profundidad.

[Sensory ganglionopathy as a manifestation of celiac disease]. / Ganglionopatia sensitiva como manifestacion de enfermedad celiaca.

INTRODUCTION: The neurological manifestations of celiac disease (CD) may be caused by the disease itself, by associated autoimmune diseases or by complications from the tumours that may develop in the long term. We report a case of sensory ganglionopathy associated to CD. CASE REPORT: A 59-year-old female with chronic diarrhoea and loss of weight, who visited because of a clinical picture of gait disorders that progressed to the point where she was barely able to walk. Having been diagnosed with CD, finding a sensory ganglionopathy with dysautonomia (an atypical manifestation of this disease) led to a diagnosis of associated Sjogren's syndrome (SS). CONCLUSIONS: The neurological manifestations of CD are very varied, but in the presence of a sensory ganglionopathy, a neurological picture that is atypical in this disease, it becomes necessary to suspect SS, which is an infrequent but well established association. Likewise, all patients with SS must be screened for CD, which (albeit subclinically) can be complicated in the long term by the development of tumours. The differential diagnosis of the neurological manifestations of CD and of sensory ganglionopathy, as well as the association between celiac disease and SS, is also discussed.

[Steinert's disease and refusal to treatment]. / Enfermedad de Steinert y rechazo de la actuación médica.

TITLE: Enfermedad de Steinert y rechazo de la actuación médica.

[Orthostatic tremor: an enigmatic condition]. / Temblor ortostatico: una entidad enigmatica.

INTRODUCTION: Orthostatic tremor is a rare kind of tremor which is clinically characterised by a feeling of instability or being about to fall that is experienced on standing up, which disappears or improves on walking and is absent when sitting or lying down. AIM: To shed light on the main features of this tremor syndrome. DEVELOPMENT: First, its clinical spectrum is defined, with emphasis on the key characteristics that enable us to make an initial approximation to its syndromes. Then the main neurophysiological features that make up the electromyographic profile of orthostatic tremor are described. Finally, the pathophysiological hypotheses regarding the genesis of this kind of tremor are addressed and the therapeutic options currently available are described. CONCLUSIONS: The convergence of all the data reviewed provides a complete, critical analysis of this enigmatic motor disorder, thus allowing a rigorous approach to its main characteristics, which makes both its clinical recognition and its therapeutic management easier.

[Reversal of vision metamorphopsia as a manifestation of cerebellar infarct]. / Metamorfopsia invertida como manifestación de un infarto cerebeloso.

INTRODUCTION: Reversal of vision metamorphopsia is a disorder affecting the visuospatial perception of objects, without any changes in their shape, size or colour. It generally involves a full 180 degrees rotation of the visual field in the coronal plane. Its chief causation is vertebrobasilar ischaemia, although the phenomenon has also been linked to many other conditions, such as multiple sclerosis, epilepsy, migraine or traumatic head and neck injuries. Some notable features of reversal of vision metamorphopsia are the wide topographic variety of the lesions responsible for the condition, the transient nature of the symptom and its improvement or resolution in the presence of certain stimuli. CASE REPORT: A 35-year-old male with a sudden episode of instability that prevented him from walking, together with vomiting and reversal of vision metamorphopsia that lasted for an hour. A magnetic resonance scan enabled us to identify an acute ischaemic cerebellar lesion as the cause of the condition. CONCLUSIONS: The variety of locations of the lesions that give rise to reversal of vision metamorphopsia would be mainly due to the multisensory nature of the neurons in the posterior parietal cortex, the area of the brain where the visuospatial integration of images is performed. These neurons receive visual, proprioceptive and vestibular afferences, which means that any lesions that occur in these three systems or in the central integrator itself could cause the phenomenon of reversal of vision metamorphopsia.