Paralog Studies Augment Gene Discovery: DDX and DHX Genes.

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization.

Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in ACTA1, two (8%) in KLHL40, and one in TPM2 (4%) and TPM3 (4%). In the NEB-related families, 25 different variants, 11 of them novel, were identified; splice site (10/25) and frame shift (9/25) mutations were the most common. Mutation c.24579 G>C was recurrent in three unrelated patients from the same region, suggesting a common ancestor. Clinically, the "typical" form was the more frequent and caused by mutations in the different NM genes. Phenotypic heterogeneity was observed among patients with mutations in the same gene. Respiratory involvement was very common and often out of proportion with limb weakness. Muscle MRI patterns showed variability within the forms and genes, which was related to the severity of the weakness. Considering the high frequency of NEB mutations and the complexity of this gene, NGS tools should be combined with CNV identification, especially in patients with a likely non-identified second mutation.

Comparison of child self-reports and parent proxy-reports on quality of life of children with attention deficit hyperactivity disorder.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a neurobiological condition that affects 3%-7% of the pediatric population and significantly compromises the quality of life (QoL) of these individuals. The aim of the current study was to compare child self-reports and parent proxy reports on the QoL of children with ADHD. METHODS: Forty-five children with ADHD, combined type, aged 8-12 years without comorbidities, were compared with 43 typically developing children. PedsQL™ 4.0 (Pediatric QoL Inventory™) Generic Core Scales (physical, emotional, social, and school functioning) were completed by families and children self-reporting their health-related QoL. RESULTS: Children with ADHD reported themselves significantly lowered their PedsQL™ scores on all dimensions in comparison to typically developing children. Statistically significant differences were observed in social functioning (p = 0.010), school functioning (p <0.001), psychosocial health (p <0.001), and total score (p = 0.002). The physical functioning and emotional functioning dimensions did not differ significantly between groups, with p = 0.841 and p = 0.070, respectively. Parents of children with ADHD also reported lower PedsQL™ scores, with statistically significant differences in all dimensions. The relationship between child self-reports and parent proxy reports indicated that there is greater agreement among children with ADHD, except for the school functioning. CONCLUSIONS: This suggests that children with the disorder and their parents have a perception of the functional limitations the disorder brings. It is therefore important to undertake studies to verify the QoL in children with ADHD that aim to provide and measure the scope of the well-being of these children.

Brazilian Portuguese Childhood Autism Spectrum Test: an investigation of the factor structure of autistic traits in school-aged children from Brazil.

OBJECTIVE: There is limited evidence about the cross-cultural validity of autistic symptoms in school-aged children in Brazil. We used data from a large school survey to evaluate the factor structure of autism symptoms in community-dwelling children and adolescents. METHODS: We translated the Childhood Autism Spectrum Test to Brazilian Portuguese and performed factor analyses to investigate the factor structure of parent-reported autistic symptoms in a large sample (n=8,571) of children/adolescents from a school survey in the metropolitan area of São Paulo. RESULTS: Autistic symptoms were best conceptualized under a correlated-factors model with two factors: one predominantly characterized by social-communication symptoms and the other by symptoms of inflexible/restricted language, behaviors, and interests. CONCLUSIONS: These findings provide evidence that the structure of autistic symptoms in Brazil is similar to that described in other countries, indicating the cross-cultural validity of autism in Brazil.

Efficacy and safety of methylphenidate in treating ADHD symptoms in children and adolescents with uncontrolled seizures: a Brazilian sample study and literature review.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is observed in 30% of children and adolescents with epilepsy. Recent studies have demonstrated the safety of methylphenidate (MPH) in patients with controlled epilepsy. There are few studies of patients with uncontrolled epilepsy. The goal was to study the efficacy and safety of MPH use in children and adolescents diagnosed with ADHD and uncontrolled epilepsy. METHODS: We evaluated 24 patients ranging from 7 to 16 years of age who took MPH for 6 months. Inclusion criteria were at least two epileptic seizures in the previous 6 months and a diagnosis of ADHD based on DSM-IV criteria. CONCLUSION: Patients were classified according to ADHD subtype as follows: 41.7% inattentive type, 37.5% combined, and 20.8% hyperactive/impulsive type; 58.3% had partial epilepsy and 41.7% generalized epilepsy. There was an overall improvement in ADHD symptoms in 70.8% of patients, and there was no increase in frequency of epileptic seizures in 22 patients (91.6%).

