The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy.

Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and immunohistochemical features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 causative variant to a Bethlem muscular dystrophy phenotype.

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review.

Background: Rho-related BTB domain-containing protein 2 (RHOBTB2) is a protein that interacts with cullin-3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients. Methods: We present a case series of seven patients with RHOBTB2-related disorders (RHOBTB2-RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2-RD. Results: The seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4-12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3-14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid-attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu). Conclusion: RHOBTB2-RD is characterized by developmental delay or intellectual disability, early-onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2-RD.

Genotype and Phenotype Characterization of Patients with Mucopolysaccharidosis IV-A in Chile.

Introduction: Morquio syndrome or mucopolysaccharidosis type IV-A (MPS IV-A) is an autosomal recessive disease caused by biallelic variants in the GALNS gene, encoding the lysosomal enzyme GalN6S, responsible for glycosaminoglycan keratan sulfate and chondroitin-6-sulfate degradation. Studies have shown that the degree of evolutionary and chemical divergence of missense variants in GalN6S when compared to ancestral amino acids is associated with the severity of the syndrome, suggesting a genotype-phenotype correlation. There is little information on Latin American patients with MPS IV-A that replicate these findings. This study aimed to characterize the phenotype and genotype from patients with MPS IV-A, who are under Enzyme Replacement Therapy at the Children's Neuropsychiatry Service of the Hospital Clínico San Borja Arriarán, Santiago, Chile, and to determine if there is any association between genotype and phenotype with those findings. Methods: Information was collected from medical charts, all patients went through a GalN6S enzymatic activity measurement in leukocytes from peripheral blood, and the GALNS gene was sequenced for all cases. Results: 12 patients with MPS IV-A were recruited, all patients presented multisystem involvement, mostly skeletal, and 75% of cases underwent surgical interventions, and cervical arthrodesis was the most frequent procedure. In regards of the genotype, the two most frequent variants were c.319+2T>C (n = 10, 41.66%) and p.(Arg386Cys) (n = 8, 33.33%), the first one was previously described in 2018 in a patient from Chile [Bochernitsan et al., 2018]. Conclusion: This is the first time that a genotype-phenotype correlation has been studied by analyzing the variants effect on the molecular structure of human GalN6S and the evolutionary conservation degree of affected residues in a cohort of patients in Chile. Albeit our work could not find statistically significant associations, we may infer that the evolutionary conservations of affected amino acids and the effect of variants on enzyme structure may play a main role. Further analyzes should consider a meta-analysis of published cases with genotype data and larger samples and include other variables that could provide more information. Finally, our data strongly suggest that variant c.319+2T>C could have a founder effect in Chilean patients with MPS IV-A.

ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization.

BACKGROUND: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts. METHODS: We developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA). RESULTS: ClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes. CONCLUSIONS: ClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses.

Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis-A Systematic Review.

Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet. We performed a systematic review and a meta-analysis of all published papers reporting the incidence of anti-NMDAR encephalitis in a definite country or region. We performed several multivariate spatial autocorrelation analyses to analyze the spatial variations in the incidence of anti-NMDA encephalitis depending on its geographical localization and temperature. Finally, we performed seasonal analyses in two original datasets from France and Greece and assessed the impact of temperature using an exposure-lag-response model in the French dataset. The reported incidence of anti-NMDAR encephalitis varied considerably among studies and countries, being higher in Oceania and South America (0.2 and 0.16 per 100,000 persons-year, respectively) compared to Europe and North America (0.06 per 100,000 persons-year) (p < 0.01). Different regression models confirmed a strong negative correlation with latitude (Pearson's R = -0.88, p < 0.00001), with higher incidence in southern hemisphere countries far from the equator. Seasonal analyses showed a peak of cases during warm months. Exposure-lag-response models confirmed a positive correlation between extreme hot temperatures and the incidence of anti-NMDAR encephalitis in France (p = 0.03). Temperature analyses showed a significant association with higher mean temperatures and positive correlation with higher ultraviolet exposure worldwide. This study provides the first evidence that geographic and climatic factors including latitude, mean annual temperature, and ultraviolet exposure, might modify disease risk.

