ABSTRACT
BACKGROUND AND OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing. METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region. RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes. CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.
ABSTRACT
BACKGROUND AND OBJECTIVES: To study the clinical and laboratory features of antineurofascin-155 (NF155)-positive autoimmune nodopathy (AN). METHODS: Patients with anti-NF155 antibodies detected on routine immunologic testing were included. Clinical characteristics, treatment response, and functional scales (modified Rankin Scale [mRS] and Inflammatory Rasch-built Overall Disability Scale [I-RODS]) were retrospectively collected at baseline and at the follow-up. Autoantibody and neurofilament light (NfL) chain levels were analyzed at baseline and at the follow-up. RESULTS: Forty NF155+ patients with AN were included. Mean age at onset was 42.4 years. Patients presented with a progressive (75%), sensory motor (87.5%), and symmetric distal-predominant weakness in upper (97.2%) and lower extremities (94.5%), with tremor and ataxia (75%). Patients received a median of 3 (2-4) different treatments in 46 months of median follow-up. Response to IV immunoglobulin (86.8%) or steroids (72.2%) was poor in most patients, whereas 77.3% responded to rituximab. HLA-DRB1*15 was detected in 91.3% of patients. IgG4 anti-NF155 antibodies were predominant in all patients; anti-NF155 titers correlated with mRS within the same patient (r = 0.41, p = 0.004). Serum NfL (sNfL) levels were higher in anti-NF155+ AN than in healthy controls (36.47 vs 7.56 pg/mL, p < 0.001) and correlated with anti-NF155 titers (r = 0.43, p = 0.001), with I-RODS at baseline (r = -0.88, p < 0.001) and with maximum I-RODS achieved (r = -0.58, p = 0.01). Anti-NF155 titers and sNfL levels decreased in all rituximab-treated patients. DISCUSSION: Anti-NF155 AN presents a distinct clinical profile and good response to rituximab. Autoantibody titers and sNfL are useful to monitor disease status in these patients. The use of untagged-NF155 plasmids minimizes the detection of false anti-NF155+ cases. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that anti-NF155 antibodies associate with a specific phenotype and response to rituximab.
Subject(s)
Autoantibodies/blood , Autoimmune Diseases of the Nervous System , Cell Adhesion Molecules/immunology , Immunologic Factors/pharmacology , Nerve Growth Factors/immunology , Ranvier's Nodes/immunology , Rituximab/pharmacology , Adult , Aged , Autoimmune Diseases of the Nervous System/blood , Autoimmune Diseases of the Nervous System/drug therapy , Autoimmune Diseases of the Nervous System/immunology , Autoimmune Diseases of the Nervous System/physiopathology , Female , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
We report the case of a patient with a clinical phenotype characterized by distal lower limb weakness and pes cavus. The electrophysiological study showed slightly reduced or normal amplitude of motor potentials, a decremental response to repetitive nerve stimulation and post-exercise facilitation. Muscle biopsy showed only mild neurogenic features. Genetic analysis included a clinical exome sequencing, followed by Sanger analysis. Three-dimensional (3D) models were generated with a SwissModel (https://swissmodel.expasy.org/) to explain the clinical observations and reinforce the pathogenic nature of the genetic variant identified. Genetic analysis demonstrated a new de novo heterozygous in frame deletion of the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing, which removes five aminoacids in the C2B domain of synaptotagmin-2 protein, that cause a profound effect on the structure and function of this synaptic vesicle protein. We identified a de novo genetic variant in the SYT2 gene, further supporting its association with a highly stereotyped clinical and electrophysiological phenotype. Our case showed electrophysiological features consistent with a presynaptic dysfunction in the neuromuscular junction with normal post-exercise amplitudes, not supporting the presence of predominant axonal damage. Although the analysis of SYT2 gene should be included in genetic analysis of patients presenting with this clinical phenotype that mimics motor neuropathy, clinicians have to consider the study of neuromuscular transmission to early identify this potentially treatable condition.
Subject(s)
Muscle Weakness/physiopathology , Neuromuscular Diseases/diagnosis , Neuromuscular Junction/physiopathology , Peripheral Nervous System Diseases/diagnosis , Synaptotagmin II/genetics , Adult , Electrodiagnosis , Frameshift Mutation , Humans , Lower Extremity/physiopathology , Male , Neuromuscular Diseases/genetics , Neuromuscular Diseases/physiopathology , Pedigree , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/physiopathologyABSTRACT
Fundamento: En la primavera de 1998 hubo un brote de gastroenteritis aguda en Guadarrama (Comunidad de Madrid, España) que afectó sobre todo a niños en edad preescolar. Métodos: Se hizo un estudio descriptivo y analítico (casos y controles) del brote. Se tomaron muestras para estudio microbiológico de las heces de los afectados. Se inspeccionó el sistema de captación de agua de consumo de propiedad municipal y se tomaron muestras para análisis microbiológico. Resultados: Veintiún niños/as de 0 a 5 años presentaron diarrea líquida de más de 5 días de duración. Se encontró una asociación estadísticamente significativa entre el consumo de agua del grifo y la gastroenteritis [OR=5,73 (1,18-43,30); p<0,05]. No se halló asociación con otras variables investigadas. Se detectaron ooquistes de Cryptosporidium parvum en heces de ocho de las personas afectadas. Se observaron deficiencias en el sistema de captación y depuración de agua de consumo público de propiedad municipal pero no se encontraron ooquistes en los análisis del agua. Conclusiones: Los resultados de la investigación epidemiológica sustentan que el origen del brote de gastroenteritis por Cryptosporidium parvum fue el agua del grifo. Aunque no se detectó este parásito en los análisis de agua, esto es explicable por las dificultades que entraña esta técnica. En la revisión bibliográfica, no se han hallado descripciones de brotes epidémicos similares en nuestro país, pero según algunos informes, no son infrecuentes en países de nuestro entorno. Por tanto, Cryptosporidium parvum debería ser tenido en cuenta en el diagnóstico y manejo de estas situaciones (AU)