Associations between Attention-Deficit Hyperactivity Disorder (ADHD) Treatment and Patient Nutritional Status and Height.

Attention-deficit hyperactivity disorder (ADHD) has been found to co-occur frequently with obesity, although the reasons for this association are unknown. The aim of this study was to compare the nutritional profile of a Brazilian cohort of ADHD patients with that of the general population and to analyze the association between ADHD drug treatment (with methylphenidate), nutritional status, and height of these individuals. In the first phase of the study, we designed the nutritional and height profile of 93 ADHD patients (5.1 to 13.8 years old) and compared it to a control group. In the second phase, we analyzed the association of the use of methylphenidate with nutritional status and height. The results showed that the prevalence of overweight/obesity was statistically higher in the cohort of ADHD patients compared to controls (40.9% vs. 34.7%; P < 0.05). After treating ADHD patients with methylphenidate, a statistically significant decrease in the BMI z-score was observed (0.695 vs. 0.305; P < 0.01). On the other hand, no significant impact on height was detected after treatment (0.189 vs. 0.248; P = 0.298). In conclusion, the results suggest that the use of methylphenidate in patients who have ADHD and obesity is relevant not only for controlling ADHD symptoms but also for improving the nutritional status of these individuals. Moreover, the treatment did not affect the patients' height.

[Acute necrotizing encephalopathy: patient with a relapsing and lethal evolution]. / Encefalopatia necrotizante aguda: paciente com evolução recidivante e letal.

Acute necrotizing encephalopathy was initially reported in Japanese children. The rapid evolution and symmetrical brain lesions seen in the brainstem, cerebellum and specially in the thalamus characterize the disease. We studied a 7-month-old-girl, who presented with two episodes of rapid loss of consciousness and paresis without metabolic disturbances. At the first time she had a rapid improvement, but at the second episode the course was fulminant and in two days she lapsed into a clinical state of brain death. The magnetic resonance studies showed symmetrical lesions in the thalamus and additional lesions involving the brainstem and the cerebellum.

Brazilian Portuguese Childhood Autism Spectrum Test: an investigation of the factor structure of autistic traits in school-aged children

Objective: There is limited evidence about the cross-cultural validity of autistic symptoms in school-aged children in Brazil. We used data from a large school survey to evaluate the factor structure of autism symptoms in community-dwelling children and adolescents. Methods: We translated the Childhood Autism Spectrum Test to Brazilian Portuguese and performed factor analyses to investigate the factor structure of parent-reported autistic symptoms in a large sample (n=8,571) of children/adolescents from a school survey in the metropolitan area of São Paulo. Results: Autistic symptoms were best conceptualized under a correlated-factors model with two factors: one predominantly characterized by social-communication symptoms and the other by symptoms of inflexible/restricted language, behaviors, and interests. Conclusions: These findings provide evidence that the structure of autistic symptoms in Brazil is similar to that described in other countries, indicating the cross-cultural validity of autism in Brazil.

The relationship between motor skills, ADHD symptoms, and childhood body weight.

