Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Sleep Problems, Circadian Rhythms, and Their Relation to Behavioral Difficulties in Children and Adolescents with Autism Spectrum Disorder.

This was an exploratory cross-sectional study comparing 45 children with ASD to 24 typically developing drug-naïve controls, group-matched on age, sex, and body mass index. Objective data was obtained using the following: an ambulatory circadian monitoring device; saliva samples to determine dim light melatonin onset (DLMO): and three parent-completed measures: the Child Behavior Checklist (CBCL); the Repetitive Behavior Scale-Revised (RBS-R); and the General Health Questionnaire (GHQ28). The CBCL and RBS-R scales showed the highest scores amongst poor sleepers with ASD. Sleep fragmentation was associated with somatic complaints and self-injury, leading to a higher impact on family life. Sleep onset difficulties were associated with withdrawal, anxiety, and depression. Those with phase advanced DLMO had lower scores for "somatic complaints"; "anxious/depressed" state; and "social problems", suggesting that this phenomenon has a protective role.

Response to Melatonin Treatment in Children With Autism spectrum Disorder and Relationship to Sleep Parameters and Melatonin Levels.

Melatonin is one of the most used pharmacologic treatments for sleep problems in autism spectrum disorder, though its relationship with circadian and sleep parameters is still not well stablished. A naturalistic study was conducted in children with autism spectrum disorder, previously drug-naïve, before and after treatment with immediate-release melatonin. Circadian rhythms and sleep parameters were studied using an ambulatory circadian-monitoring device, and saliva samples were collected enabling determination of dim light melatonin onset. Twenty-six children with autism spectrum disorder (age 10.50 ± 2.91) were included. Immediate-release melatonin modified circadian rhythm as indicated by wrist skin temperature, showing an increase at night. A positive correlation was found between time of peak melatonin and sleep efficiency improvement values. Sleep-onset latency and efficiency improved with immediate-release melatonin. Immediate-release melatonin could be an effective treatment to improve sleep onset and restore a typical pattern of wrist temperature, which appears to be lost in autism spectrum disorder.

[Oral desensitization with Ketocal® in an infant with ketogenic diet and cow's milk protein allergy]. / Desensibilización con Ketocal® en lactante con dieta cetogénica y alergia a proteínas de leche de vaca.

Introduction: Introduction: ketogenic diet is a treatment with proven efficacy in drug-refractory childhood epilepsy. Cow's milk protein allergy may be a limitation for treating infants with ketogenic diet, as they need a product that contains cow's milk protein (Ketocal®). Case report: we report the case of an infant with a drug-refractory epileptic encephalopathy and IgE-mediated cow's milk protein allergy, who started a classic ketogenic diet. Oral desensitization was achieved with Ketocal 3:1®, allowing its use in the diet and achieving a clinical improvement with seizure control. Discussion: a patient with epilepsy and cow's milk protein allergy can benefit from the ketogenic diet, since it is possible to perform an oral immunotherapy with Ketocal®, also achieving a probable resolution of his/her allergy.

Introducción: Introducción: la dieta cetogénica es un tratamiento con eficacia demostrada en la epilepsia infantil refractaria a fármacos. La alergia a la proteína de leche de vaca puede ser una limitación para tratar a lactantes con dieta cetogénica, ya que necesitan un producto que contiene proteínas de leche de vaca (Ketocal®). Caso clínico: presentamos el caso de un lactante con una encefalopatía epiléptica refractaria a fármacos y alergia a las proteínas de leche de vaca IgE mediada al que se quiere instaurar una dieta cetogénica clásica. Se consigue la desensibilización con Ketocal 3:1®, pudiendo utilizarlo en la dieta y logrando una mejoría clínica con el control de las crisis. Discusión: un paciente con epilepsia y alergia a las proteínas de leche de vaca puede beneficiarse de la dieta cetogénica, ya que es posible realizar una inmunoterapia oral con Ketocal® y conseguir, además, una probable resolución de su alergia.

Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation.

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3' end of the gene, confirming the genotype-phenotype correlation initially described.

Glut1 deficiency is a rare but treatable cause of childhood absence epilepsy with atypical features.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare genetic disorder caused by pathogenic variants in SLC2A1, resulting in impaired glucose uptake through the blood-brain barrier. Our objective is to analyze the frequency of GLUT1-DS in patients with absences with atypical features. Sequencing analysis and detection of copy number variation of the SLC2A1 gene was carried out in patients with atypical absences including: early-onset absence, intellectual disability, additional seizure types, refractory epilepsy, associated movement disorders, as well as those who have first-degree relatives with absence epilepsy or atypical EEG ictal discharges. Of the 43 patients analyzed, pathogenic variations were found in 2 (4.6%). Six atypical characteristics were found in these 2 patients. The greater the number of atypical characteristics presenting in patients with absence seizures, the more likely they have a SLC2A1 mutation. Although GLUT1-DS is an infrequent cause of absence epilepsy, recognizing this disorder is important, since initiation of a ketogenic diet can reduce the frequency of seizures, the severity of the movement disorder, and also improve the quality of life of the patients and their families.

[Do children with attention deficit and hyperactivity disorder (ADHD) have a diferent gait pattern? Relationship between idiopathic toe-walking and ADHD]. / ¿Caminan de manera diferente los niños con trastorno por déficit de atención hiperactividad (TDAH)? Relación entre marcha de puntillas idiopática y TDAH.

INTRODUCTION: Idiopathic toe-walking (ITW) is described as a gait pattern with no contact between the heels and the ground in children older than 3years. The diagnosis is clinical, making it necessary to rule out other neurological and orthopaedic conditions. A relationship between ITW and vestibular dysfunction and/or proprioceptive sensibility has been proposed. Children with neurodevelopmental disorders (autism, language and cognitive disorders) often have ITW. OBJECTIVES: To determine the frequency of ITW in children with attention deficit disorder and hyperactivity (ADHD). PATIENTS AND METHOD: A study was conducted on children diagnosed with ADHD, with normal neurological examination, with no alterations in MRI scan, cognitive disorder or autism. A complete clinical anamnesis was performed and Achilles shortening was measured with a goniometer. RESULTS: The study included 312 children with a mean age of 11 years (73.7% boys). The ADHD combined subtype was the most frequent (53.8%), followed by the inattentive (44.9%), and hyperactive (1.3%). ITW was observed in 20.8% of patients, particularly in the combined subtype (P=.054). Only 32 of them (49.2%) had Achilles shortening. ITW was associated with sociability disorders (P=.01), absence of pain in legs (P=.022), and family history of ITW (P=.004). Only 11% had previously visited a doctor for this reason. CONCLUSIONS: As in other neurodevelopmental disorders, children with ADHD have frequently more ITW and Achilles shortening than controls, especially if they presented with a social communication disorder or a family history of ITW. An early diagnosis is essential to establish effective treatments.

Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes.

Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel). Using this gene panel, we were able to identify disease-causing variants in 17 out of 87 (19.5%) analyzed patients, all found in known epilepsy-associated genes (KCNQ2, CDKL5, STXBP1, SCN1A, PCDH19, POLG, SLC2A1, ARX, ALG13, CHD2, SYNGAP1, and GRIN1). Twelve of 18 variants arose de novo and 6 were novel. The highest yield was found in patients with onset in the first years of life, especially in patients classified as having early-onset epileptic encephalopathy. Knowledge of the underlying genetic cause provides essential information on prognosis and could be used to avoid unnecessary studies, which may result in a greater diagnostic cost-effectiveness.

[The importance of sleep problems in children with headache and other neurodevelopmental disorders in neuropaediatric services]. / Importancia de los problemas de sueño en los niños con cefalea y otros trastornos del neurodesarrollo en las consultas de neuropediatria.

