Characterizing SOD1 mutations in Spain. The impact of genotype, age, and sex in the natural history of the disease.

INTRODUCTION: The aim of this study is to describe the frequency and distribution of SOD1 mutations in Spain, and to explore those factors contributing to their phenotype and prognosis. METHODS: Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers. RESULTS: In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all 5 exons of SOD1, including 7 novel mutations. 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. Its frequency varied considerably between regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp(Estimate) = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (HR = 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated to faster disease progression (exp(Estimate) = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs 301 months). CONCLUSIONS: These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.

Autoantibody screening in Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. METHODS: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. RESULTS: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. CONCLUSION: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.

Serum neurofilament light chain predicts long-term prognosis in Guillain-Barré syndrome patients.

OBJECTIVE: To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS). METHODS: We measured NfL in serum (98 samples) and cerebrospinal fluid (CSF) (24 samples) of patients with GBS prospectively included in the International GBS Outcome Study (IGOS) in Spain using single-molecule array (SiMoA) and compared them with 53 healthy controls (HCs). We performed multivariable regression to analyse the association between sNfL levels and functional outcome at 1 year. RESULTS: Patients with GBS had higher NfL levels than HC in serum (55.49 pg/mL vs 9.83 pg/mL, p<0.0001) and CSF (1308.5 pg/mL vs 440.24 pg/mL, p=0.034). Patients with preceding diarrhoea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90 pg/mL vs 47.86 pg/mL vs 38.02 pg/mL, p=0.016). sNfL levels correlated with Guillain-Barré Syndrome Disability Score and Inflammatory Rasch-built Overall Disability Scale (I-RODS) at every timepoint. Patients with pure motor variant and Miller Fisher syndrome showed higher sNfL levels than patients with sensorimotor GBS (162.18 pg/mL vs 95.50 pg/mL vs 38.02 pg/mL, p=0.025). Patients with acute motor axonal neuropathy cute motor axonal neuropathy had higher sNfL levels than other variants (190.55 pg/mL vs 46.79 pg/mL, p=0.013). sNfL returned to normal levels at 1 year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14 to 2.40, p=0.009) and lower I-RODS (ß -2.60, 95% CI -4.66 to -0.54, p=0.014) at 1 year. Cut-off points predicting clinically relevant outcomes at 1 year with high specificity were calculated: inability to walk independently (>319 pg/mL), inability to run (>248 pg/mL) and ability to run (<34 pg/mL). CONCLUSION: Baseline sNfL levels are increased in patients with GBS, are associated with disease severity and axonal variants and have an independent prognostic value in patients with GBS.

Perfil neuropsicológico en pacientes con distrofia miotónica tipo 1: estudio de seguimiento a cuatro años / Neuropsychological profile in patients with myotonic dystrophy type 1: a four-year follow-up study

INTRODUCCIÓN: La distrofia miotónica tipo 1 (DM1), o enfermedad de Steinert, es un trastorno multisistémico de herencia autosómica dominante, cuya variante adulta suele cursar con deterioro cognitivo multidominio y afectación de la funcionalidad y la calidad de vida de los pacientes. OBJETIVO: Estudiar la evolución a cuatro años del funcionamiento cognitivo de una muestra de pacientes con la variante adulta de DM1. PACIENTES Y MÉTODOS: Se evalúan las funciones cognitivas de una muestra de 31 pacientes con DM1, de los cuales 24 repiten la evaluación administrada hace cuatro años en el Servicio de Neurología del Complejo Hospitalario de Navarra. Se recogen datos de los dominios neurocognitivos más relacionados con los déficits de presentación habitual en la DM1. RESULTADOS: La evaluación de seguimiento constató la afectación de las funciones visuoespaciales y visuoconstructivas y de la atención alternante de los pacientes que se sometieron al estudio, así como de su funcionamiento cotidiano informado por la familia. Estos resultados están en línea con los obtenidos cuatro años atrás, sin que se haya objetivado un deterioro significativo entre ambas mediciones. Se demuestra, además, una mayor incidencia de deterioro cognitivo en 2018, con algunos casos de evolución a demencia en la enfermedad de Steinert. CONCLUSIÓN: La evolución neuropsicológica en la DM1 parece responder a un patrón progresivo, ligado a las funciones que más se afectan desde los inicios de la fase de secuelas y que suelen corresponder a los dominios de memoria de trabajo, atención alternante y habilidades visuoespaciales y visuoconstructivas