BACKGROUND: Research has suggested an important association between motor proficiency and overweight/obesity. Many children with motor difficulties experience ADHD symptoms which have also been linked with overweight/obesity. Previous research has not considered both ADHD and motor performance when investigating their relationship with overweight/obesity. AIMS: To investigate the relationships between motor performance, ADHD symptoms, and overweight/obesity in children. METHODS AND PROCEDURES: A cross-sectional study was conducted involving189 children aged six to 10 years. Symptoms of ADHD were identified using the SNAP-IV rating scale. Motor impairment (MI) was identified using the Movement Battery Assessment for Children-2. Body composition was estimated from the Body Mass Index (BMI) based on World Health Organization child growth standards. OUTCOMES AND RESULTS: Balance was the only motor skill associated with BMI even after controlling for gender and ADHD. Group comparisons revealed that the proportion of overweight ADHD children was significantly less than the proportion of overweight control children and overweight MI children; the proportion of underweight ADHD children was significantly greater than the proportion of underweight MI children. CONCLUSIONS AND IMPLICATIONS: The results highlight the importance of taking into consideration both ADHD symptoms and motor difficulties in the assessment and intervention of physical health outcomes in children with ADHD and/or movement problems.

Episodic somnolence in an infant with Riley-Day syndrome.

Familial dysautonomia is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish population and has rarely been diagnosed in the neonatal period in unaffected families. This report describes a patient who, during the neonatal period, had episodes of marked decrease in the level of consciousness with durations of 4-15 hours. Other signs and symptoms included the absence of fungiform papillae of the tongue, areflexia, and failure to thrive. The diagnosis was confirmed by the demonstration of mutations in the IkappaB kinase complex-associated protein gene with the identification of IVS20 (+6T --> C) which is responsible for more than 99.5% of known Ashkenazi Jewish patients with familial dysautonomia. The prognosis of this disease and the possibility of genetic counseling are clearly related with an early definitive diagnosis, and this patient illustrates the importance of episodes of somnolence as a possible sign of familial dysautonomia.

Neonatal seizures: the overlap between diagnosis of metabolic disorders and structural abnormalities. Case report.

UNLABELLED: Inborn metabolic errors (IME) and cortical developmental malformations are uncommon etiologies of neonatal seizures, however they may represent treatable causes of refractory epilepsy and for this reason must be considered as possible etiological factors. This case report aims to demonstrate the importance of neuroimaging studies in one patient with neonatal seizures, even when there are clues pointing to a metabolic disorder. CASE REPORT: A previously healthy 14 day-old child started presenting reiterated focal motor seizures (FMS) which evolved to status epilepticus. Exams showed high serum levels of ammonia and no other abnormalities. A metabolic investigation was conducted with normal results. During follow-up, the patient presented developmental delay and left side hemiparesia. Seizures remained controlled with anti-epileptic drugs for four months, followed by relapse with repetitive FMS on the left side. Temporary improvement was obtained with anti-epileptic drug adjustment. At the age of 6 months, during a new episode of status epilepticus, high ammonia levels were detected. Other metabolic exams remained normal. The child was referred to a video-electroencephalographic monitoring and continuous epileptiform discharges were recorded over the right parasagittal and midline regions, with predominance over the posterior quadrant. A new neuroimaging study was performed and displayed a malformation of cortical development. Our case illustrates that because newborns are prone to present metabolic disarrangement, an unbalance such as hyperammonemia may be a consequence of acute events and conduct to a misdiagnosis of IME.

Health-related physical fitness children with severe and moderate developmental coordination disorder.

The present study aims to examine physical fitness among children with developmental coordination disorder (DCD) with varying degrees of severity (moderate and severe - mDCD, sDCD), and a group of children without DCD (wDCD), in the city of Manaus, Brazil. Initially, 180 children aged 6-10 years old participated in this study. After being diagnosed according to the DSM-IV-TR, 63 children were then divided into three groups (21 in each group). Health-related physical fitness was measured by means of the Fitnessgram, which included several core components, namely, body composition, muscle strength and endurance, flexibility, and cardiorespiratory resistance. The results showed no statistically significant differences between both groups in any of the assessed components. However, when analyzing the results of each component according to the criteria of the Fitnessgram, we observed that, regardless of the classification group, less than half of the children achieved scores that, according to the motor tests, would classify them as having a healthy fitness. Children with sDCD, mDCD and wDCD presented similar levels of health-related physical fitness, with an unsatisfactory performance for the component strength and muscular endurance. We therefore emphasize the importance of further research in this area, more particularly when it comes to following the development of motor skills and physical fitness in children with DCD, as well as the observation of the interactions between these variables over time.