Estudio de calidad de vida y comportamiento adaptativo en niños y adolescentes con discapacidad intelectual / Study of Quality of Life and Adaptive Behavior in Children and Adolescents with Intellectual Disability

Introducción: Los niños y adolescentes con discapacidad intelectual (DI) requieren de evaluaciones cognitivas, adaptativas y de calidad de vida (CV) con el fin de programar estrategias integrales de intervención basadas en sus necesidades. El objetivo de este estudio es describir CV, comportamiento adaptativo y cognición en una serie de niños y adolescentes con DI. Método: Se estudiaron 28 pacientes entre 6 a 18 años con escala de CV, evaluaciones cognitivas y comportamiento adaptativo. Resultados: En escala de CV se obtuvo una puntuación promedio, rango percentil 45-50, con menor puntaje en dimensiones de desarrollo personal, relaciones interpersonales e inclusión social. En escala de comportamiento adaptativo la mayoría de los pacientes presentaron nivel adaptativo bajo, sus dominios más afectados fueron comunicación y socialización. Al relacionar CV, comportamiento adaptativo y cognición se encontró una correlación significativa entre función adaptativa general y cognición (r = ,74, p < ,01) y entre función adaptativa e índice de calidad de vida (r = ,63, p < ,01). Conclusiones: En nuestra serie de niños y adolescentes con DI se relaciona un menor comportamiento adaptativo con menor CV y menor cognición. Inclusión social, desarrollo personal y relaciones interpersonales, así como socialización y comunicación, son las líneas a considerar como planes de intervención. (AU)

Children and adolescents with intellectual disabilities (ID) require cognitive, adaptive and quality of life (QoL) assessments in order to program integral strategies of intervention based on their needs. The objective of this study is to describe quality of life, adaptive behavior and cognition in a series of children and adolescents with ID. Method: 28 patients between 6 and 18 years old were studied with QoL scales, adaptive behavior and cognitive evaluations, and their correlations. Results: On the CV scale, an average score was obtained, 45-50 percentile range, with a lower score in dimensions of personal development, interpersonal relationships and social in-clusion. On the adaptive behavior scale, most of the patients presented a low adaptive level; their most affected domains were communication and socialization. When relat-ing QoL, adaptive behavior and cognition, a significant correlation was found between general adaptive function and cognition (r = ,74, p < ,01) and between adaptive function and quality of life index (r = ,63, p < ,01). Conclusions: In our series of children and adolescent with ID, a lower adaptive behavior is associated with a lower QoL and low-er cognition. Social inclusion, personal development and interpersonal relationships, as well as socialization and communication, are the lines to consider as intervention plans. (AU)

Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.

BACKGROUND AND OBJECTIVES: Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. METHODS: A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. RESULTS: We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. DISCUSSION: Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance.

A homozygous ABHD16A variant causes a complex hereditary spastic paraplegia with developmental delay, absent speech, and characteristic face.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous genetic disease characterized by progressive weakness and spasticity predominantly affecting the lower limbs. Complex HSP is a subset of HSP presenting with additional neuronal and/or non-neuronal phenotypes. Here, we identify a homozygous ABHD16A nonsense variant in two affected children in a Chilean family. Very recently, two groups reported patients with biallelic ABHD16A whose clinical presentation was similar to that of our patients. By reviewing the clinical features of these reports and our patients, ABHD16A-related HSP can be characterized by early childhood onset, developmental delay, intellectual disability, speech disturbance, extrapyramidal signs, psychiatric features, no sphincter control, skeletal involvement, thin corpus callosum, and high-intensity signals in white matter on T2-weighted brain MRI. In addition, our affected siblings showed a characteristic face, sleep disturbance, and nodular and hyperpigmented skin lesions, which have not previously been reported in this condition.

Impacto de brote por Covid-19 en las causas de egresos hospitalarios a nivel nacional por enfermedades del sistema nervioso central en población pediátrica durante el primer año de pandemia en Chile / Impact of Covid-19 outbreak in the causes of hospital discharges at national level due to central nervous system diseases in pediatric population during the first year of pandemic in Chile

INTRODUCCIÓN: La pandemia por Covid-19 ha generado cambios en la atención de salud nacional, observándose en este período cambios en las causas de egresos hospitalarios (EH). OBJETIVO: Analizar el impacto del brote de Covid-19 en las causas de EH por enfermedades del Sistema Nervioso Central (ESNC) en población pediátrica durante el primer año de pandemia. MÉTODO: Estudio transversal. Análisis de base de datos del Departamento de Estadística e Información en Salud en pacientes de 0 a 18 años, comparando años 2019 y 2020. RESULTADOS: En 2020 se redujeron EH por ESNC en un 39% comparado con 2019. Disminuyeron principalmente los EH por secuelas de enfermedades inflamatorias SNC, parálisis cerebral, migraña y paraplejia/cuadriplejia, aumentando los EH por isquemia cerebral transitoria, enfermedades desmielinizantes SNC y polineuropatía inflamatoria. El número EH por ESNC mensual se correlacionó con el número de casos Covid-19 (rho -0.774, p0.003) y con la movilidad mensual del país (rho 0.928, p 0.001). CONCLUSIONES: El impacto del brote Covid-19 se asoció con reducción de EH por ESNC, disminuyeron EH por patologías crónicas y aumentaron causas agudas.

