Eduardo de Paula Estephan

Background and ObjectivesATP1A3-related disorders comprise an expanding group of ultra-rare neurologic conditions, classically including rapid-onset dystonia-parkinsonism (RDP), alternating hemiple...

Background Neuromuscular disorders (NMDs) affect approximately 1 in 1,000 individuals and are clinically and genetically heterogeneous. Despite advances in genomic diagnostics, many cases remain unsolved after initial sequencing. Bioinformatic reanalysis approaches provide opportunities to identify missed variants and establish novel disease genes. Methods Preexisting next-generation sequencing datasets from 101 undiagnosed NMD families were reanalyzed using the RD-Connect Genome-Phenome Analysis Platform. The data comprised clinical exome sequencing (45 families), whole exome sequencing (31 families), and whole genome sequencing (25 families). Variant prioritization incorporated population frequency, Human Phenotype Ontology terms, in silico predictions, and genotype–phenotype correlation. Results Reanalysis identified causative variants in 17 out of 101 previously unsolved families (16.83% diagnostic yield). Eight cases harbored coding variants in known NMD genes (RYR1, AGRN, SCN4A, TTN, MYH2, GOLGA2) consistent with the observed phenotype. In five cases, intronic variants in known NMD genes (COL6A3, SGCA, DOK7, DYSF, CHRND) were considered causative following in silico predictions and careful correlation with the phenotype. One case had an extended phenotype (PTPN11), and one case had a dual diagnosis (MYH2, KIF21A). A novel ATP2A2 missense variant was identified in two unrelated families, establishing ATP2A2 as a new NMD gene. Conclusion Research-based reanalysis of preexisting NGS data improved diagnostic yield of previously unsolved cases consistent with previous literature, reinforcing the utility of in-depth, phenotype-driven reanalysis with expert review. Our study provided 17 families with unsolved NMDs with a diagnosis after having waited for a decade. This supports the routine reanalysis of unsolved NGS data, highlighting its potential to reclassify variants of unknown significance and reveal novel genes and pathomechanisms in NMDs.

Pathogenic variants of the COQ7 gene result in a spectrum of neurological diseases, mainly distal hereditary motor neuropathy (dHMN). We herein report cases of dHMN related to biallelic p.Met1? (c.3G > T [NM_016138]). We compare phenotypes among different COQ7variants reported in the literature. To describe and analyze our case series, review COQ7-related diseases, and compare our case series with the literature reports. We described 5 dHMN-p.Met1? patients and searched dHMN AND Brazil and COQ7 in the PubMed/MEDLINE, SciELO and Scopus databases. The categorical variables were expressed as absolute frequencies, and they were compared using the Fisher's exact test and odds ratios with 95%CIs; moreover, exploratory multivariate logistic models with penalization were applied to adjust the associations for genotype/geographic origin. We analyzed four patients with dHMN plus (two with pyramidal syndrome [PS], one with cerebellar ataxia [CA] and PS, and one with cognitive impairment [CI]) and one with pure dHMN. Our search identified 47 cases of COQ7-related disorders, and The p.Met1? variant was more frequent in dHMN (p < 0.001). In exploratory multivariate models adjusting for genotype/geographic origin, the associations observed in the univariate analyses were partially sustained. The p.Met1? variant remained related to earlier age at onset, CI, and proximal lower limb weakness, whereas Brazilian origin continued to show association with cerebellar manifestations. The 95%CIs were wide due to the small sample, and the results should be interpreted as exploratory. In conclusion, our findings suggest that the p.Met1? variant is associated with selected phenotype, even after adjustment for genotype/geographic origin. Brazilian origin remained independently related to cerebellar involvement, indicating potential modifying factors beyond genotype.

MUSK‐related congenital myasthenic syndrome (MUSK‐CMS) is a rare neuromuscular disorder caused by pathogenic variants in the MUSK gene. The phenotypic spectrum varies significantly, ranging from mild, fatigable muscle weakness to severe neonatal onset with respiratory failure. This study is aimed at presenting a case series of MUSK‐CMS, highlighting its clinical diversity and diagnostic challenges, and proposing a clinical classification into three distinct phenotypes. We conducted clinical and genetic analyses of six patients diagnosed with MUSK‐CMS from three tertiary centers in Brazil. Clinical evaluations encompassed assessments of muscle strength, respiratory function, bulbar symptoms, and functional performance using the 6‐min walk test (6MWT) and MG‐ADL scale. Genetic testing was performed using whole exome sequencing (WES). Treatment responses were documented. Patients ranged in age from 19 to 58 years, with symptom onset varying from congenital to 32 years of age. All but one patient exhibited bilateral ptosis, extraocular muscle weakness, and gaze limitations. Based on our cohort and a review of previously reported cases, MUSK‐CMS appears to exhibit three overlapping clinical patterns: early‐onset severe disease, ocular‐predominant involvement, and late‐onset limb‐girdle presentation. In our cohort, these phenotypes were distributed as follows: early‐onset severe ( n = 1), ocular ( n = 4), and late‐onset limb‐girdle ( n = 1). Early recognition and genetic testing are critical for optimal patient outcomes, especially in atypical or adult‐onset cases.

