Juliana Gurgel-Giannetti

Duchenne muscular dystrophy is a rare, progressive neuromuscular disorder primarily affecting boys, and it follows a predictable course. Early intervention is essential for effective management, but disparities in the care of patients with rare diseases hinder access to optimal treatment. To identify unmet needs and challenges in the care of patients with Duchenne muscular dystrophy within the Brazilian public health system compared with the private system. A cross-sectional observational study using the Delphi method was conducted with ten neurologists specialized in Duchenne muscular dystrophy. The specialists participated in rounds of surveys to reach consensus on key issues, including diagnosis, treatment, and care. Data was analyzed using descriptive statistics. According to the Delphi panel, the public health system had an average diagnostic delay of 25 months compared with 10 months in the private sector. Although genetic testing is critical, it is not funded by the public health system. Other barriers included delayed corticosteroid treatment, limited access to multidisciplinary care, and insufficient medical devices. Patients in the public health system lost ambulation earlier (11–12 years of age) than those in the private sector (13–14 years of age). Life expectancy was significantly shorter in the public system, averaging 19 to 20 years compared with 26 to 27 years of age in the private sector. There are significant disparities in the care of patients with Duchenne muscular dystrophy within Brazil's public health system, resulting in worse outcomes. Enhancing access to genetic testing and early multidisciplinary care is crucial to improve the quality of life and survival of these patients.

*Correspondence: lahdecarvalho@gmail.com. Abstract Background: The Chikungunya disease is an arboviral infection caused by an alphavirus. The disease was first reported in the 1960’s, but major outbreaks became more evident on the tropics in early 2000’s. Systemic and neurological complications are being increasingly recognized since then. Objective: To report two different Central Nervous System (CNS) manifestations of the chikungunya virus (CHIKV) in the early infancy and neonatal period. Methods: The patients were clinically evaluated and had imaging, laboratorial and serology studies performed. Results: Case 1 – Five-month-old female patient, living on the rural district of a northern Minas Gerais city, first presented with high fever and inconsolable crying. She developed bullous and erythematous skin lesions on the third day. As the disease progressed, pancytopenia, hepatic and renal disfunction became more evident. At this point, dialyses was prescribed. Alongside with ionic instability and systemic disfunctions, the patient presented with Status epilepticus, resolved after a 10mg/kg phenobarbital attack. Head computed tomography presented with cortical atrophy. Cerebrospinal fluid (CSF) analyzes showed no signs of inflammation and was negative for CHIKV. CHIKV disease was confirmed through serology exams which demonstrated high IgM serum levels. Case 2 – Female term newborn, born in Belo Horizonte, presenting with sepsis-like symptoms (respiratory distress) on the first day of life. The mom had a history of fever and erythematous lesions during childbirth. The patient evolved with cardiac arrhythmia, feeding intolerance, glycemic instability and bullous skin lesions. Neonatal seizures controlled with 20mg/kg phenobarbital attack. Transfontanelle ultrasound revealed subependymal hemorrhage on the left side and CSF studies had an inflammation pattern with elevated protein (847mg/dL). CHIKV vertical infection was confirmed through newborn and mother positive serum RT-PCR studies. Conclusion: CHIKV infection became a common viral disease in South America on the last few years. Hence, knowledge of the various systemic and neurological symptoms is essential for optimal recognition and for guiding the treatment plan. This series of cases shows two pediatric patients, from different age groups. The former fulfilling criteria for CHIKV encephalopathy (Case 1) and the latter (Case 2) the CHIKV encephalitis. Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