INTRODUCTION: The Covid-19 pandemic has been associated with modifications in national health care, with changes in causes of hospital discharges (HD) in this period. OBJECTIVE: To analyze the impact of the Covid-19 outbreak on causes of HD due to Central Nervous System Diseases (CNSD) in pediatric population during the first year of pandemic. METHOD: Cross-sectional study. Analysis of database of the Department of Statistics and Health Information in patients aged 0 to 18 years, comparing 2019 and 2020. RESULTS: In 2020, HD due to CNSD were reduced in 39% compared to 2019. HD causes that mainly decreased were inflammatory CNS disease sequelae, cerebral palsy, migraine and paraplegia/cuadriplegia. The HD that increased were transient cerebral ischemia, CNS demyelinating diseases and inflammatory polyneuropathy. The monthly HD due to CNSD number was correlated with the number of Covid-19 cases (rho -0.774, p0.003) and with the country's monthly mobility (rho 0.928, p 0.001). CONCLUSIONS: Covid-19 pandemic was associated with a reduction in HD due to CNSD, with decrease of EH due to chronic pathologies and increase of acute diseases

[Prevalence estimation of Autism Spectrum disorders in chilean urban population]. / Estimación de la prevalencia de trastorno del Espectro Autista en población urbana chilena.

INTRODUCTION: The prevalence of Autism Spectrum Disorder has increased, varying between 0.5 and 1% around the world. The prevalence of ASD in Chile is unknown. OBJECTIVE: To estimate the prevalence of ASD in two urban communes of Santiago, Chile. SUBJECTS AND METHOD: Cross-sectional epidemiological study. 272 children aged between 18-30 months who attended well-child visits at two Family Health Centers in two urban communes of Santiago participated. Consecutive sampling was used and chil dren who were already being monitored by neurology were excluded. Screening was performed using the Modified Checklist for Autism in Toddlers (M-CHAT). Those children with altered M-CHAT were evaluated by a pediatric neurologist at the San Borja Arriarán Clinical Hospital and diagnosed with ASD according to clinical criteria. The Autism Diagnostic Observation Schedule - Second Ver sion (ADOS-2) was used as a diagnostic complement. The prevalence of ASD was estimated with a 95% confidence interval. RESULTS: 44 children had altered M-CHAT; 5 of them were clinically diagno sed with ASD. A 1.95% prevalence of ASD (95% CI 0.81-4.63) was obtained, with a sex distribution of 4 boys per 1 girl. CONCLUSIONS: This study is the first estimate of ASD prevalence in two communes of Santiago, Chile. A high prevalence of this condition was observed, which highlights the need for obtaining resources for an early multidisciplinary approach for these patients.

Hypomyelination and Congenital Cataract: Identification of a Novel likely pathogenic c.414+1G>A in FAM126A gene Variant.

It is key to expand the differential diagnosis and consider possible genetic etiologies on a patient with congenital cataracts associated with clinical features, such as leukodystrophy or polyneuropathy.

[Therapeutic use of robotics in children with Autism Spectrum Disorder]. / Uso terapéutico de robótica en niños con Trastorno del Espectro Autista.

INTRODUCTION: Robot-assisted Therapy (RAT) can improve the behavior of children with Autism Spectrum Disorder (ASD) in a spontaneous and entertaining way. There are no previous experiences of this type of inter vention in our country. OBJECTIVE: To describe a clinical experience of using RAT and its impact on the behaviors of a group of children with ASD, in a therapeutic context. PATIENTS AND METHOD: Quasi experimental clinical experience type study. 4 children with a clinical diagnosis of ASD were selected, supported by the ADOS-2 (Autism Diagnostic Observation Schedule); aged between 9 and 13 years, and normal IQ according to the WISC-III (Wechsler Intelligence Scale for Children). This study was approved by the Central Metropolitan Ethics Committee. Patients attended 10 structured robot-as sisted therapy sessions, working collaboratively in pairs. Workshop attendance and parent and child satisfaction were evaluated through surveys, the adaptive behavior with the Vineland scale, and so cial interaction with video coding guidelines. RESULTS: Patients presented a very good adherence and satisfaction with the activity. There was an improvement in socialization behaviors and social age. Video-coding showed an increase in social interaction and improvement in the behavior of the pa tients after attending workshops. CONCLUSIONS: We observed that the experience with RAT, adapted to the context of a Chilean public health center, was highly attractive and beneficial for patients with ASD, improving core symptoms such as difficulties in social interaction and behavioral problems.