INTRODUCTION. Myotonic dystrophy type 1 (MD1), or Steinert's disease, is a multisystemic disorder of autosomal dominant inheritance, whose adult variant usually presents with multidomain cognitive impairment and affects patients' functionality and quality of life. AIM. To study the four-year history of cognitive functioning in a sample of patients with the adult variant of MD1. PATIENTS AND METHODS. The neurocognitive functions of a sample of 31 patients with MD1 are evaluated, of whom 24 repeat the test administered four years ago in the Neurology Service of the Complejo Hospitalario of Navarra. Data are collected from the cognitive domains that are most related to the deficits that usually present in MD1. RESULTS. The follow-up evaluation found that the visuospatial and visuoconstructive functions and alternating attention of the patients who underwent the study were affected, as was their daily functioning reported by the family. These results are in line with those obtained four years earlier, with no significant deterioration observed between the two measurements. A higher incidence of cognitive impairment was also displayed in 2018, with some cases of progression to dementia in Steinert's disease. CONCLUSION. Neurocognitive progression in MD1 seems to respond to a progressive pattern of degeneration, linked to the functions that are most affected from the beginning of the sequelae phase and which usually correspond to the domains of working memory, alternating attention, and visuospatial and visuoconstructive abilities

A Novel Missense Variant Associated with A Splicing Defect in A Myopathic Form of PGK1 Deficiency in The Spanish Population.

Phosphoglycerate kinase (PGK)1 deficiency is an X-linked inherited disease associated with different clinical presentations, sometimes as myopathic affectation without hemolytic anemia. We present a 40-year-old male with a mild psychomotor delay and mild mental retardation, who developed progressive exercise intolerance, cramps and sporadic episodes of rhabdomyolysis but no hematological features. A genetic study was carried out by a next-generation sequencing (NGS) panel of 32 genes associated with inherited metabolic myopathies. We identified a missense variant in the PGK1 gene c.1114G > A (p.Gly372Ser) located in the last nucleotide of exon 9. cDNA studies demonstrated abnormalities in mRNA splicing because this change abolishes the exon 9 donor site. This novel variant is the first variant associated with a myopathic form of PGK1 deficiency in the Spanish population.

Hiperexcitabilidad nerviosa en el síndrome de Michaelis-Manz / Nerve hyperexcitability in Michaelis-Manz syndrome

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[A descriptive study of the neuropsychological and psychopathological profile in patients with type 1 myotonic dystrophy]. / Estudio descriptivo del perfil neuropsicologico y psicopatologico en pacientes con distrofia miotonica tipo 1.

INTRODUCTION: Type 1 myotonic dystrophy (MD-1) or Steinert disease is a multisystemic progressive disorder. Studies have shown cognitive deficits, depressive symptoms and a high incidence of anxiety personality traits that compromise both the functionality and the quality of life of these patients. AIM: To describe the cognitive and psychopathological profile of a sample of patients with the adult variant of MD-1. PATIENTS AND METHODS: A sample of 27 patients diagnosed with MD-1 was selected from those being followed up in the neurology service of the Complejo Hospitalario de Navarra. Eligibility criteria were age under 50 years and the absence of any other pathology or physical condition that prevented them from performing the psychological evaluation. A neuropsychological evaluation battery specifically designed for this kind of pathology was used, together with psychopathological and functionality measures. RESULTS: The neuropsychological evaluation revealed mainly deficits in visual-constructional and visuospatial skills, alternating attention and in other-reported dysexecutive signs and symptoms. The group of patients did not present any clinically significant symptoms of depression or anxiety, but did score high on obsession-compulsion, interpersonal sensitivity, paranoid ideation and psychoticism. The results point towards a deterioration in functionality. CONCLUSIONS: In the integral approach to MD-1, the characterisation and developmental monitoring of the cognitive, psychopathological and personality profile, as well as the level of functionality, all contribute to an improvement in the quality of life of these patients.

TITLE: Estudio descriptivo del perfil neuropsicologico y psicopatologico en pacientes con distrofia miotonica tipo 1.Introduccion. La distrofia miotonica tipo 1 (DM-1) o enfermedad de Steinert es un trastorno multisistemico y progresivo. Se han encontrado deficits cognitivos, clinica depresiva y alta incidencia de rasgos de personalidad ansiosos con afectacion tanto en la funcionalidad como en la calidad de vida de estos pacientes. Objetivo. Describir el perfil cognitivo y psicopatologico de una muestra de pacientes con la variante adulta de DM-1. Pacientes y metodos. Se selecciono una muestra de 27 pacientes con diagnostico de DM-1 en seguimiento en el Servicio de Neurologia del Complejo Hospitalario de Navarra. Los criterios de inclusion fueron tener menos de 50 anos y descartar cualquier otra patologia o condicion fisica que impidiese realizar la evaluacion psicologica. Se utilizo una bateria de evaluacion neuropsicologica especificamente disenada para este tipo de patologia, ademas de medidas de psicopatologia y funcionalidad. Resultados. La evaluacion neuropsicologica reflejo, principalmente, deficits en habilidades visuoconstructivas, visuoespaciales, atencion alternante y en sintomatologia disejecutiva heteroinformada. El grupo de pacientes no presento sintomatologia depresiva ni ansiosa clinicamente significativa, pero si puntuaciones elevadas en obsesion-compulsion, sensibilidad interpersonal, ideacion paranoide y psicoticismo. Los resultados orientaron hacia un deterioro en la funcionalidad. Conclusiones. En el abordaje integral de la DM-1, la caracterizacion y el seguimiento evolutivo del perfil cognitivo, psicopatologico y de personalidad, asi como del nivel de funcionalidad, contribuyen a la mejora de la calidad de vida de estos pacientes.

