Objective This study aimed to compare the diagnostic yield of genome sequencing (GS) versus exome sequencing (ES) in a pediatric population, with a focus on determining whether GS offers a significant advantage over ES in identifying genetic variants. Methods A retrospective analysis of prospectively allocated pediatric patients was performed on 297 pediatric patients who underwent next-generation sequencing. Of these, 59.6% (177) underwent only ES, 32.3% (96) underwent only GS, and 8.1% (24) had both tests. Diagnostic positivity rates were compared between ES and GS, and subgroup analyses were performed based on clinical characteristics. Results GS demonstrated a higher positivity rate (51.7%) compared to ES (42.8%), with a 95.8% concordance between tests in patients who underwent both. However, the added diagnostic yield of GS was less than 10%. Greater GS positivity was identified in a group of children with neurological, musculoskeletal, growth disorder and craniofacial anomalies. Deep intronic variants were identified in two cases that underwent GS, but only one had also undergone ES. Limitations in medical record completeness and data quality were noted, which could affect the study's generalizability. Conclusion GS offered a modest increase in diagnostic yield over ES, particularly for detecting deep intronic variants. Some conditions had greater GS positivity, but the interpretation deserves caution as issues regarding homogeneity and sample selection may have influenced this result.

INTRODUCTION:GM2 gangliosidoses and Niemann-Pick type C disease (NPC) belong to a group of rare, progressive neurodegenerative lysosomal diseases that cause diverse neurological symptoms. Disease-modifying therapies exist for NPC, but not for GM2 gangliosidoses. Nizubaglustat is in development for both conditions. METHODS:In RAINBOW, a phase 2, double-blind, placebo-controlled multicenter trial, participants with GM2 gangliosidoses or NPC were randomized 1:1:1 to receive once-daily nizubaglustat 3 mg, nizubaglustat 9 mg, or placebo for 12 weeks, after which participants could enter a double-blind extension period and receive nizubaglustat 3 mg or 9 mg. Primary outcomes were plasma pharmacokinetics, pharmacodynamics, and the safety of nizubaglustat over 12 weeks. Clinical outcomes included changes from baseline in Scale for the Assessment and Rating of Ataxia (SARA), functional SARA scores, and Inventory on Non-Ataxia Signs (INAS) count during the extension; these outcomes were evaluated separately from the double-blind, placebo-controlled analyses at 12 weeks. RESULTS:Among 13 participants (GM2 gangliosidoses [n = 7], NPC [n = 6]; mean age, 18.6 years; 53.8% male), nizubaglustat demonstrated rapid absorption accompanied by dose-dependent reductions in plasma C16/C18 glucosylceramides. Most adverse events were mild to moderate and manageable. Pharmacokinetics, safety, and tolerability data established an optimal nizubaglustat dose (9 mg, adjusted for weight). During the extension (n = 11), 45.5% of participants had improved by ≥1 point or stabilized in SARA, 54.6% in functional SARA, and 63.7% in INAS; seizure frequencies were reduced from baseline. CONCLUSIONS:Nizubaglustat demonstrated a favorable safety profile and potential clinical benefits by reducing disease progression and seizure burden in participants with GM2 gangliosidoses or NPC, supporting advancement to a phase 3 trial in a larger cohort.

This study presents the case of a patient with Mucopolysaccharidosis III (Sanfilippo syndrome) associated with systemic lupus erythematosus (SLE). A case report was carried out on a patient with MPS IIIB associated with SLE and a literature review was carried out regarding the co-occurrence of SLE in patients with lysosomal diseases. The patient exhibited symptoms including persistent diarrhea and motor impairment from early childhood and was diagnosed with Mucopolysaccharidosis III at 4 years of age. Subsequently, he developed epilepsy, myelodysplasia, and at 14 years old, severe complications including renal failure and hematological abnormalities, culminating in a diagnosis of lupus membranous glomerulonephritis. Mucopolysaccharidosis III is a rare disorder characterized by the accumulation of heparan sulfate within lysosomes, whereas SLE is an autoimmune disease with broad clinical heterogeneity. Lysosomal abnormalities may disrupt immune responses and contribute to the development of autoimmunity. In conclusion, the coexistence of these disorders presents significant diagnostic challenges and may reflect a possible causal association, although further research is needed to clarify the underlying mechanisms.

