RESUMO
BACKGROUND: Biallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood. OBJECTIVE: We report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1. METHODS: Whole exome sequencing was used to detect variants in FXR1. RESULTS: Common clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei. CONCLUSION: FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype-phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.
Assuntos
Doenças Musculares , Humanos , Linhagem , Mutação , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Homozigoto , Creatina Quinase/genética , Proteínas de Ligação a RNA/genéticaRESUMO
BACKGROUND AND PURPOSE: Mos scales currently used to evaluate spinal muscular atrophy (SMA) patients have only been validated in children. The aim of this study was to assess the construct validity and responsiveness of several outcome measures in adult SMA patients. METHODS: Patients older than 15 years and followed up in five referral centres for at least 6 months, between October 2015 and August 2020, with a motor function scale score (Hammersmith Functional Motor Scale Expanded [HFMSE], Revised Upper Limb module [RULM]) were included. Bedside functional scales (Egen Klassification [EK2], Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) were also collected when available. Spearman's rho correlations (rs) and Bangdiwala's concordance test (B) were used to evaluate the scales' construct validity. Monthly slopes of change were used to calculate their responsiveness of the scales. RESULTS: The study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong correlations with each other (rs > 0.70). A floor effect in motor function scales was found in the weakest patients (HFMSE < 5 and RULM < 10), and a ceiling effect was found in stronger patients (HFMSE > 60 and RULM > 35). The ALSFRS-R (B = 0.72) showed a strong ability to discriminate between walkers, sitters and non-sitters, and the HFMSE (B = 0.86) between walkers and sitters. The responsiveness was low overall, although in treated patients a moderate responsiveness was found for the ALSFRS-R and HFMSE in walkers (0.69 and 0.61, respectively) and for EK2 in sitters (0.65) and non-sitters (0.60). CONCLUSIONS: This study shows the validity and limitations of the scales most frequently used to assess adult SMA patients. Overall, bedside functional scales showed some advantages over motor scales, although all showed limited responsiveness.
Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Criança , Adulto , Humanos , Avaliação de Resultados em Cuidados de Saúde , Extremidade SuperiorRESUMO
BACKGROUND AND PURPOSE: The aim was to assess the safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients. METHODS: Patients older than 15 years and followed for at least 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM) in five referral centers were included. The clinical and patients' global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percentage predicted forced vital capacity were collected when available. RESULTS: Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p < 0.001) after 6 months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (odds ratio [OR] 1.15, p = 0.006), the 6-min walk test (OR = 1.07, p < 0.001) and the EK2 (OR = 0.81, p = 0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p = 0.033), ALSFRS-R (p = 0.005) and EK2 (p < 0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being a non-sitter was associated with less response to treatment, whilst a longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild. CONCLUSIONS: Nusinersen treatment is associated with some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.
Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Adulto , Humanos , Injeções Espinhais , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/efeitos adversos , Atrofias Musculares Espinais da Infância/tratamento farmacológicoRESUMO
Neurological complications of Epstein Barr virus (EBV) infection are infrequent and may include occasionally encephalitis, usually with a benign evolution. We here report on an aggressive case of EBV encephalitis in a 14-year-old boy with extensive basal ganglia involvement, and to a lesser degree of brain cortex who presented atypically with akinetic mutism and non-convulsive status epilepticus, requiring intensive care but showed a favorable outcome. EBV encephalitis is uncommon and its best management is unclear. Its pathophysiology is not well understood but could include autoimmunity. Onconeuronal and synaptic antibodies were negative in serum and cerebrospinal fluid, including the dopamine D2 receptor. To the best of our knowledge, this is the first report to evaluate antibodies to D2 receptors in EBV encephalitis. Corticosteroid therapy is usually recommended but the use of acyclovir is controversial. Intensive care is required in severe cases to assure a favorable outcome.
Assuntos
Afasia Acinética/fisiopatologia , Doenças dos Gânglios da Base/fisiopatologia , Encefalite Viral/fisiopatologia , Infecções por Vírus Epstein-Barr/fisiopatologia , Estado Epiléptico/fisiopatologia , Adolescente , Afasia Acinética/diagnóstico por imagem , Afasia Acinética/imunologia , Afasia Acinética/terapia , Anticonvulsivantes/uso terapêutico , Autoanticorpos/imunologia , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/imunologia , Doenças dos Gânglios da Base/terapia , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/imunologia , Edema Encefálico/fisiopatologia , Edema Encefálico/terapia , Cromonar , Eletroencefalografia , Encefalite Viral/diagnóstico , Encefalite Viral/imunologia , Encefalite Viral/terapia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/terapia , Glucocorticoides/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Receptores de Dopamina D2/imunologia , Recuperação de Função Fisiológica , Estado Epiléptico/imunologia , Estado Epiléptico/terapiaRESUMO
BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.
Assuntos
Distrofia Miotônica/diagnóstico , Seguimentos , Humanos , Distrofia Miotônica/complicações , Guias de Prática Clínica como AssuntoRESUMO
OBJECTIVE: To determine whether congenital arhinia/Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2 seemingly unrelated disorders both caused by heterozygous pathogenic missense variants in the SMCHD1 gene, might represent different ends of a broad single phenotypic spectrum associated with SMCHD1 dysfunction. METHODS: We examined and/or interviewed 14 patients with FSHD2 and 4 unaffected family members with N-terminal SMCHD1 pathogenic missense variants to identify BAMS subphenotypes. RESULTS: None of the patients with FSHD2 or family members demonstrated any congenital defects or dysmorphic features commonly found in patients with BAMS. One patient became anosmic after nasal surgery and one patient was hyposmic; one man was infertile (unknown cause) but reported normal pubertal development. CONCLUSION: These data suggest that arhinia/BAMS and FSHD2 do not represent one phenotypic spectrum and that SMCHD1 pathogenic variants by themselves are insufficient to cause either of the 2 disorders. More likely, both arhinia/BAMS and FSHD2 are caused by complex oligogenic or multifactorial mechanisms that only partially overlap at the level of SMCHD1.