INTRODUCTION: Sleep disorders are common in children with neurological disorders. The aim of this study is to know the opinion of neuropediatricians and the prevalence of these disturbances in Spain. PATIENTS AND METHODS: Multicenter cross-sectional study (12 Spanish hospitals, 15 researchers). BEARS survey was collected in three groups: A (2-5 years), (6-12 years), and C (> 12 years). The opinion of neuropediatricians was also collected. RESULTS: 939 questionnaires were filled. The main results in groups B and C were ADHD (32.4% and 30.1% respectively) and headache (25.1% and 27.6% respectively), whereas in group A neurodevelopmental disorders (32.4%) and epilepsy (21.4%) were the main diagnoses. Disturbances in at least one area of sleep were found in 92% of children in group A (n = 209, mean 3 years), 64.2% in group B (n = 534, mean 9.4 years) and 58.2% in group C (n = 196, mean 13.7 years). Sixty-one surveys were answered by neuropediatricians (16.75% of the total sent), estimating that less than a quarter of the patients (24.5%) suffered. Even, up to 23% of doctors claimed that the prevalence of sleep disorders was < 10%. CONCLUSIONS: 58-92% of parents-patients under follow up at a neuropediatrician office in Spain have some degree of disturbed sleep. Although most neurologists emphasize the importance of an early diagnosis and treatment of sleep disorders in children with neurological disorders, its frequency is often underestimated (risk of underdiagnosis).

TITLE: Importancia de los problemas de sueño en los niños con cefalea y otros trastornos del neurodesarrollo en las consultas de neuropediatria.Introduccion. Los trastornos de sueño son frecuentes en niños con trastornos neurologicos. El objetivo del estudio es conocer la opinion de los neuropediatras y su prevalencia real en España. Pacientes y metodos. Estudio transversal multicentrico (12 hospitales españoles, 15 investigadores). Se administro la encuesta Bedtime, Excesive Daytime Sleepiness, Awakenings, Regularity, Sleep-Disordered Breathing (BEARS) y se definieron tres grupos: A (2-5 años), B (6-12 años) y C (> 12 años). Asimismo, se recogio la opinion de neuropediatras de la Sociedad Española de Neuropediatria mediante una encuesta anonima. Resultados. Se recogieron 939 encuestas. Los principales motivos de consulta en los grupos B y C fueron trastorno por deficit de atencion/hiperactividad (32,4% y 30,1%, respectivamente) y cefalea (25,1% y 27,6%, respectivamente), y en el grupo A, los trastornos del neurodesarrollo (32,4%) y la epilepsia (21,4%). Al menos un area del sueño alterada se encontro en el 92,9% de niños del grupo A (n = 209; media: 3 años), en el 64,2% del grupo B (n = 534; media: 9,4 años) y en el 58,2% del grupo C (n = 196; media: 13,7 años). Se recibieron 61 encuestas respondidas por los neuropediatras (16,75% de las enviadas), quienes estimaban que los trastornos del sueño afectaban a menos de una cuarta parte de sus pacientes (24,5%), y hasta un 23% afirmo que la prevalencia era inferior al 10%. Conclusion. El 58-92% de los padres-pacientes que acuden a consultas de neuropediatria refiere tener algun aspecto del sueño alterado. Aunque la mayoria de los neuropediatras subraya la importancia de un diagnostico y tratamiento de los trastornos de sueño de los niños con trastornos neurologicos, se suele infraestimar su frecuencia e importancia.

[Benign childhood epilepsies: academic difficulties and behavioural disorders]. / Epilepsias benignas de la infancia: dificultades académicas y alteraciones comportamentales.

