Joana Afonso Ribeiro

A PRRT2 é uma proteína membranar plasmática pré-sináptica envolvida na libertação de neurotransmissores. As doenças associadas às variantes patogénicas do PRRT2 incluem um espectro de condições de hereditariedade autossómica dominante e apresentação paroxística. As três principais são a epilepsia autolimitada do lactente, a discinésia paroxística cinesigénica e a enxaqueca hemiplégica, mas outras apresentações têm sido reportadas. Os indivíduos com variantes patogénicas do PRRT2 podem apresentar-se com um ou mais fenótipos em simultâneo ou de forma subsequente. Relatamos 5 casos de epilepsia autolimitada do lactente com início entre os 4 e 10 meses e 1 caso de discinésia paroxística cinesigénica aos 8 anos, todos associados à variante patogénica c.649dup p.(Arg217Profs*8) em heterozigotia do PRRT2. Esta série de casos ilustra o espetro clínico inter e intra-individual, a variabilidade fenotípica inter e intra-familiar, a boa resposta à terapêutica com bloqueadores dos canais de sódio e o carácter autolimitado desta doença.

Rett syndrome (RTT) is a neurological disorder caused by mutations in the MECP2 gene. It is characterized by apparently normal early neurodevelopment followed by psychomotor regression between 6 and 18 months. There is no cure, and treatment is multidisciplinary, focusing on improving quality of life and functionality. This study aims to characterize RTT patients and evaluate clinical patterns, interventions, and outcomes. A retrospective cohort study was conducted of children diagnosed with RTT and a pathogenic MECP2 variant, followed at a Portuguese tertiary pediatric hospital from 2010 to 2024. Electronic medical records were reviewed, and epidemiological and clinical data were collected. Twelve RTT patients were followed (91.7% female). The median age at symptom onset was 15 months, and at diagnosis, 35 months. Seven patients (58.3%) had classic RTT. Molecular analysis identified 10 different MECP2 variants, all de novo mutations. Epilepsy and constipation were the most common comorbidities. Five patients (41.7%) were wheelchair-dependent, and two required non-invasive respiratory support. Almost all patients received physical, occupational, and speech therapies. The median number of chronic medications per patient was two, primarily anticonvulsants. The median number of medical specialties per patient was two, with neuropediatrics and neurodevelopmental pediatrics being the most frequent. Conclusions: RTT prevalence remained stable over 20 years, with a decreased median age at diagnosis, likely due to increased awareness and genetic testing. No clear genotype–phenotype correlation was found. RTT diagnosis remains based on clinical features, particularly neurodevelopmental regression. A multidisciplinary approach was critical, with patients receiving various therapies and support. This study provides valuable insights into RTT in Portugal, contributing to global knowledge. What is known:• Rett syndrome is a rare neurodevelopmental disorder primarily affecting females, characterized by regression of motor and communication skills.• Limited long-term data exist on clinical progression and functional outcomes in pediatric Rett syndrome. What is new:• A decreasing age at diagnosis was observed, likely reflecting increased awareness and access to genetic testing.• In an era of promising clinical trials for potential curative treatments, an individualized, multidisciplinary approach remains the standard of care in most countries, including Portugal.

Neuromuscular disorders are a group of rare heterogenous diseases with profound impact on quality of life, for which overall pediatric prevalence has rarely been reported. The purpose of this study was to determine the point prevalence of pediatric neuromuscular disorders and its subcategories in the central region of Portugal. Retrospective case identification was carried out in children with neuromuscular disorders seen between 1998 and 2020 from multiple data sources. Demographics, clinical and molecular diagnoses were registered. On January 1, 2020, the point overall prevalence in the population <18 years of age was 41.20/100 000 (95% confidence interval 34.51-49.19) for all neuromuscular disorders. The main case proportion were genetic disorders (95.7%). We found a relatively higher occurrence of limb-girdle muscular dystrophies, congenital myopathies, and spinal muscular atrophy and a slightly lower occurrence of Duchenne muscular dystrophy, hereditary spastic paraparesis, and acquired neuropathies compared to previous studies in other countries. Molecular confirmation was available in 69.5% of pediatric neuromuscular patients in our cohort. Total prevalence is high in comparison with the data reported in the only previous study on the prevalence of pediatric neuromuscular disorders in our country. Our high definitive diagnostic rate underscores the importance of advances in investigative genetic techniques, particularly new sequencing technologies, in the diagnostic workup of neuromuscular patients.

Acute cerebellitis is a rare disease resulting from dysfunction of the cerebellum or its connections, with infectious or inflammatory causes, varied clinical manifestations, and evidence of predominantly cerebellar inflammation on magnetic resonance imaging (MRI). It belongs to the spectrum of acute post-infectious cerebellar ataxia, a self-limited disease whose therapeutic approach is individualized. Three clinical cases of cerebellar ataxia in pediatric age are described. In case 1, there is a post-infectious context associated with Epstein-Barr virus. In case 2, there is a possible Mycoplasma pneumoniae post-infectious context, with MRI revealing cerebellar inflammation. Steroids were used in both cases. Case 3 presents severe cerebellar post-infection symptoms associated with varicella zoster virus, and human immunoglobulin was given. Evolution was favorable in all. These cases demonstrate the variable spectrum of post-infectious cerebellar ataxia and the different therapeutic options used, depending on the clinical presentation and individual characteristics of affected children.

RNA-targeting splicing modulators have revolutionized modern medicine by allowing reversible regulations of gene expression. Branaplam was the first molecule found to specifically modulate a splicing behaviour at a particular splice site. Originally, branaplam was developed as a splicing modulator for spinal muscular atrophy (SMA), the second most common autosomal recessive disease and the primary cause of genetic infant mortality. More recently, its use in Huntington’s disease (HD), a fatal autosomal dominant neurodegenerative disease with limited symptomatic control, has been investigated. This review comprehensively analyzes branaplam’s development program in both clinical conditions mentioned, projecting some of the aspects that may require further investigation when considering splicing modulators, as a therapeutic class, in these diseases.

Background: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items.Objectives: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia.Methods: In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow‐up assessment after 1 year.Results: An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose‐finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow‐up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset.Conclusion: Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology‐specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.