Mitochondrial Complex IV deficiency, Nuclear Type 1, is a genetic metabolic disorder inherited in an autosomal recessive pattern, characterized by rapid and progressive neurodegeneration and encephalopathy. We present a 2-year-old female patient, daughter of healthy, and consanguineous parents, born at term with normal newborn screening results. At 1 year and 7 months, she began experiencing recurrent vomiting, developmental regression, and a significant drop in weight and height percentiles. Laboratory tests revealed elevated lactate and MRI findings suggestive of mitochondrial disease. Whole-exome sequencing (WES) identified a pathogenic variant in the SURF1 gene (OMIM # 220,110) c.552del (p.Lys185Argfs*3). Mitochondrial Complex IV deficiency, Nuclear Type 1, associated with the SURF1 gene clinical symptoms include developmental delays, motor abnormalities, and recurrent episodes of metabolic crisis. The combined prevalence of mitochondrial disorder is approximately one in 4300 children, making these disorders one of the most common neurometabolic conditions in pediatrics. The late-onset in this case report, at 1 year and 7 months, represents a unique feature, as most cases manifest earlier. The findings emphasize the need for clinicians to consider SURF1-related mitochondrial Complex IV deficiency even in patients presenting later in childhood. This case also highlights the importance of multidisciplinary management and supports further research into genotype–phenotype correlations, prognostic markers, and potential therapeutic approaches, which remain limited for this condition.

BackgroundNiemann-Pick type C (NPC) disease is a rare neurodegenerative disorder with a wide spectrum of clinical manifestations and genetic variability. This cross-sectional study aimed to comprehensively describe the neuropsychological impact of NPC and investigate its correlation with specific genotypes.ResultsEight patients from six unrelated families were included in this study. Their age at symptom onset ranged between 2 and 16 years, with all patients presenting with ataxia, dysarthria, and cognitive impairment. Following the initiation of miglustat treatment, five patients showed a decrease in the Scale for the Assessment and Rating of Ataxia (SARA) score, whereas three demonstrated subsequent increases. Five patients underwent brain magnetic resonance imaging scans, revealing white matter abnormalities and/or brain volumetric reduction in three cases. Despite the small sample size, the overall cognitive performance of the cohort was significantly below the average. The Family Environment Scale highlighted positive structural patterns, particularly regarding Personal Growth and System Maintenance. Genetic analysis identified five mutations in the NPC1 gene that correlated with the severity of impairments and clinical outcomes.ConclusionThis study indicated a consistent association between cognitive and behavioral impairments, with severity correlating with age and specific genetic variants. Notably, one subgroup showed a higher prevalence of psychotic and behavioral symptoms, suggesting a potential link with specific genetic variants.

This retrospective observational study investigates the clinical and neuroimaging profiles of children with cerebral palsy and explores the contribution of genetic factors to its etiology. We reviewed 302 pediatric cases diagnosed with cerebral palsy in Southern Brazil during 2023. Neuroimaging abnormalities were present in 92.1% of cases, with leukomalacia being most frequent. Neonatal encephalopathy emerged as the leading etiology, followed by prematurity and genetic conditions. Genetic testing was performed in 68 patients, identifying 29 distinct genes, notably in cases with preserved imaging or kernicterus. Dyskinetic and ataxic cerebral palsy were more often associated with normal neuroimaging, although not necessarily with positive genetic findings. Some patients with kernicterus also had genetic etiology, especially G6PD. The study reinforces that normal imaging does not exclude underlying genetic causes, especially in patients lacking perinatal complications or exhibiting dyskinetic patterns. These findings emphasize the complementary roles of neuroimaging and genetic in the multifactorial nature of cerebral palsy.

Objective: To analyze the first referral service for rare diseases accredited by the Ministry of Health, focusing on referral from the primary care network to diagnosis. Methods: This is a descriptive study with patients treated between 2016 and 2021 at a referral hospital service located in Curitiba. Clinical and epidemiological data were obtained from medical records and the results of genetic tests from the hospital's clinical analysis laboratory. Qualitative data were expressed as absolute and relative frequency, and quantitative data were expressed as median and interquartile range and compared using the Kruskal-Wallis test. Results: A total of 1,751 patients were included, 34.1% were diagnosed with rare diseases, with a mean time of 3.0 years, with mucopolysaccharidosis type II (4.0%) and tuberal sclerosis (3.9%) being the most frequent. Longer time to diagnosis (p-value 0.004) and specialized care (p-value <0.001) were observed in patients from the interior of Paran & aacute;, compared to those residing in Curitiba and the metropolitan region. Conclusion: Diagnosis of rare diseases occurred in approximately one third of cases. The average time to diagnosis suggests a possible positive impact of the implementation of the referral service. Longer time to diagnosis and specialized care observed in patients from the interior of Parana represent challenges in appropriate referral to specialized units.