The nerve terminal and muscle membrane compose the neuromuscular junction. After opening the voltage-gated calcium channels, action potentials from the motor axons provoke a cascade for the acetylcholine release from synaptic vesicles to the synaptic cleft, where it binds to its receptor at the muscle membrane for depolarization. Low amplitude compound muscle action potential typically presents in presynaptic disorders, increasing by more than 100% after a 10-second effort in the Lambert-Eaton myasthenic syndrome and less in botulism. Needle electromyography may show myopathic motor unit action potentials and morphological instability (“jiggle”) due to impulse blocking. Low-frequency repetitive nerve stimulation (RNS) is helpful in postsynaptic disorders, such as myasthenia gravis and most congenital myasthenic syndromes, where the number of functioning acetylcholine receptors is reduced. Low-frequency RNS with a decrement >10% is abnormal when comparing the 4th to the first compound muscle action potential amplitude. High-frequency RNS is helpful in presynaptic disorders like Lambert-Eaton myasthenic syndrome, botulism, and some rare congenital myasthenic syndromes. The high-frequency RNS releases more calcium, increasing the acetylcholine with a compound muscle action potential increment. Concentric needle records apparent single-fiber action potentials (spikes). A voluntary activation measures the jitter between spikes from two endplates. An electrical activation measures the jitter of one spike (one endplate). The jitter is the most sensitive test for detecting a neuromuscular junction dysfunction. Most neuromuscular junction disorders are responsive to treatment.

The RASopathies are a group of genetic rare diseases caused by mutations affecting genes involved in the RAS/MAPK (RAS–mitogen activated protein kinase) pathway. Among them, PTPN11 pathogenic variants are responsible for approximately 50% of Noonan syndrome (NS) cases and, albeit to a lesser extent, of Leopard syndrome (LPRD1), which present a few overlapping clinical features, such as facial dysmorphism, developmental delay, cardiac defects, and skeletal deformities. Motor impairment and decreased muscle strength have been recently reported. The etiology of the muscle involvement in these disorders is still not clear but probably multifactorial, considering the role of the RAS/MAPK pathway in skeletal muscle development and Acetylcholine Receptors (AChR) clustering at the neuromuscular junction (NMJ). We report, herein, four unrelated children carrying three different heterozygous mutations in the PTPN11 gene. Intriguingly, their phenotypic features first led to a clinical suspicion of congenital myasthenic syndrome (CMS), due to exercise-induced fatigability with a variable degree of muscle weakness, and serum proteomic profiling compatible with a NMJ defect. Moreover, muscle fatigue improved after treatment with CMS-specific medication. Although the link between PTPN11 gene and neuromuscular transmission is unconfirmed, an increasing number of patients with RASopathies are affected by muscle weakness and fatigability. Hence, NS or LPDR1 should be considered in children with suspected CMS but negative genetic workup for known CMS genes or additional symptoms indicative of NS, such as facial dysmorphism or intellectual disability.

Background The COVID-19 pandemic has brought substantial challenges for current practices in treating hereditary neuromuscular disorders (hNMDs). However, this infection has not been the only concern for these patients. Social distancing has compromised multidisciplinary assistance and physical activity, and has brought about several mental health issues. We presented a follow-up on 363 patients with hNMDs at a Brazilian tertiary center during the peak of the COVID-19 pandemic. Objective We aimed to show the frequency and severity of SARS-CoV-2 infection among hNMD patients and to demonstrate the effects of the pandemic on life habits, disease progression and multidisciplinary supportive care status. Methods Three hundred and sixty-three patients (58% male and 42% female) were followed for three months through three teleconsultations during the peak of the COVID-19 pandemic in Brazil. Results There were decreases in the numbers of patients who underwent physical, respiratory and speech therapies. For several patients, their appetite (33%) and sleep habits (25%) changed. Physical exercises and therapies were interrupted for most of the patients. They reported new onset/worsening of fatigue (17%), pain (17%), contractions (14%) and scoliosis (7%). Irritability and sleep, weight and appetite changes, and especially diminished appetite and weight loss, were more frequent in the group that reported disease worsening. There was a low COVID-19 contamination rate (0.8%), and all infected patients had a mild presentation. Conclusion The isolation by itself was protective from a COVID-19 infection perspective. However, this isolation might also trigger a complex scenario with life habit changes that are associated with an unfavorable course for the NMD.

Background: Myasthenia gravis is largely a treatable disease, but it can result in significant morbidity and even mortality, which can usually be avoided, or at least mitigated, with timely diagnosis and appropriate treatment of the disease. Objective: this review aims to summarize the main practical aspects of the diagnostic approach, treatment and care of myasthenic patients. Methods: The authors performed a non-systematic critical review summarizing the main practical aspects of myasthenia gravis. Results: Most patients with myasthenia have autoantibodies targeted at acetylcholine receptors or, less commonly, muscle-specific kinase - MuSK. Electrophysiology plays an important role in the diagnosis of neuromuscular junction dysfunction. The central clinical manifestation of myasthenia gravis is fatigable muscle weakness, which can affect eye, bulbar, respiratory, and limb muscles. With rare exceptions, patients have a good response to symptomatic treatment, but corticosteroids and/or immunosuppressants are usually also necessary to obtain good control of the manifestations of the disease. Conclusion: Knowledge of the peculiar aspects of their clinical and electrophysiological presentations is important for the diagnosis. Likewise, specific treatment and response time to each drug are crucial for proper care.

Objectives: To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis.Methods: Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non‐CMS molecular diagnosis.Results: Seventy‐nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty‐one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non‐CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS.Conclusions: Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.