*Correspondence: claracpinhati@hotmail.com. Abstract Case Presentation: We present the case of a female patient, healthy until 6 months old, when she presented a first episode of hypotonia and weakness in lower members that occurred 3 days after pentavalent and inactivated polio vaccination. The symptoms lasted 7 days and were followed by progressive improvement without any treatment, but she remained with distal motor deficit. Later, she presented two other episodes of muscle weakness, the first at 1 year old, that occurred 7 days after triple viral and pneumococcal vaccination, and the second at 2 years and 8 months old, after a bug bite. On both occasions, she was admitted to the hospital, diagnosed with Guillain-Barré syndrome (GBS) and treated with intravenous immunoglobulin, followed by partial improvement of the symptoms. Electroneuromyography revealed chronic motor axonal polyradiculoneuropathy. Magnetic resonance imaging of the brain and spine were normal. At 2 years and 10 months, the patient was referred to a pediatric neurology center, with suspicion of recurrent Guillain-Barré syndrome. Genetic testing was requested, and exome study revealed a new mutation in the CD59 gene, in homozygosity. This mutation was initially considered a variant of uncertain significance (VUS),but was later reclassified as pathogenic after immunophenotyping test revealed total CD59 deficiency. The patient was treated with Eculizumab (30 doses) and followed by a multidisciplinary team for over one year. She has not presented any new episodes of weakness and exhibited significant improvement of motor function since the beginning of the treatment. Discussion: CD59 deficiency is a rare disease characterized by the presence of chronic hemolysis and, less frequently, recurrent demyelination of the peripheral nervous system, resembling GBS. The case above presented clinical phenotype, laboratory and genotype consistent with CD59 congenital deficiency, confirmed by immunophenotyping test. Previous studies in medical literature are scarce, but have demonstrated benefit in the use of Eculizumab for the prevention of new episodes of demyelination and, in some cases, improvement of the motor deficit, which is consistent with what was observed in our patient. Final Comments: The present report demonstrated that recurrent episodes of peripheral demyelination may be associated to genetic conditions such as congenital deficiency of CD59. The genetic diagnosis allowed appropriate treatment with excellent clinical response. Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

*Correspondence: claragc@gmail.com. Abstract Background: LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal recessive disease caused by mutations in the LAMA2 gene. It varies in severity, from a severe form of congenital muscular dystrophies (CMD-LAMA2) - in which most patients never achieve walking capacity - to a more rare and less severe form of limb-girdle muscular dystrophy (LGMD-23). Objective: To describe and establish genotype–phenotype correlations in a large Brazilian cohort. Methods: Clinical and genetic data of LAMA2-RD patients enrolled from six research centers (FMUSP, Escola Paulista de Medicina, FMUFMG, Hospital de Clínicas de Porto Alegre, FHEMIG, Hospital Infantil Albert Sabin) between March 2018 and April 2023 were collected and analyzed. Results: One hundred and twelve patients were included: 79 (75.2%) patients never achieved walking capacity, and 26 (24.8%) patients were able to walk. 84 patients were submitted to brain MRI, and from those 12 patients (14.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),12 patients (14.2%) presented with epilepsy, and 8 (9.5%) had intellectual disability. We found 46 distinct mutations and twenty-two variants were novel (52%). The top three high-frequency disease-causing variants in Brazilian patients were: 1) c.1255del (p.Ile419Leufs*4) in 22 patients; 2) c.2461A>C (Thr821Pro) in 15 patients and 3) c.3976C>T (p.Arg1326*). The frameshift variant c.1255del (p.Ile419Leufs*4) was never published and is probably a founder mutation in Brazil, with all patients unable to walk. All the 15 patients with at least one c.2461A>C (Thr821Pro) mutation were able to walk. Null variants were more frequent in LAMA2-CMD (56.9%) than in LGMDR23 (21.4%), while missense disease-causing variants were more frequent in LGMDR23 than in LAMA2-CMD (P = .0072; OR:6.48). One intronic variant never published (c.4960-17C>A) was found in four patients, one in homozygous. A functional study was performed using muscle biopsy and revealed the presence of the transcript r.4959_4960ins[4960-15_4960-1], which affects intron 34. This transcript is out-of-frame (p.Arg1653_Ala1654insAsnLeuAspHisTer) and creates a different splicing site. Final Comments: This study provides better understanding of genotype–phenotype correlations in LAMA2-related muscular dystrophy and supports therapeutic targets for future research. Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