We present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug-resistant epilepsy. Brain magnetic resonance imaging revealed distinctive features, including a Z-shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion. Whole-exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val). The neurodevelopmental disorder associated with the ARF3 gene is exceptionally rare, with only two previously documented cases in the literature. This disorder is characterized by global developmental delay and brain malformations, particularly affecting the white matter, cerebellum, and brainstem. It can also manifest as acquired microcephaly and epilepsy. These phenotypic characteristics align with Golgipathies, underscoring the significance of considering this group of conditions in relevant clinical contexts. In cases where a Z-shaped morphology of the brainstem is observed, ARF3-associated disorder should be included in the list of differential diagnoses.

IntroductionMucopolysaccharidoses (MPS) constitute a group of progressive and multisystemic inherited metabolic diseases that profoundly affect both the mental health of patients and the wellbeing of their families. This study aims to evaluate the impact of MPS on family functioning and related factors.Methods and resultsTwenty-five patients with MPS, including types I (n = 4), II (n = 11), IIIB (n = 2), IVA (n = 3), and VI (n = 5), and their families participated in this study. The mean patient age was 13 years [standard deviation (SD): 7.7 years]. Behavioral and emotional problems were noted in 9.1% of all patients. While the type of MPS did not directly influence mental problems, the presence of neuronal involvement did (p = 0.006). Patients with MPS III exhibited difficulties primarily in emotional areas, conduct, hyperactivity, and peer problems. Importantly, both patients with MPS II and those with MPS III experienced a significant impact on communication [mean scores for communication domain: MPS II, 35.6 (SD: 24.3); MPS III, 35.0 (SD: 22.6)]; poorer communication was directly linked to worse adaptive behavior (p = 0.012), and worse adaptive behavior was associated with lower quality of life (p = 0.001). Quality of life and caregiver burden among family members did not significantly differ across MPS types; however, higher caregiver burden was negatively associated with quality of life (p = 0.002). Concerning family functioning, the most impacted domains included independence, intellectual/cultural orientation, activity/recreation, and expressiveness. Domain scores did not vary based on MPS type, treatment, or neurological involvement. Quality-of-life scores were positively associated with the cultural/intellectual domain score.ConclusionThe impacts of quality of life and family extend beyond clinical characteristics and MPS type, strongly influenced by patient cognition and communication, as well as type of family functioning, especially those with greater cultural/intellectual skills of their family members. A multidisciplinary approach addressing the broader needs of individuals with MPS becomes essential. Techniques aimed at improving communication, including prompt interventions such as speech therapy and augmentative and alternative communication strategies, can contribute to overall family functioning improvement.

INTRODUÇÃO: A síndrome relacionada à mutação no gene N-alfa-acetiltransferase 10 (NAA10), autossômica recessiva ligada ao X, Síndrome de Ogden, cursa em meninos com atraso grave no desenvolvimento neuropsicomotor, hipotonia central, dismorfias, malformações cardíacas e morte precoce nos primeiros meses de vida. RELATO DE CASO: Lactente, masculino, com hipotonia e dismorfias: fronte proeminente, fácies triangular, microftalmia bilateral, fenda palpebral oblíqua superior e epicanto, filtro nasolabial aumentado, lábio superior afilado, cabelos loiros e esparsos, cílios longos e claros. Atraso global do desenvolvimento neuropscimotor, episódios de curta duração de movimentos oromastigatórios, sialorreia, nistagmo horizontal, com sonolência excessiva e hiporresponsividade, queda de saturação de oxigênio e bradicardia. Eletroencefalograma: surtos de ondas lentas difusos. Ecocardiograma e eletrocardiograma sem alterações. Ressonância de crânio: espessamento cortical em lobo frontal direito, pequena área de encefalomalácia; indícios de insulto isquêmico pregresso; áreas de alteração de sinal na substância branca central e profunda adjacente aos ventrículos laterais com leve ectasia compensatória dos mesmos; e afilamento difuso do corpo caloso de natureza indeterminada, iniciado tratamento. Genoma identificou presença de variante provavelmente patogênica no gene NAA10. Em uso de fenobarbital e oxcarbazepina e acompanhamento multiprofissional. DISCUSSÃO/CONCLUSÃO: Muitos pacientes apresentam alterações na neuroimagem, predominando: hipoplasia do corpo caloso e microcefalia. Epilepsia em torno de 69%, generalizada, descritas mioclonias palpebrais ou espasmos, ou como identificado neste paciente: automatismos oromastigatórios. Há necessidade de incluir a Síndrome de Ogden nos diagnósticos diferenciais e da investigação do gene NAA10 em painéis de epilepsia e deficiência intelectual.