Motor profile of children with attention deficit hyperactivity disorder, combined type.

OBJECTIVES: The aim of this study was to assess the motor profile of children with attention deficit hyperactivity disorder (ADHD), combined type. METHOD: The case group consisted of 34 treatment-naive, male patients, aged 7-11 years, who had been diagnosed with ADHD, combined type, without comorbidities (except oppositional defiant disorder). The control group was composed of 32 age- and gender-matched, typically developing children. The evaluation was made using the Motor Development Scale, which assessed global and fine motricity, balance, body scheme, and spatial and temporal organization. RESULTS: The results showed that the motor quotients in all areas studied were lower in the ADHD group than in the control group, although in most cases they represent normal values relative to the scale (53% were classified as having "normal medium" motor development, 29% "normal low", 9% "very low", 6% "normal high" and 3% as "lower"). Statistically significant differences between groups were observed in general motor age, general motor quotient, balance, spatial organization, and fine and global motricity. CONCLUSION: Difficulties in motor performance were observed in the children with ADHD, combined type. The identification of such deficits may assist in the design of therapeutic protocols for the treatment of children with this type of ADHD.

Assessment of motor skills and school performance in children diagnosed with attention deficit hyperactivity disorder

Abstract This study was designed to analyze the association between motor skills and school performance in elementary school children with attention deficit hyperactivity disorder (ADHD). Two groups of children were evaluated. The experimental group contained 55 students of both sexes, age 7 to 10, who had been clinically diagnosed with ADHD; the control group consisted of 55 children with typical motor development. The results showed no association between motor skills and school performance in the experimental group, although there was a statistically significant difference between manual dexterity and writing performance in the control group. Although we found no relationship between motor skills and school performance in children with ADHD, we believe that having specialized professionals monitor these children may be beneficial. Early diagnosis of impaired motor skills and poor school performance may lead to better developmental opportunities and a better quality of life.

Attention deficit and hyperactivity disorder in people with epilepsy: diagnosis and implications to the treatment.

The association between attention deficit and hyperactivity disorder (ADHD) and epilepsy can cause significant impact on the social life of affected individuals and their families. Clinical studies suggest that 30-40% of people with epilepsy also have ADHD. There are no studies which demonstrate that short or long-term treatment with methylphenidate increases the risk of seizures. Some studies attempt to relate drug interactions between methylphenidate and antiepileptic drugs, but adverse effects of methylphenidate have not been shown clearly. This review presents some neurobiological and physiopathogenic aspects, common to ADHD and epilepsy, from recent research studies, related to pharmacology, neuroimaging and electroencephalography. Possible risk of occurrence of seizures associated with the use of methylphenidate are also discussed.

Spondylocostal dysostosis associated with methylmalonic aciduria.

Spondylocostal dysostosis (SCD) is a genetic disorder characterized by vertebral segmentation and formation defects associated with changes of the ribs. Autosomal dominant and recessive modes of inheritance have been reported. Methylmalonic aciduria (MMA) is an inborn error of propionate or cobalamin metabolism. It is an autosomal recessive disorder and one of the most frequent forms of branched-chain organic acidurias. Here we report on a case of a Brazilian boy with both diseases. As we know, it is the first case in the literature with the occurrence of both SCD and MMA--the first a skeletal disease and the latter an inborn error of metabolism.

Attention deficit and hyperactivity disorder in people with epilepsy: diagnosis and implications to the treatment / Transtorno de déficit de atenção e hiperatividade em pessoas com epilepsia: diagnóstico e implicações para o tratamento

The association between attention deficit and hyperactivity disorder (ADHD) and epilepsy can cause significant impact on the social life of affected individuals and their families. Clinical studies suggest that 30-40 percent of people with epilepsy also have ADHD. There are no studies which demonstrate that short or long-term treatment with methylphenidate increases the risk of seizures. Some studies attempt to relate drug interactions between methylphenidate and antiepileptic drugs, but adverse effects of methylphenidate have not been shown clearly. This review presents some neurobiological and physiopathogenic aspects, common to ADHD and epilepsy, from recent research studies, related to pharmacology, neuroimaging and electroencephalography. Possible risk of occurrence of seizures associated with the use of methylphenidate are also discussed.