[Children and adolescents with intellectual disabilities studied with genetic tests according to their clinical phenotype]. / Estudio genético de acuerdo a características fenotípicas de niños y adolescentes con discapacidad intelectual de etiología indeterminada.

INTRODUCTION: Intellectual disability (ID) is a neurodevelopmental disorder characterized by limitations in intellec tual and adaptive functioning, of various etiologies, including genetic causes. OBJECTIVE: to describe genetic studies carried out in a series of children and adolescents with ID of previously undetermined etiology, considering their phenotypic characteristics. PATIENTS AND METHOD: Descriptive study of a series of patients with ID aged 6 to 18 years. Clinical records, cognitive assessment results (Wechsler -TADI), and genetic study performed were reviewed. They were classified according to phenotypic characteristics into Group 1 patients without a specific phenotype, Group 2: patients with Angel- man- and Rett-like neurodevelopmental disorders phenotype, and Group 3: patients with difficult- to-control seizures. Group 1 was studied with CMA and Groups 2 and 3 with specific genetic panels. RESULTS: 18 patients were described, average age 11 years, male predominance, non-consanguineous parents, and with history of psychomotor retardation. Common comorbidities were epilepsy, autism spectrum disorder (ASD), and behavioral difficulties. Most had a neurological examination without focus and had TADI with very poor developmental ages. In Group 1, there was one patient with a 16p11.2 microdeletion and in Group 3 a duplication of the IQSEC2 gene was found in a patient with difficult-to-control seizures. CONCLUSIONS: The phenotypic characteristics allow to guide the choice of specific genetic studies in children and adolescents with ID of previously undetermined etiology to approach the etiological diagnosis.

Autism screening and conditional cash transfers in Chile: Using the Quantitative Checklist (Q-CHAT) for early autism detection in a low resource setting.

LAY ABSTRACT: Getting a diagnosis of autism can take long, because autism is different across people, but also because it depends on the way it gets diagnosed. This is especially important in poorer countries or in the case of poor people living in wealthier countries that have significant groups of disadvantaged communities. We adapted a 10-item version of the Q-CHAT-25 questionnaire for use in routine health check-ups programme in Chile and recruited 287 participants under the age of three divided into three groups: Controls (125), Developmental Delay (149) and Autism Spectrum Condition (13). Our results show that a short questionnaire for autism screening can be successfully applied in a health-check programme in poor resource settings. Our results show that our questionnaire had good overall performance, not different to its longer version, the Q-CHAT-25. Our questionnaire was autism specific, with good sensitivity and reliability, and is suitable to be used in a screening setting. This study provides evidence that the implementation of Autism Spectrum Condition screening programmes using the Q-CHAT-10 provides value for money and improves diagnosis of Autism Spectrum Condition in those participating in routine health check-up programmes in developing countries or poor areas of wealthy countries.

Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world.

AIM: Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, leading to progressive deterioration of neurological functions commonly occurring in children aged 2-4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes. METHODS: Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in São Paulo, Brazil, in October 2018. RESULTS: Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified. CONCLUSION: Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy.

A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction.

Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.

Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex.

Position of Experts Regarding Follow-Up of Patients with Neuronal Ceroid Lipofuscinosis-2 Disease in Latin America

Abstract Given the lack of standardized guidance for follow-up of patients with neuronal ceroid lipofucsinosis-2 disease in Latin-American countries and the heterogeneity of the region, an expert panel was created with the participation of 11 pediatric neurologists from Colombia, Argentina, Brazil and Chile. The aim of the expert panel was to describe a framework for standardized follow-up in patients with neuronal ceroid lipofucsinosis-2 disease, on or off therapy, that could benefit patients and treating physicians alike. Experts made recommendations in the following areas: seizures, abnormal movements and ataxia, sleep disorders and pain, cognitive function, visual function, hearing and speech, cardiac function, quality of life, and motor function. Recommendations include the most appropriate tools for use in the Latin-American context and health care systems, and provide feasible follow-up guidance, applicable in public and private healthcare facilities. They take into consideration the availability of clinical assessment resources, tools (scales, questionnaires, paraclinical tests) and access to these tools in Latin-American countries, as well as other regional and local needs defined by the participating experts.