Developmental outcome of electroencephalographic findings in SYNGAP1 encephalopathy.

SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials.

L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Cross-cultural validation and psychometric properties of the Spanish version of the quality of life in Childhood epilepsy Questionnaire (QOLCE-55).

OBJECTIVE: The aims of the present study were to translate and validate the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) into Spanish. METHODS: A backtranslation procedure was used to translate the English version of QOLCE-55 to Spanish, and subsequently, parents of 88 children (aged four to 12 years), completed the Spanish version of three self-reported questionnaires: the QOLCE-55, the Pediatric Quality-of-Life Inventory (PedsQLTM 4.0), and the Pediatric Sleep Questionnaire (PSQ). Seven to 10 days later, parents completed the questionnaires again under the same conditions. RESULTS: Internal consistency was between 0.669 and 0.968 for the four subscales: cognitive (CF), emotional (EF), social (SF) and physical functioning (PF); and 0.954 for the total score. The test-retest reliability assessed with the intraclass correlation coefficient obtained values from 0.683 for SF to 0.962 for CF. The standard error of measurement for the total score was 5.776, and the minimal detectable change was 16.01. Spearman correlations between the total score of the Spanish version of the QOLCE-55 with the subscales was 0.760 for the CF, 0.776 for the EF, 0.799 for the SF, and 0.682 for the PF (p < 0.001). Convergent validity of QOLCE-55 with the PedsQLTM 4.0 scale was -0.962 (p < 0.001), and the discriminant validity of the QOLCE-55 with PSQ was 0.154 (p = 0.272). This version presented a correlation with maximum lifetime consumption of anti-epileptic drugs (0.500; p < 0.001), and current consumption (0.448; p < 0.001). CONCLUSIONS: The Spanish version of the QOLCE-55 has demonstrated adequate psychometric properties, indicating that it can be confidently used to measure the health-related quality-of-life (HRQoL) in children with epilepsy in a Spanish-speaking population. These results corroborate the instrument's cross-cultural validity.

A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

Sotos Syndrome and Nephrocalcinosis, a Rare But Possible Association due to Impact on Contiguous Genes.

One-month old breastfeeding infant, full-term birth, with normal anthropometric measurements at birth is referred to Pediatric Nephrology due to a nephrocalcinosis. The patient presents dysmorphic features and heart disease. A metabolic study is conducted on blood and urine yielding results within normal parameters, except for renal concentration test and acidification test. At 6 months of age, patient presents overgrowth, which along with other clinical signs arouse suspicion of Sotos Syndrome. Molecular genetic testing detects heterozygous deletion in 5q35 between bands q35.2 and q35.3, affecting genes NSD1, SLC34A1 and FGFR4, which is compatible with this syndrome and with nephrocalcinosis as a rare association.

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.

Impact of COVID19 pandemic on patients with rare diseases in Spain, with a special focus on inherited metabolic diseases.

Introduction: The Covid-19 pandemic soon became an international health emergency raising concern about its impact not only on physical health but also on quality of life and mental health. Rare diseases are chronically debilitating conditions with challenging patient care needs. We aimed to assess the quality of life and mental health of patients with rare diseases in Spain, with a special focus on inherited metabolic disorders (IMD). Methods: A prospective case-control study was designed, comparing 459 patients suffering from a rare disease (including 53 patients with IMD) and 446 healthy controls. Quality of life (QoL) and mental health were assessed using validated scales according to age: KINDL-R and the Pediatric Symptom Checklist (PSC) for children and the WhoQoL-Bref questionnaire, GAD and PHQ-9 in adults. Results: First, children and adults (but not adolescents) with IMD showed greater psychological effects than controls (p = 0.022, p = 0.026 respectively). Second, when comparing QoL, only adult patients with IMD showed worse score than controls (66/100 vs 74,6/100 respectively, p = 0.017). Finally, IMD had better quality of life than other rare neurological and genetic diseases (p = 0.008) or other rare diseases (p < 0.001 respectively) but similar alteration of the mental status. Conclusions: Our data show that the pandemic had a negative impact on mental health that is more evident in the group of patients with IMD. Young age would behave as a protective factor on the perception of QoL. Furthermore, patients with IMD show a better QoL than other rare diseases.

