Strategy for genetic analysis in hereditary neuropathy.

Inherited neuropathies are a heterogeneous group of slowly progressive disorders affecting either motor, sensory, and/or autonomic nerves. Peripheral neuropathy may be the major component of a disease such as Charcot-Marie-Tooth disease or a feature of a more complex multisystemic disease involving the central nervous system and other organs. The goal of this review is to provide the clinical clues orientating the genetic diagnosis in a patient with inherited peripheral neuropathy. This review focuses on primary inherited neuropathies, amyloidosis, inherited metabolic diseases, while detailing clinical, neurophysiological and potential treatment of these diseases.

Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies.

BACKGROUND AND PURPOSE: To describe a large series of patients with α, ß, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 ß-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and ß-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% ß-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.

Phenotypic correlations in a large single-center cohort of patients with BSCL2 nerve disorders: a clinical, neurophysiological and muscle magnetic resonance imaging study.

BACKGROUND AND PURPOSE: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMNs). A series of BSCL2 patients is presented and clinical, neurophysiological and muscle magnetic resonance imaging (MRI) findings are correlated. METHODS: Twenty-six patients from five families carrying the p.N88S mutation were identified. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth, spastic paraplegia), physical examination, disability measured as a modified Rankin Scale score and neurophysiological findings were collected. A whole body muscle MRI had been performed in 18 patients. The pattern of muscle involvement on T1-weighted and short time inversion recovery sequences was analysed. Hierarchical analysis using heatmaps and an MRI Composite Score were generated. Statistical analysis was carried out with STATA SE v.15 (TX, USA). RESULTS: The mean age was 51.54 ± 19.94 years and 14 patients were men. dHMN was the most common phenotype (50%) and five patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (modified Rankin Scale score 1.34 ± 1.13) although median time since onset of disease was 32 years (range 10-47). Charcot-Marie-Tooth-like patients were more disabled and disability correlated with age. On muscle MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI Composite Score was strongly correlated with disability. CONCLUSION: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials.

Psychiatric burden in a cohort of adults with Niemann Pick type C disease: from psychotic symptoms to frontal lobe behavioral disorders.

OBJECTIVES: To describe Niemann-Pick type C (NP-C) behavioral symptoms (focusing on psychotic symptoms) and its relation to frontal lobe functioning. METHODS: We retrospectively reviewed medical charts of NP-C-patients followed in the Lysosomal Diseases reference center in Paris Pitié-Salpêtrière. We collected demographic data, psychiatric clinical manifestations, psychometric scales, and extended neuropsychological data including executive and behavioral frontal lobe functions evaluations. RESULTS: Nineteen patients were included in the study with ten of them having experienced at least one acute psychotic episode, being inaugural for six of them. Most of the patients suffered from behavioral (15/17) and cognitive disorders (18/19) (including executive dysfunction (11/12), apathy (13/17), impaired social cognition (11/13) and stereotyped behaviors (5/10). For five patients, quality of life was significantly impaired by these abnormal behaviors. Concerning frontal neuropsychological evaluation, Facial emotion recognition was by far the most performed neuropsychological test (n = 8) and the score was always abnormal. It is noteworthy that psychotic symptoms were often drug resistant (8/9) and that Miglustat was associated with a better control of psychotic symptoms. CONCLUSIONS: We report a high frequency of psychiatric symptoms in NP-C encompassing acute psychotic manifestations, often presenting early in the course of the disease with atypical features. We also report disabling behavioral manifestations related to frontal dysfunction.

Epidemiology of ataxia and hereditary spastic paraplegia in Spain: A cross-sectional study.

INTRODUCTION: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. PATIENTS AND METHODS: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. RESULTS: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. CONCLUSIONS: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.

Attention to acute cerebrovascular disease in Guipúzcoa: description of the results of a reference hospital in a centralized care model.

INTRODUCTION: In the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario Donostia (HUD), improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model. MATERIAL AND METHODS: We performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients' baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year. RESULTS AND DISCUSSION: We identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in < 6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2. CONCLUSIONS: After the strategic changes implemented in acute stroke care in Guipuzkoa, including the centralisation of the acute stroke care model, mortality rates at discharge and at one year are lower in 2015 than the previously reported rates, with similar rates of independence. These results are consistent with those published by other Spanish and European centres.

Attention to acute cerebrovascular disease in Guipúzcoa: Description of the results of a reference hospital in a centralized care model. / Atención a la enfermedad cerebrovascular aguda en Guipúzcoa: descripción de los resultados de un hospital de referencia en un modelo de atención centralizado.

INTRODUCTION: In the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario Donostia (HUD), improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model. MATERIAL AND METHODS: We performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients' baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year. RESULTS AND DISCUSSION: We identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in <6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2. CONCLUSIONS: After the strategic changes implemented in acute stroke care in Guipuzkoa, including the centralisation of the acute stroke care model, mortality rates at discharge and at one year are lower in 2015 than the previously reported rates, with similar rates of independence. These results are consistent with those published by other Spanish and European centres.

Atención a la enfermedad cerebrovascular aguda en Guipúzcoa: descripción de los resultados de un hospital de referencia en un modelo de atención centralizado / Attention to acute cerebrovascular disease in Guipúzcoa: Description of the results of a reference hospital in a centralized care model

Introducción: En los últimos 15 años se han introducido importantes mejoras en la atención de la enfermedad cerebrovascular aguda (ECVA) en Guipúzcoa, que incluyen la implementación de un modelo centralizado en el Hospital Universitario Donostia (HUD), una mejor coordinación entre profesionales, campañas para su detección precoz, nuevos tratamientos, Unidad de Ictus y una rehabilitación específica. El objetivo de este trabajo es describir los resultados de un hospital de referencia (HUD) en un modelo de atención centralizado. Material y métodos: Estudio observacional retrospectivo de una muestra de pacientes dados de alta en el periodo de agosto-diciembre del año 2015 del HUD con diagnóstico de ECVA (CIE-9-MC-430-436 excepto 43310). Revisión de las características basales, atención en fase aguda y resultados funcionales y de mortalidad al alta y al año. Resultados y discusión: Se incluyó a 536 pacientes cuya media de edad fue de 73,6 años y cuya comorbilidad era elevada. El ictus isquémico supuso el 64,8% de las altas, seguido de la ECVA hemorrágica (20%) y del accidente isquémico transitorio (14,8%). Se atendió en < 6 h a un 53% de pacientes, activándose el «código ictus» en un 37,1%. Un 52,2% ingresó en la Unidad de Ictus. Un 11,34% de los pacientes con ictus isquémico recibió terapia por vía intravenosa y un 9,5% trombectomía mecánica. Un 12,1% de los pacientes con ECVA hemorrágica fue intervenido quirúrgicamente. El 56% inició rehabilitación en el hospital y un 39,6% la mantuvo al alta. La mortalidad al alta fue de un 13,8% y al año de un 25,9% (ictus isquémico: 25,3% y ECVA hemorrágica: 47,5%), menor a la descrita previamente en Guipúzcoa. Al año, un 62,5% de los pacientes tenían un ÿndice de Barthel 95-100 y un 50% una puntuación en escala de Rankin modificada 0-2. [...] (AU)

Introduction: In the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario Donostia (HUD), improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model. Material and methods: We performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients’ baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year. Results and discussion: We identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in < 6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2. [...] (AU)