Estudio descriptivo del perfil neuropsicológico y psicopatológico en pacientes con distrofia miotónica tipo 1 / A descriptive study of the neuropsychological and psychopathological profile in patients with type 1 myotonic dystrophy

Introducción. La distrofia miotónica tipo 1 (DM-1) o enfermedad de Steinert es un trastorno multisistémico y progresivo. Se han encontrado déficits cognitivos, clínica depresiva y alta incidencia de rasgos de personalidad ansiosos con afectación tanto en la funcionalidad como en la calidad de vida de estos pacientes. Objetivo. Describir el perfil cognitivo y psicopatológico de una muestra de pacientes con la variante adulta de DM-1. Pacientes y métodos. Se seleccionó una muestra de 27 pacientes con diagnóstico de DM-1 en seguimiento en el Servicio de Neurología del Complejo Hospitalario de Navarra. Los criterios de inclusión fueron tener menos de 50 años y descartar cualquier otra patología o condición física que impidiese realizar la evaluación psicológica. Se utilizó una batería de evaluación neuropsicológica específicamente diseñada para este tipo de patología, además de medidas de psicopatología y funcionalidad. Resultados. La evaluación neuropsicológica reflejó, principalmente, déficits en habilidades visuoconstructivas, visuoespaciales, atención alternante y en sintomatología disejecutiva heteroinformada. El grupo de pacientes no presentó sintomatología depresiva ni ansiosa clínicamente significativa, pero sí puntuaciones elevadas en obsesión-compulsión, sensibilidad interpersonal, ideación paranoide y psicoticismo. Los resultados orientaron hacia un deterioro en la funcionalidad. Conclusiones. En el abordaje integral de la DM-1, la caracterización y el seguimiento evolutivo del perfil cognitivo, psicopatológico y de personalidad, así como del nivel de funcionalidad, contribuyen a la mejora de la calidad de vida de estos pacientes (AU)

Introduction. Type 1 myotonic dystrophy (MD-1) or Steinert disease is a multisystemic progressive disorder. Studies have shown cognitive deficits, depressive symptoms and a high incidence of anxiety personality traits that compromise both the functionality and the quality of life of these patients. Aim. To describe the cognitive and psychopathological profile of a sample of patients with the adult variant of MD-1. Patients and methods. A sample of 27 patients diagnosed with MD-1 was selected from those being followed up in the neurology service of the Complejo Hospitalario de Navarra. Eligibility criteria were age under 50 years and the absence of any other pathology or physical condition that prevented them from performing the psychological evaluation. A neuropsychological evaluation battery specifically designed for this kind of pathology was used, together with psychopathological and functionality measures. Results. The neuropsychological evaluation revealed mainly deficits in visual-constructional and visuospatial skills, alternating attention and in other-reported dysexecutive signs and symptoms. The group of patients did not present any clinically significant symptoms of depression or anxiety, but did score high on obsession-compulsion, interpersonal sensitivity, paranoid ideation and psychoticism. The results point towards a deterioration in functionality. Conclusions. In the integral approach to MD-1, the characterisation and developmental monitoring of the cognitive, psychopathological and personality profile, as well as the level of functionality, all contribute to an improvement in the quality of life of these patients (AU)

Myasthenia gravis: sleep quality, quality of life, and disease severity.

INTRODUCTION: There is much research on quality of life in myasthenia gravis (MG), and its relationship to disease severity is well-established. However, evidence regarding sleep disturbance in MG is inconclusive. METHODS: To evaluate sleep and quality of life among clinically stable MG patients, 54 subjects were investigated by means of the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and 15-Item-Quality-Of-Life Instrument for MG (MG-QOL15). RESULTS: A pathological PSQI score, which was observed in 59% of patients, was increased in subjects with active disease compared with patients in clinical remission [odds ratio = 4.3; confidence interval 95% (1.0-17.6); P = 0.04]. We found a relationship between PSQI and MG-QOL15 scores in patients with clinically active disease (r = 0.62; P < 0.001). CONCLUSIONS: Our study highlights the high prevalence of sleep disturbance among MG patients. Disease severity may be considered to be a MG-specific risk factor for patient-reported sleep disturbance. The MG-QOL15 and PSQI should be used to estimate the impact of the disease on sleep and quality of life.