*Correspondence: lahdecarvalho@gmail.com. Abstract Case Presentation: 11-year-old female patient, single child of non-consanguineous healthy parents. She had normal psychomotor development until 5 years old, when she started epileptic seizures during sleep, characterized as focal motor with good response to oxcarbazepine. At the age of 7, she manifested with dystonia in the upper limbs, worse on the left side and cervical region, controlled with the use of trihexyphenidyl combined with baclofen and diazepam. She also evolved with a learning disorder and attention deficit with low school performance. During the investigation, she performed an EEG which revealed signs of immaturity and video-EEG showing paroxysmal events without electrographic correspondence, with nonspecific findings. MRI of the brain was normal. A New Generation Sequencing genetic study using a multigene panel revealed a heterozygous mutation in the KCTN1 gene; which promotes the substitution of the amino acid glycine for serine at codon 288 (p.Gly288Ser), classified as pathogenic. Discussion: KCNT1-related epilepsy is associated with two phenotypes - epilepsy of infancy with migrating focal seizures (EIMFS) with onset at 6 months of age associated with developmental regression and autonomic manifestations and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) with childhood-onset epileptic seizures with normal EEG or low-incidence paroxysms, movement disorder with tonic phenomena and dystonia, in addition to psychiatric and learning disorders, similar to that presented by the patient. KCNT1 mutations were described in the literature associated with the ADNFLE phenotype with penetrance close to 80%, refractory epilepsy, severe intellectual deficit and higher frequency of psychiatric disorders compared to other genes correlated with the same phenotype. Final Comments: The KCNT1 gene presents with atypical epileptic seizures with usually normal EEG and early dystonia. Identifying the mutation allows the conduction of the appropriate treatment in order to avoid the motor sequelae of dystonia and a worse cognitive decline without proper management. In addition, through diagnosis, the family can be informed about the disease and undergo genetic counseling. Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

*Correspondence: claracpinhati@hotmail.com. Abstract Background: Nemaline myopathy (NM) is a common structural congenital myopathy, with significant clinical and genetic heterogeneity. Objective: Perform the assessment of respiratory, motor function and the quality of life of patients with different clinical forms of NM. Methods: A cross-sectional study in line with a prospective cohort was carried out in neuromuscular disease reference ambulatory of Hospital das Clínicas in Universidade Federal de Minas Gerais including patients with nemaline myopathy whose diagnosis was made by muscle biopsy and / or histochemical study or genetic study. The sample underwent clinical evaluation, tests to assess respiratory, motor function and QQV. Results: 11 patients with NM were included, divided into 2 groups according to the clinical classification of NM: intermediate form (n = 4) and typical form (n = 7). The intermediate group had worse motor function, respiratory function (seated CV and PFT) and QOL relative to the functional capacity compared to the typical group. The indirect assessment of diaphragmatic strength, through SNIP, showed diaphragmatic weakness in both groups. Conclusion: Patients with NM, in their different clinical forms, may present different levels of respiratory, motor impairment and QOL, justifying the phenotypic variability, which is a characteristic sign of the disease. The importance of diaphragmatic assessment must be stressed, especially in patients with a typical clinical form who may have severe respiratory failure with mild motor impairment and preserved walking ability. The physiotherapeutic evaluation of these patients is of fundamental importance so that the therapeutic plans for rehabilitation are drawn up with greater precision and specificity. Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

*Correspondence: elice.batista@einstein.br. Abstract Background: Spinal muscular atrophy (SMA) is a rare disease characterized by progressive loss of motor neurons located in the anterior horn of the spinal cord and brainstem, leading to progressive muscle atrophy and weakness. The most common form of SMA (5q SMA) is caused by bi-allelic mutations in the SMN1 gene on chromosome 5q13.2, classified into subtypes, according to the age of onset and the maximum motor function achieved. The journey to diagnosis can last for years and have a wide and significant impact on patients' lives. Objective: To map the time interval between the appearance of the first signs and symptoms and the achievement of the 5q SMA diagnosis using a genetic report in Latin American patients with 5q SMA. Methods: This study is a clinical multicounty registry for SMA diseases that includes patients with 5q SMA types 1, 2, and 3 of all ages and both sexes, treated in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, and Uruguay). The time interval between the appearance of the first signs and symptoms until obtaining the confirmatory genetic diagnosis of 5q SMA will be analysed. Results: Currently 213 participants were included (Argentina: 27, Brazil: 136, Colombia: 33, Chile: 17), with an average age of 13.7 (years), being 99 (46.5%) female and 114 (53,5%) male. The study is ongoing, and it is intended to reach around 300 participants in the next 3 months. Preliminary results show subtype 2(45.5%) constitutes the largest number of participants in this study, followed by subtypes 3(38.0%) and 1(16.4%). The mean time to reach the confirmatory molecular report of 5q SMA varies greatly across countries. Of the patients included in the study so far, 134 (63%) use or have had access to disease modifying therapy for SMA and 79 (37%) never had access. Analysing the reality of how long these patients take to confirm the genetic diagnosis of SMA 5q is of great relevance for greater assertiveness in the clinical management of the disease and access to treatments that modify the course of the disease. Conclusion: 5q SMA is a progressive degenerative disease, and it is of fundamental importance that diagnostic confirmation occurs as early as possible. Knowing the time profile of patients with 5q SMA diagnosis in Latin America is of fundamental importance for us to advance in screening strategies essential to improve patient care. This study is supported by Biogen. Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