Spanish translation, cross-cultural adaptation, and initial assessment of psychometric properties of the Life in Childhood Epilepsy Questionnaire (QOLCE-16).

OBJECTIVE: The aim of this study was the translation and cultural adaptation (TCA) of the Spanish version of the16-item Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-16) and an initial assessment of its psychometric properties. METHODS: The English version of the QOLCE-16 was cross-culturally adapted into Spanish using a back TCA procedure. Subsequently, for the process of validation of the Spanish version of QOLCE-16, the parents of 75 children with epilepsy (CWE) completed the QOLCE-16 questionnaire, the Pediatric Quality-of-Life Inventory (PedsQL™ 4.0), and the Pediatric Sleep Questionnaire (PSQ) twice in an interval of 7-10 days. The psychometric properties of the four domains of functioning (cognitive, emotional, social, and physical functioning subscales) were analyzed, together with the total QOLCE-16 score using Classical Test Theory. RESULTS: The scores of the Spanish version of the QOLCE-16 were obtained (alpha coefficient: 0.882, intraclass coefficient: 0.945). The standard error of measurement for the total score was 4.58, and the minimal detectable change was 13.44. Construct validity was tested using Confirmatory Factor Analysis. The estimates of the loadings for the four factors were higher than 0.35 and significant (α = 0.05). The four-factor model for QOLCE-16 [Chi- squared (p = 0.0540), comparative fit index = 0.985, Tucker-Lewis index = 0.982, root mean square error of approximation = 0.056 (0.000-0.0987), weighted root mean square residual = 0.707] showed good fit to these data. Convergent validity with PedsQL™ 4.0. was 0.791 and the discriminant validity of the QOLCE-16 with PSQ was -0.280. CONCLUSIONS: The Spanish version of the QOLCE-16 displays good psychometric properties of validity and reliability. All goodness-of-fit indices represent a good model fit, maintaining the multidimensional Health-related quality-of-life (HRQoL) model of the original English version. The Spanish version of this test can be used reliably to assess HRQoL in CWE in a Spanish-speaking population.

The clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1.

Glucose transporter 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder caused by haploinsufficiency of the GLUT1 glucose transporter (encoded by SLC2A1) leading to defective glucose transport across the blood-brain barrier. This work describes the genetic analysis of 56 patients with clinical or biochemical GLUT1DS hallmarks. 55.4% of these patients had a pathogenic variant of SLC2A1, and 23.2% had a variant in one of 13 different genes. No pathogenic variant was identified for the remaining patients. Expression analysis of SLC2A1 indicated a reduction in SLC2A1 mRNA in patients with pathogenic variants of this gene, as well as in one patient with a pathogenic variant in SLC9A6, and in three for whom no candidate variant was identified. Thus, the clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1.

Dissecting the transcriptional program of phosphomannomutase 2-deficient cells: Lymphoblastoide B cell lines as a valuable model for congenital disorders of glycosylation studies.

Congenital disorders of glycosylation (CDG) include 150 genetically and clinically heterogeneous diseases, showing significant glycoprotein hypoglycosylation that leads to pathological consequences in multiple organs and systems whose underlying mechanisms are not yet understood. A few cellular and animal models have been used to study specific CDG characteristics, although they have given limited information due to the few CDG mutations tested and the still missing comprehensive molecular and cellular basic research. Here, we provide specific gene expression profiles, based on ribonucleic acid (RNA) microarray analysis, together with some biochemical and cellular characteristics of a total of nine control Epstein-Barr virus-transformed lymphoblastoid B cell lines (B-LCL) and 13 CDG B-LCL from patients carrying severe mutations in the phosphomannomutase 2 (PMM2) gene, strong serum protein hypoglycosylation and neurological symptoms. Significantly dysregulated genes in PMM2-CDG cells included those regulating stress responses, transcription factors, glycosylation, motility, cell junction and, importantly, those related to development and neuronal differentiation and synapse, such as carbonic anhydrase 2 (CA2) and ADAM23. PMM2-CDG-associated biological consequences involved the unfolded protein response, RNA metabolism and the endoplasmic reticulum, Golgi apparatus and mitochondria components. Changes in the transcriptional and CA2 protein levels are consistent with the CDG physiopathology. These results demonstrate the global transcriptional impact in phosphomannomutase 2-deficient cells, reveal CA2 as a potential cellular biomarker and confirm B-LCL as an advantageous model for CDG studies.

Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum.

BACKGROUND: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present. METHODS: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. RESULTS: Patients harbouring GRIN1 disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. CONCLUSIONS: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies.

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients.

In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.

Síndrome de depleción de ADN mitocondrial tipo 13: un caso con un inicio poco común / Mitochondrial DNA depletion syndrome-13: a case with an unusual onset

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Transición de la epilepsia del niño al adulto. Dificultades en un objetivo no demorable / Transition from child to adult epilepsy. Difficulties with an objective that cannot be delayed

La atención pediátrica de un proceso crónico se ve limitada por el momento a partir del cual el seguimiento clínico y terapéutico debe continuarlo el especialista del área con dedicación al adulto. El retraso de la transición de la pediatría a la medicina del adulto puede originarse por causas familiares o del paciente, o bien por el profesional que diagnosticó la enfermedad. La primera emana de la incertidumbre ante lo desconocido, más intensa cuanto mayor ha sido la dificultad diagnóstica y terapéutica, al temer que el paciente se desestabilice. La segunda atañe al especialista pediátrico, que creó lazos de dependencia con el paciente por las dificultades del proceso, e incluso por el deseo de no perder protagonismo en el mismo. Demorar la transición genera problemas perjudiciales para el niño, pues superada la adolescencia mantendrá una nociva dependencia familiar y del pediatra, retrasando el necesario conocimiento de la propia enfermedad y de las limitaciones que pueden condicionarle, e impidiéndole desarrollar mecanismos para enfrentarse a su realidad vital. Más adelante, cuando llega el necesario paso a la medicina del adulto, aflora la inmadurez, que incrementa las dificultades por desconocer tanto la enfermedad como los signos de alarma, revelando inseguridad en las situaciones que vayan apareciendo. El problema se soluciona con un cambio lento y progresivo, que debe coordinarse en consultas mixtas atendidas por especialistas pediátricos y de adultos. En esta publicación se analiza esta problemática y se revisan las soluciones aconsejadas para su mejor desarrollo

Paediatric care of a chronic process is limited by the moment when the clinical and therapeutic follow-up must be continued by a specialist from the area for adults. The delay in the transition from paediatrics to adult medicine can be due to causes attributable to the patient or his/her relatives, or the professional who diagnosed the disease. The former arises from the uncertainty of facing the unknown, which becomes more intense when the diagnosis and treatment have been difficult, as there is a fear of upsetting the stability of the patient. The latter concerns the paediatric specialist, who created ties of dependence with the patient due to the difficulties involved in the process, and perhaps even owing to a wish to avoid playing a less important role in it. Delaying the transition gives rise to problems that are detrimental for the child, because after adolescence there will still be a harmful dependence on the family and the paediatrician, which will delay the necessary knowledge of their own illness and of the limitations that can condition them. As a result this can prevent them from developing mechanisms for coming to terms with the reality of their own life situation. Later on, when it comes to taking the necessary step into adult medicine, immaturity appears, which increases the difficulties due to a lack of knowledge of both the disease and the tell-tale signs of alarm, revealing insecurity in the different situations that arise. The problem can be solved by a slow progressive change which must be coordinated in mixed outpatient departments with the presence of specialists for both paediatric and adult patients. This publication offers an analysis of this problem and a review of the solutions recommended to implement them in the best possible way

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia's encephalopathy.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients.