A associação entre transtorno de déficit de atenção / hiperatividade (TDAH) e epilepsia pode causar importante impacto na vida social dos indivíduos afetados e seus familiares. Estudos clínicos sugerem que 30-40 por cento das pessoas com epilepsia também apresentam TDAH. Não existem publicações que evidenciem que o tratamento a curto ou longo prazo com metilfenidato aumente o risco de ocorrência de crises epilépticas, e alguns estudos procuram relacionar as interações medicamentosas entre o metilfenidato e as drogas antiepilépticas, porém não foram demonstrados os possíveis efeitos do metilfenidato de uma maneira clara. Apresenta-se a seguir, revisão sobre os aspectos neurobiológicos e fisiopatogênicos comuns ao TDAH e epilepsia, a partir de pesquisas recentes relacionadas a estudos de farmacologia, neuroimagem e eletroencefalografia, e discuti-se os possíveis riscos da ocorrência de crises epilépticas associadas ao uso de metilfenidato.

Griscelli syndrome: characterization of a new mutation and rescue of T-cytotoxic activity by retroviral transfer of RAB27A gene.

Griscelli syndrome (GS) is caused by mutations in the MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) genes, all of which lead to a similar pigmentary dilution. In addition, GS1 patients show primary neurological impairment, whereas GS2 patients present immunodeficiency and periods of lymphocyte proliferation and activation, leading to their infiltration in many organs, such as the nervous system, causing secondary neurological damage. We report the diagnosis of GS2 in a 4-year-old child with haemophagocytic syndrome, immunodeficiency, and secondary neurological disorders. Typical melanosome accumulation was found in skin melanocytes and pigment clumps were observed in hair shafts. Two heterozygous mutant alleles of the RAB27A gene were found, a C-T transition (C352T) that leads to Q118stop and a G-C transversion on the exon 5 splicing donor site (G467+1C). Functional assays showed increased cellular activation and decreased cytotoxic activity of NK and CD8+ T cells, associated with defective lytic granules release. Myosin-Va expression and localization in the patient lymphocytes were also analyzed. Most importantly, we show that cytotoxic activity of the patient's CD8+ T lymphocytes can be rescued in vitro by RAB27A gene transfer mediated by a recombinant retroviral vector, a first step towards a potential treatment of the acute phase of GS2 by RAB27A transduced lymphocytes.

Encefalopatia necrotizante aguda: paciente com evolução recidivante e letal / Acute necrotizing encephalopathy: patient with a relapsing and lethal evolution

A encefalopatia necrotizante aguda foi descrita inicialmente em crianças japonesas e se caracteriza por rápida evolução e lesões simétricas no tronco encefálico, cerebelo e especialmente nos tálamos. Avaliamos uma menina de 7 meses de idade, que apresentou dois episódios de depressão da consciência de rápida instalação e paresias, sem alterações metabólicas. Houve uma rápida melhora na primeira crise, porém o segundo episódio foi fulminante, tendo evoluído para estado de morte encefálica em dois dias. Os estudos de ressonância magnética mostraram lesões simétricas nos tálamos e acometimento também do tronco encefálico e cerebelo.

Acute necrotizing encephalopathy was initially reported in Japanese children. The rapid evolution and symmetrical brain lesions seen in the brainstem, cerebellum and specially in the thalamus characterize the disease. We studied a 7-month-old-girl, who presented with two episodes of rapid loss of consciousness and paresis without metabolic disturbances. At the first time she had a rapid improvement, but at the second episode the course was fulminant and in two days she lapsed into a clinical state of brain death. The magnetic resonance studies showed symmetrical lesions in the thalamus and additional lesions involving the brainstem and the cerebellum.