Objective ANO5‐related myopathy is an important cause of limb‐girdle muscular dystrophy (LGMD) and hyperCKemia. The main descriptions have emerged from European cohorts, and the burden of the disease worldwide is unclear. We provide a detailed characterization of a large Brazilian cohort of ANO5 patients. Methods A national cross‐sectional study was conducted to describe clinical, histopathological, radiological, and molecular features of patients carrying recessive variants in ANO5. Correlation of clinical and genetic characteristics with different phenotypes was studied. Results Thirty‐seven patients from 34 nonrelated families with recessive mutations of ANO5 were identified. The most common phenotype was LGMD, observed in 25 (67.5%) patients, followed by pseudometabolic presentation in 7 (18.9%) patients, isolated asymptomatic hyperCKemia in 4 (10.8%) patients, and distal myopathy in a single patient. Nine patients presented axial involvement, including one patient with isolated axial weakness. The most affected muscles according to MRI were the semimembranosus and gastrocnemius, but paraspinal and abdominal muscles, when studied, were involved in most patients. Fourteen variants in ANO5 were identified, and the c.191dupA was present in 19 (56%) families. Sex, years of disease, and the presence of loss‐of‐function variants were not associated with specific phenotypes. Interpretation We present the largest series of anoctaminopathy outside Europe. The most common European founder mutation c.191dupA was very frequent in our population. Gender, disease duration, and genotype did not determine the phenotype.
Background Spinal muscular atrophy type 1 (SMA1) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival. Objective: To report the evaluation of the nusinersen, an antisense oligonucleotide, on the motor function of SMA1. Methods This was a longitudinal and observational study to assess the outcomes of nusinersen therapy in SMA1 patients using the HINE-2 and CHOP-INTEND scales. Results Twenty-one SMA1 patients (52.4% males) were included; the mean age at first symptoms was 2.7 months (SD =±1.5), and the mean disease duration at first dose was 34.1 (SD =±36.0) months. During posttreatment, the mean gain on the CHOP-INTEND was 4.9, 5.9, 6.6, and 14 points after 6, 12, 18, and 24 months, respectively. Starting medication with a disease duration of less than 12 months and/or without invasive ventilation were predictors of response on CHOP-INTEND. Of the patients, 28.6% acquired a motor milestone or gained at least three points on the HINE-2. The daily time for ventilatory support was reduced after treatment in most of the patients with noninvasive ventilation at baseline. No change in the daytime use of ventilation was observed in most of the patients using invasive ventilation at baseline. Conclusions Nusinersen produces improvements in motor and respiratory functions, even in long-term SMA1 patients. However, patients under invasive ventilation at the beginning of the treatment experience little benefit.
ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.ConclusionsPatients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.
Spinal muscular atrophy (SMA) is genetic and progressive, caused by large bi-allelic deletions in the SMN1 gene, or the association of a large deletion and a null variant. Objective: To evaluate the evidence about cognitive outcomes in spinal muscular atrophy (SMA). Methods: Searches on the PUBMED/Medline, Web of Knowledge and Scielo databases retrieved 26 studies (1989 to 2019, descriptors “spinal muscular atrophy” and “cognition”). Nine studies were selected according to the eligibility criteria: (1) cognition tested in individuals with SMA; (2) written in English or Spanish. The Risk of Bias in Non-Randomized Studies of Interventions was used to describe design, bias, participants, evaluation protocol and main findings. This study was registered on the International prospective register of systematic reviews (PROSPERO). Results: Three studies described normal cognition. In another three studies, cognitive outcomes were above average. Cognitive impairment was found in three studies. Poor cognitive performance was more frequently reported in studies that were recent, included children with SMA type I and that employed visual/auditory attention and executive function tests. Protocols and cognitive domains varied, precluding metanalysis. Conclusion: The severity of motor impairment may be related to cognitive outcomes: studies that included a higher number/percentage of children with SMA type I found cognitive impairment. The establishment of gold-standard protocols is necessary. Further studies should compare the cognitive outcomes of subjects with SMA types I to IV.
A 62-year-old man presented with seven years of progressive dysphagia, dysphonia and difficulty in closing both eyes. His examination showed weakness and atrophy of facial and bulbar muscles without ocular involvement ( Figure A, B and C). Single-fiber electromyography revealed increased jitter ( Figure D). To evaluate for concurrent myopathy, a muscle biopsy was performed and showed angulated atrophic type II fibers, a particular finding described in patients with myasthenia gravis 1,2 ( Figure E). Acetylcholine receptor antibody was positive (2.2 nmol/L). Pronounced facial and tongue atrophy is uncommon in myasthenia gravis and usually associated with the muscle-specific receptor tyrosine kinase antibody, which was negative in this patient 3,4 .
Background: Spinal muscular atrophy (SMA) is a neurodegenerative disease of lower motor neurons associated with frequent occurrence of spinal deformity. Nusinersen is an antisense oligonucleotide that increases SMN protein level and is administrated by frequent intrathecal lumbar injections. Thus, spinal deformities and previous spinal surgery are important challenges for drug delivery in SMA. Objective: To report imaging methods used for Nusinersen injection in SMA patients. Methods: Nusinersen injection procedures in SMA types 2 and 3 patients who had previous spinal surgery were analyzed retrospectively to describe the imaging and puncture procedures, as well as the occurrence of complications. Results: Nine SMA patients (14 to 50 years old) underwent 57 lumbar punctures for nusinersen injection. Six patients had no interlaminar space available; in five of them, a transforaminal approach was used, and another one underwent a surgery to open a posterior bone window for the injections. Transforaminal puncture was performed using CT scan in three cases and fluoroscopy in the other two, with a similar success rate. One patient in the transforaminal group had post-procedure radiculitis, and another one had vagal reaction (hypotension). In three cases, with preserved interlaminar space, injections were performed by posterior interlaminar puncture, and only one adverse event was reported (post-puncture headache). Conclusion: In SMA patients with previous spinal surgery, the use of imaging-guided intervention is necessary for administering intrathecal nusinersen. Transforaminal technique is indicated in patients for whom the interlaminar space is not available, and injections should always be guided by either CT or fluoroscopy.
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