Melatonin is synthesized from serotonin and it is excreted as sulphatoxymelatonin in urine. We aim to evaluate urinary sulphatoxymelatonin as a biomarker of brain serotonin status in a cohort of patients with mutations in genes related to serotonin biosynthesis. We analized urinary sulphatoxymelatonin from 65 healthy subjects and from 28 patients with genetic defects. A total of 18 patients were studied: 14 with autosomal dominant and recessive guanosine triphosphate cyclohydrolase-I deficiency; 3 with sepiapterin reductase deficiency; and 1 with aromatic L-amino acid decarboxylase deficiency. Further 11 patients were studied after receiving serotoninergic treatment (serotonin precursors, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors): 5 with aromatic L-amino acid decarboxylase deficiency; 1 with sepiapterin reductase deficiency; 3 with dihydropteridine reductase deficiency; and 2 with 6-pyruvoyltetrahydropterin synthase deficiency. Among the patients without therapy, 6 presented low urinary sulphatoxymelatonin values, while most of the patients with guanosine triphosphate cyclohydrolase-I deficiency showed normal values. 5 of 11 patients under treatment presented low urine sulphatoxymelatonin values. Thus, decreased excretion of sulphatoxymelatonin is frequently observed in cases with severe genetic disorders affecting serotonin biosynthesis. In conclusion, sulphatoxymelatonin can be a good biomarker to estimate serotonin status in the brain, especially for treatment monitoring purposes.

Nivel formativo sobre trastornos del espectro autista (TEA) entre los pediatras de atención hospitalaria / Level of training in autistic spectrum disorders among hospital paediatricians

Introducción: La formación en trastornos del espectro autista (TEA) por parte de los pediatras es esencial para su diagnóstico precoz. Sin embargo, son escasos los estudios que han cuantificado este conocimiento, por lo que el objetivo principal es determinar el nivel formativo sobre TEA entre pediatras de atención hospitalaria en diferentes comunidades e identificar aspectos a mejorar. Material y métodos: Un total de 157 pediatras de atención hospitalaria de 3 comunidades autónomas completó el cuestionario online sobre TEA, estructurado en 3 partes (sociodemográfico, nivel formativo y opinión). Los datos fueron analizados con SPSS (versión 15). Resultados La media ± desviación estándar de puntuaciones en el cuestionario fue 20,34±2,43 (puntuación máxima posible: 23). Un 65% puntúa en todos los dominios igual o superior a la media. Los conceptos menos conocidos son: patrones restringidos de conducta, concepto general TEA y comorbilidades posibles. No hay diferencias estadísticamente significativas en cuanto a las puntuaciones entre diferentes grupos de pediatras según variables sociodemográficas. Un 64% de los pediatras opina que su conocimiento sobre TEA es limitado. Destaca un desconocimiento importante sobre la disponibilidad de recursos, presente en todas las comunidades estudiadas. Conclusiones Existe un adecuado nivel general de conocimientos sobre TEA entre los pediatras, pero un deficiente conocimiento en la parte práctica del manejo de estos pacientes y en la coordinación entre los diferentes equipos que participan en el cuidado de estos. Los esfuerzos deberían centrarse en lograr una buena comunicación entre estos equipos y en mantener actualizados los conocimientos sobre TEA a todos los niveles (AU)

Background: Training in autistic spectrum disorders is crucial in order to achieve an early diagnosis. However, the number of papers describing this training is limited. This study describes this level of knowledge among paediatricians from tertiary care hospitals in different regions of Spain and detects areas that need improvement. Material and method: A total of one hundred and fifty-seven (157) paediatricians working in tertiary healthcare hospitals located in three different regions in Spain consented to complete an online questionnaire divided in three sections (socio-demographic, knowledge about childhood autism, and opinion). Data were analysed using SPSS version 15. Results: The total mean score of participating paediatricians in the questionnaire was 20.34 (± 2.43 SD) out of a total possible score of 23. Approximately two-thirds (65%) of paediatricians scored more or equal to the mean score. The knowledge gap was found to be higher with symptoms of repetitive behaviour patterns, concept of autism, and comorbidity, with no statistical significance. There were no differences in paediatrician scores within different socio-demographic groups. Just under two-thirds (64%) of paediatricians subscribed to the opinion that their own knowledge about autism is limited, and there is a significant lack of knowledge about facilities in every region. Conclusions: There is a sufficient level of knowledge about autism among paediatricians in tertiary healthcare, although a lack of awareness about the management of these patients, with poor coordination between the different specialists that are involved in their treatment. Efforts should focus on achieving a better coordination between these specialists, and update the knowledge gaps identified (AU)