INTRODUCTION: Some papers published in the literature have shown that patients can present behavioural disorders and learning difficulties in benign childhood epilepsies (BCE). AIMS: To review the patients diagnosed with BCE in our hospital and to determine whether they present such disorders. PATIENTS AND METHODS: The study consisted in a retrospective review of the medical records of patients diagnosed with BCE. An electroencephalogram (EEG) or video-EEG-polygraph recordings were performed on all patients during sleep. The Wechsler Intelligence Scale for Children was used to evaluate intelligence. RESULTS: Data were collected for 102 patients diagnosed with BCE. Dispersed attention was observed in 51.6% of the patients with rolandic epilepsy and 16.2% displayed an impulsive temperament. In the group of patients with Panayiotopoulos syndrome, 30.3% displayed dispersed attention and 27.3% presented an impulsive temperament. A psychometric evaluation was carried out in 43 patients. The overall mean intelligence quotient was 95 (range: 55-126). In the three groups, academic achievement was good in approximately half the sample, regular in about 30% and poor in around 15%. In the group with rolandic epilepsy, the EEG showed a relation between frontal (p = 0.039) and occipital paroxysms (p = 0.004) and poorer academic achievement. In this group, the children with behaviours classed as dispersed, impulsive or hyperactive showed left-side paroxysms more frequently (p = 0.030). CONCLUSIONS: BCE are conditions with a good prognosis, but seem to be associated to learning and behavioural disorders. Neuropsychological studies should be conducted on these patients to detect these disorders.

Procalcitonin, a high acute phase reactant in antiepileptic hypersentivity syndrome in pediatric age.

Antiepileptic hypersensitivity syndrome (AHS) is a potentially life-threatening syndrome in pediatric cases. It is associated with aromatic anticonvulsivant drugs and others antibiotics with or without associated reactivation of virus. The pathogenesis of the process is not clear. Clinical feature of this syndrome include cutaneous reactions, fever and lymphadenopathies, but different organs can be involved. In laboratory analyses we can find leucocytosis, eosinophilia, and increase in transaminase levels. Significant elevation of procalcitonin (PCT) has been described in two adults patients. This study we report two cases of a 14-year-old male and a 13-year-old female with a AHS and a high level of the PCT. These are the first cases described in pediatric age. Establishing a diagnosis of AHS is important to avoid the use of the involved drug. The treatment is based on the withdrawal of the drugs that are supposed and if there is no improvement or a deterioration of the patient, the use of systemic corticosteroids is often useful.

[Characteristics and evolution of patients with Alice in Wonderland syndrome]. / Características y evolución de los pacientes con síndrome de Alicia en el País de las Maravillas.

INTRODUCTION: Alice in Wonderland syndrome is a process characterized for complex disorders of the visual perception with multiple etiologies. AIM: To evaluate the clinical, electrophysiological, etiological characteristics and natural evolution in children with Alice in Wonderland syndrome. PATIENTS AND METHODS: We have realized a retrospective study by what means of a review of 20 clinical histories of 18 year old minor patients diagnosed of Alice in Wonderland syndrome from January 1995 until February 2010. RESULTS: The average of age to the diagnosis was 9.5 ± 3.8 years (range: 4-16 years). It appeared in an acute way in 85% and progressive in 15%. 90% had micropsias and/or macropsias, 85% distortion of the form of the objects, 80% displacement of objects, 45% disturbances of body image, 45% acceleration of the time and 30% sensation of unreality. 95% of the children had many episodes a day; these episodes lasted less than 3 minutes in 90%. Electroencephalogram was realized in all the patients, it was abnormal in 11 cases, in one case was found and epileptic foci (left temporal) and in 10 cases was found posterior slow waves. The tests of neuroimagen were normal in all the patients. The visual evoked potentials were realized in 7 children; five of these children showed higher amplitude in evoked potentials and two of these children had normal. The infectious etiology was found in nine cases (five partners to Epstein-Barr virus), migraine in eight, toxins in two and epilepsy in one case. 80% did not have recurrence. CONCLUSIONS: Alice in Wonderland syndrome is a benign process with trend to spontaneous resolution and without recurrence in the majority of the occasions. The principal etiologies are migraine and Epstein-Barr virus infection.