BACKGROUND:Opsoclonus-myoclonus syndrome (OMS) is a rare neuroinflammatory disorder characterized by ataxia, opsoclonus, and myoclonus. Clinical diagnosis of OMS has been challenging; therefore, we sought to determine the clinical and treatment profiles of patients with OMS at the largest pediatric hospital in Latin America. METHODS:We analyzed the data of patients diagnosed with OMS between 2010 and 2020 at Pequeno Principe Hospital (Brazil) to determine the corresponding clinical profile more accurately. RESULTS:Of the approximately 50,000 visitors to our pediatric neurology department from 2010 to 2020, 10 patients with OMS were observed. Five nontumor cases included three parainfectious and two idiopathic cases. The median time from symptom onset to diagnosis was 34 days. All patients with diagnostic OMS criteria in the idiopathic, nontumor group underwent whole-exome sequencing, with potentially pathogenic mutations identified in two cases. Nine patients were treated with methylprednisolone pulse, followed by oral steroids; eight received one or more intravenous immunoglobulin treatments; and six received azathioprine and cyclophosphamide. Complete symptomatic recovery was observed in only one patient. CONCLUSIONS:OMS diagnosis remains challenging. Diagnostic suspicion is necessary to improve the management of these patients and allow early immunosuppressive treatment. Paraneoplastic etiology is the most prevalent. In idiopathic patients who do not respond to immunosuppressive treatment, tests, such as whole-exome sequencing, may reveal a differential diagnosis. Genetic alterations that increase the risk of tumors may be an important clue to the pathophysiology of OMS.

Resumo Objetivo: Analisar o primeiro serviço de referência em doenças raras credenciado pelo Ministério da Saúde, com foco no encaminhamento desde a rede primária até o diagnóstico. Métodos: Trata-se de um estudo descritivo com pacientes atendimentos entre 2016 e 2021 em serviço hospitalar de referência localizado de Curitiba. Dados clínicos e epidemiológicos foram obtidos de registros médicos e os resultados de exames genéticos do laboratório de análises clínicas do hospital. Dados qualitativos foram expressos como frequência absoluta e relativa, e os quantitativos por mediana e intervalo interquartil e comparados pelo teste Kruskal-Wallis. Resultados: Foram incluídos 1.751 pacientes, 34,1% obtiveram diagnóstico de doenças raras, com tempo médio de 3,0 anos, sendo a mucopolissacaridose tipo II (4,0%) e esclerose tuberal (3,9%) as mais frequentes. Maior tempo até obter diagnóstico (p-valor 0,004) e atendimento especializado (p-valor<0,001) foram observados em pacientes do interior do Paraná, em comparação com aqueles que residem em Curitiba e região metropolitana. Conclusão: O diagnóstico de doenças raras ocorreu em cerca de um terço dos casos. O tempo médio até o diagnóstico sugere possível impacto positivo da implementação do serviço de referência. Maior tempo até o diagnóstico e atendimento especializado observado em pacientes do interior do Paraná representam desafios no encaminhamento adequado para unidades especializadas.

Introduction Neuronal ceroid lipofuscinoses (CLNs) are a group of lysosomal storage disorders of genetic origin, characterized by progressive neurodegeneration and intracellular accumulation of autofluorescent lipopigment. Thirteen genes related to CLNs are currently described, showing genetic and allelic heterogeneity, most of them with an autosomal recessive pattern. Due to the few descriptions of cases related to CLNs in Brazil, it is necessary to describe the phenotypic and genotypic characteristics of these patients. This study aims to evaluate the genotypic profile and correlate it with the phenotypic characteristics of patients with CLN in a children's hospital. Methods This study was performed as a descriptive cross-sectional study with analysis of medical records, imaging, and laboratory tests of patients who had a confirmed molecular diagnosis of CLN. Results The sample consisted of 11 patients from nine families with different subtypes of CLNs (CLN2, 5, 6, 7, and 8), with CLN2 being the most prevalent in the study. A total of 16 mutation variants were identified in genes associated with the five CLNs described in this study, with typical and atypical clinical phenotypes depending on the subtype and its variants. Conclusion Novel mutations identified in the patients in this study showed phenotypes of rapid and severe progression in the CLN2 patient and similar characteristics in CLN6 and CLN7 patients, as previously described in the literature.