*Correspondence: claracpinhati@hotmail.com. Abstract Background: Fatigue is a frequent disabling primary symptom in Spinal Muscular Atrophy (SMA) patients. It results in low levels of physical activity, significantly impairing patients' quality of life. Objective: To evaluate perceived and physiological fatigue in individuals with SMA type 2 and 3, and to establish its relationship with other important aspects, such as muscle strength, motor and respiratory function. Methods: We evaluated fatigue in children and adults with a confirmed genetic diagnosis for SMA, in a cross-sectional observational study, using the Fatigue Severity Scale (FSS, Portuguese version) and Multidimensional Fatigue Scale (PedsQL MFS, Portuguese version) to assessment of perceived fatigue and repeated nine hole peg test (r9HPT) and Endurance Shuttle Walk Test (ESWT) to assess physiological fatigue. Factors associated with fatigue, including muscle strength, motor function and vital capacity (VC) were also evaluated. Results: In total, 28 participants with SMA types 2 and 3 were included, with a mean age of 20.6 ± 11.8 years. Participants' reports of perceived fatigue through the PedsQL MFS were similar to those of caregivers. Perceived fatigue was similar for SMA type 2 and 3 participants (PedsQL MFS self-report: 75.9; 70.5). Perceived fatigue was common in adult participants with 58.4% reporting abnormal or several fatigue (FSS > 4). Perceived fatigue was not associated with motor function, respiratory function and physiological fatigue. All correlations showed alpha levels of p > 0.05. In the evaluation of physiological fatigue through the r9HPT, it was observed that SMA type 2 participants showed significantly worse performance than participants with type 3. The results of the r9HPT were shown to be correlated with the VC and muscle strength of elbow flexors, with a value of p < 0.05. In ambulatory patients who performed the ESWT, none were able to complete the maximum time of 1200 seconds. The median time the test was interrupted was 186.9 seconds, which represents 16% of the maximum time. Conclusion: Fatigue is a frequent and relevant complaint in SMA patients. The relationship between perceived and physiological fatigue is complex and requires a multifactorial approach that encompasses the various mechanisms involved in fatigue in SMA. Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

*Correspondence: gurgelgiannetti@gmail.com. Abstract Background: Spinal Muscular Atrophy (SMA) is the second most common neuromuscular disease in childhood, with an estimated incidence of 1 in 11,000 live births. It leads to progressive muscle weakness and consequently affects functional motor skills. In the last years, therapies that modify the natural history of SMA have been developed, making the use of instruments capable of objectively detecting the response to treatment and clinical evolution of patients essential. Objective: To translate and cross-culturally adapt to Portuguese-Brazil and determine the reliability and validity of the HFMSE (Portuguese-Brazil). Investigate the relationship of motor function with other measures, such as vital capacity (VC), peak cough flow (PCF), muscle strength and joint amplitudes. Methods: The translation process and cross-cultural adaptation followed international guidelines recommendations. Two examiners assessed the participants for interrater reliability, through the analysis of Kappa reliability agreement (k) and Intraclass Correlation Coefficient (ICC). Validation consisted of applying the HFMSE scale and analyzing its correlation with other relevant variables, such as muscle strength, respiratory function and joint amplitudes. Results: The HFMSE was successfully translated and cross- culturally adapted to Portuguese-Brazil. Twenty-eight children/adults SMA type 2 and 3 were enrolled in the study (Type 2 = 14; Type 3 = 14). Fifteen (54%) were women and mean age of 20,6 ± 11, 8 years old. The ICC for the total score showed very high reliability (ICC =1.00). A statistically significant correlation was observed between the HFMSE and the VC measurement (p < 0.001), however there was no significance (p > 0.05) for the PCF measurement. Regarding the presence of contractures, it was observed that hip and knee flexor contractures are found in 92.9% of SMA type 2 participants and are directly correlated with the score obtained in the HFMSE (p < 0.05). The muscle strength values obtained using the manual dynamometer were significantly higher in SMA type 3 participants compared to type 2 SMA participants. Through the results, it was possible to observe that the knee extensors (2.4 ± 3.1 lbs) were the most compromised muscle group in both phenotypes. Conclusion: The HFMSE (Portuguese-Brazil) proved to be valid and reliable for the evaluation of patients with SMA type 2 and 3 in Brazil Article published online: 12 May 2025 © 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil