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Pathogenic variants of the aggrecan (ACAN) gene have been associated with a wide spectrum of growth modifications ranging from idiopathic short stature to severe skeletal dysplasia. We reported a case of an 8-year-old male observed in a pediatric endocrinology consultation for short stature (-3.46 standard deviation score). Investigation revealed a bone age advance of less than one year, somatotropin stimulation tests with clonidine and L-DOPA level of below 7 ng/dL, the normal value of insulin-like growth factor 1, and normal brain magnetic resonance. He started treatment with subcutaneous somatropin by 8.8 years. Over the years some traits on physical examination became more notorious, namely an upper segment longer than the lower, muscled appearance, broad thumbs, macrocranea, and mild bilateral eyelid ptosis. Clinical exome sequencing revealed a pathogenic variant c.1020del in the ACAN gene.

INTRODUCTION: Pathogenic variants in HIVEP2 have been associated with a neurodevelopmental disorder mainly characterized by intellectual disability, severe language impairment, and motor developmental delay. Since its first description in 2016, only 15 patients have been described in the literature. METHODS: Here, we report 2 additional unrelated Portuguese children presenting intellectual disability and motor delay in whom de novo nonsense pathogenic variants in HIVEP2 have been identified by next-generation sequencing analysis. RESULTS: In patient 1, the variant c.2827C>T, p.(Arg943*) was detected, whereas patient 2 carried the variant c.6667C>T, p.(Arg2223*). Interestingly, patient 1 presented with a rapid growth of the occipitofrontal diameter in the first months of life due to external hydrocephalus, a feature that, as far as we know, has never been reported in patients with HIVEP2 pathogenic variants. CONCLUSION: This report expands the phenotypic spectrum of this rare syndrome and provides deeper insights by comparing the clinical features of our patients with previously reported affected individuals.

Objective To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge. Conclusion COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Autism Spectrum Disorder is a Neurodevelopmental Disorder characterized by deficits in social interaction and by the presence of restricted, repetitive and stereotyped patterns of behaviours, interests, and activities. The aetiology of Autism Spectrum Disorder is often genetic, with several monogenic diseases clearly associated with this disorder. Significant advances in molecular genetics have increased the rate of etiological diagnosis of Autism Spectrum Disorder to about 30-40% in the last decade.The establishment of a definitive etiological diagnosis facilitates referral to community support services, contributes to knowledge of possible associated medical conditions and prevention of morbidity and mortality, while also eliminating inadequate diagnostic tests and allowing individualized genetic counselling.The authors present a proposal for an etiological investigation of this pathology, including criteria for performing complementary metabolic evaluation, neuroimaging and electroencephalography, and various genetic studies (conventional cytogenetics, Array-Comparative Genomic Hybridization, targeted molecular studies, multi-gene panels and Whole Exome Sequencing)., A Perturbação do Espetro do Autismo é uma Perturbação do Neurodesenvolvimento, que se carateriza por défice na interação social e pela presença de padrões restritos, repetitivos e estereotipados de comportamentos, interesses e atividades. A etiologia das Perturbações do Espetro do Autismo é frequentemente genética, existindo várias doenças monogénicas claramente associadas a esta perturbação. Avanços significativos na genética molecular aumentaram a taxa de diagnóstico etiológico para cerca de 30 a 40% na última década. O estabelecimento de um diagnóstico etiológico definitivo facilita a referenciação para os serviços de apoio na comunidade, contribui para o conhecimento de eventuais condições médicas associadas e para a prevenção da morbimortalidade, elimina a realização de exames auxiliares de diagnóstico inadequados e facilita o aconselhamento genético individualizado. Os autores apresentam uma proposta de investigação etiológica desta patologia, incluindo critérios para realização de avaliação metabólica complementar, realização de neuroimagem e eletroencefalograma e variados estudos genéticos (citogenética convencional, arrays de hibridização genómica comparativa, estudos moleculares dirigidos, painéis multigénicos e sequenciação exómica completa).

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation.\ud \ud Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations.\ud \ud Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge.\ud \ud Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Defectos en el complejo mitocondrial ETF/ETF-QO (ETF - flavoproteína transferidora de electrones; ETFQO - flavoproteína transferidora de electrones ubiquinona oxidorreductasa), resultan en la disfunción secundaria de 11 deshidrogenasas que utilizan este complejo para transferir los electrones a la cadena de transporte electrónico, bloqueando la β-oxidación de los ácidos grasos, de aminoácidos y de la colina. Defectos en el funcionamiento del complejo resultan en una deficiencia multiple de acil-CoA deshidrogenasas (MADD; aciduria glutárica tipo II; OMIM 231680) que representa un grupo muy heterogéneo de enfermedades metabólicas tanto desde el punto de vista clínico como molecular. Pueden tener como causa mutaciones en los genes que codifican para las subunidades del complejo (ETFA, ETFB y ETFDH), genes que codifican los transportadores de riboflavina, del transporte ó de la síntesis del FAD. Bioquímicamente, las MADD se caracterizan por la acumulación de acilcarnitinas de cadena corta, media y larga, siendo su detección la abordaje primaria al diagnóstico, incluso en cribado neonatal. La multiplicidad de defectos genéticos que pueden cursar por una disfunción del complejo ETF/ETF-QO (creyéndose que siguen sin estar identificados todos), el hecho de que no siempre están presentes los marcadores bioquímicos evidentes (acumulación de las acilcarnitinas características) y la grande variabilidad clínica son factores que conducen a una dificultad aumentada en de diagnóstico de este grupo de errores congénitos del metabolismo. En este panorama el conocimiento de la epidemiologia molecular es fundamental. Los autores presentaran las bases moleculares de los trastornos en el funcionamiento del complejo ETF/ETF-QO en Portugal. info:eu-repo/semantics/publishedVersion

Mutations in the ALS2 gene cause three distinct disorders: infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and autosomal recessive juvenile amyotrophic lateral sclerosis. We present a review of the literature and the case of a 16-year-old boy who is, to the best of our knowledge, the first Portuguese case with infantile ascending hereditary spastic paraplegia. Clinical investigations included sequencing analysis of the ALS2 gene, which revealed a heterozygous mutation in exon 5 (c.1425_1428del p.G477Afs*19) and a heterozygous and previously unreported variant in exon 3 (c.145G>A p.G49R). We also examined 42 reported cases on the clinical characteristics and neurophysiological and imaging studies of patients with known ALS2 gene mutations sourced from PubMed. This showed that an overlap of phenotypic manifestations can exist in patients with infantile ascending hereditary spastic paraplegia, juvenile primary lateral sclerosis, and juvenile amyotrophic lateral sclerosis.