Brown-Vialetto-Van Laere syndrome or riboflavin transporter deficiency is a rare and genetically determined condition that results in a spectrum of neurological signs and symptoms from generalized muscle weakness to cranial nerve involvement with medullary symptoms and respiratory failure. Most patients have SLC52A3 gene biallelic variants, but some of them may have impairment of SLC52A2 gene, both related to the cell transport of riboflavin. We report the case of three unrelated Brazilian patients under 18 years of age with this diagnosis confirmed by molecular genetic sequencing. We observed that the clinical manifestations found were compatible with those already described in the literature by age group. Unusual findings of retinitis pigmentosa and immunodeficiency were identified related to pathogenic variants in the SLC52A2 gene. All patients received riboflavin replacement at a therapeutic dose without gastrointestinal intolerance and with clinical improvement after starting treatment.

BACKGROUND:Autoimmune encephalitis (AIE) is a group of inflammatory diseases characterized by the presence of antibodies against neuronal and glial antigens, leading to subacute psychiatric symptoms, memory complaints, and movement disorders. The patients are predominantly young, and delays in treatment are associated with worse prognosis. OBJECTIVE:With the support of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, ABN) and the Brazilian Society of Child Neurology (Sociedade Brasileira de Neurologia Infantil, SBNI), a consensus on the diagnosis and treatment of AIE in Brazil was developed using the Delphi method. METHODS:A total of 25 panelists, including adult and child neurologists, participated in the study. RESULTS:The panelists agreed that patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques. Children should also be screened for anti-myelin oligodendrocyte glucoprotein antibodies (anti-MOG). Treatment should be started within the first 4 weeks of symptoms. The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis, the second-line includes rituximab and/or cyclophosphamide, while third-line treatment options are bortezomib and tocilizumab. Most seizures in AIE are symptomatic, and antiseizure medications may be weaned after the acute stage. In anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the panelists have agreed that oral immunosuppressant agents should not be used. Patients should be evaluated at the acute and postacute stages using functional and cognitive scales, such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Modified Rankin Scale (mRS), and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). CONCLUSION:The present study provides tangible evidence for the effective management of AIE patients within the Brazilian healthcare system.

Objective The aim of the present study is to evaluate the necessity of performing lumbar puncture in patients experiencing febrile seizures, considering the epidemiology specific to Brazil. Methods A retrospective cross-sectional study was performed from January 2017 to December 2021. Results A total of 469 children with seizure and fever were analyzed. The identified event was the first in 65.9% (n = 309). A total of 54.2% (n = 254) of patients had a simple febrile seizure. Infectious focus, excluding previous central nervous system (CNS) infection, was identified in 35.6% (n = 167) patients. Meningitis was identified in 7.7% (n = 36) patients, all of them were viral. Patients with CNS infection had a higher frequency of symptoms such as nausea and vomiting, drowsiness, headache, and higher level of leukocytosis. A longer duration of fever was found to be more strongly associated with CNS infection. Conclusions When considering the use of lumbar puncture in febrile seizure, it is important to conduct a comprehensive evaluation that considers multiple factors, including clinical signs, symptoms, and the overall clinical context. Meningeal signs may be less prominent, and other symptoms such as lethargy, irritability, and vomiting may serve as more reliable indicators. Although clinical examination suggestive of meningitis remains an important factor, the recurrence of febrile seizures and a longer length of fever can provide additional insights and aid in decision-making regarding lumbar puncture.

Case presentation: Full term newborn, Apgar 9/9, with no family history of neurological diseases, developed breathing and feeding difficulties, reason why was admitted at the hospital on her 7th life day. On examination, presented craniofacial dysmorphic features, anisocoria reactive to light, absence of blink reflex, divergent strabismus with discreet skew deviation, hypertonia of limbs and clonic movements, rough skin with diffuse maculopapular lesions, with furfuraceous scaling. The patient was hospitalized and stabilized in the UCI, needing OTI. In the first investigation, the infectious triage and cerebral USG were normal. The MRI of the 9th day of life evidenced cerebral edema, bilateral injury of the thalamus and a high lactate at spectroscopy. The patient progressed with seizures crisis of difficult control, due to that, hypoproteic diet was initiated, with good response. The treatable diseases panel showed absence of variants that isolated would justify the clinical picture. A complete sequencing of the genome revealed variant c.377+1G>A, p.(?) on the intronic region that succeeds the exon 5 of the MOCS2 gene, in homozygous, diagnosing molybdenum cofactor deficiency B. MRI of the 7th month of life revealed plenty of areas with cystic degeneration, important volumetric encephalic reduction and reduction of the N-acetylaspartate peak. Nowadays she's at home, being treated with Phenobarbital, Levetiracetam, Oxcarbazepine, L-carnitine, Pyridoxine and Clonazepam.