A novel human Cdh1 mutation impairs anaphase promoting complex/cyclosome activity resulting in microcephaly, psychomotor retardation, and epilepsy.

The Fizzy-related protein 1 (Fzr1) gene encodes Cdh1 protein, a coactivator of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). Previously, we found that genetic ablation of Fzr1 promotes the death of neural progenitor cells leading to neurogenesis impairment and microcephaly in mouse. To ascertain the possible translation of these findings in humans, we searched for mutations in the Fzr1 gene in 390 whole exomes sequenced in trio in individuals showing neurodevelopmental disorders compatible with a genetic origin. We found a novel missense (p.Asp187Gly) Fzr1 gene mutation (c.560A>G) in a heterozygous state in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, psychomotor retardation, and refractory epilepsy. Cdh1 protein levels in leucocytes isolated from the patient were significantly lower than those found in his parents. Expression of the Asp187Gly mutant form of Cdh1 in human embryonic kidney 293T cells produced less Cdh1 protein and APC/C activity, resulting in altered cell cycle distribution when compared with cells expressing wild-type Cdh1. Furthermore, ectopic expression of the Asp187Gly mutant form of Cdh1 in cortical progenitor cells in primary culture failed to abolish the enlargement of the replicative phase caused by knockout of endogenous Cdh1. These results indicate that the loss of function of APC/C-Cdh1 caused by Cdh1 Asp187Gly mutation is a new cause of prenatal microcephaly, psychomotor retardation, and severe epilepsy. Read the Editorial Highlight for this article on page 8. Cover Image for this issue: doi: 10.1111/jnc.14524.

[Attention deficit/hyperactivity disorder. Study habits]. / Trastorno por déficit de atención/hiperactividad. Hábitos de estudio.

Attention deficit / hyperactivity disorder (ADHD) is one of the most prevalent disorders in the child-youth population, with a known impact on learning and school performance. Lack of attention, associated executive dysfunction and comorbid problems -particularly those related to learning and anxiety-, strongly determine this conceptual domain. Affected youths have more problems for taking notes, completion of homework, school programming and less motivation to study. Despite greater dedication to homework and greater use of support resources, school failure and nonachievement of curricular objectives are more frequent in these patients. The early diagnosis of ADHD and its comorbidities, the adequate and individualized psychoeducational and pharmacological intervention, have been shown to improve academic prognosis in the short and long term. For this purpose, the active participation of health and education professionals is essential.

El trastorno por déficit de atención/hiperactividad (TDAH) es uno de los trastornos más prevalentes en la población infanto-juvenil, con un impacto ya conocido sobre el aprendizaje y rendimiento escolar. La falta de atención, la disfunción ejecutiva asociada y los problemas comórbidos ­particularmente los relacionados con el aprendizaje y la ansiedad­, condicionan marcadamente este dominio conceptual. Los jóvenes afectos, tienen más problemas para la toma de apuntes, finalización de trabajos, programación escolar y menor motivación al estudio. A pesar de una mayor dedicación al estudio y mayor uso de recursos de apoyo, el fracaso escolar y la no consecución de objetivos curriculares son más frecuentes en estos pacientes. El diagnóstico temprano del TDAH y sus comorbilidades, la intervención psicoeducativa y farmacológica adecuada e individualizada, han demostrado mejorar el pronóstico académico a corto y largo plazo. Para este propósito, es imprescindible la participación activa de profesionales de la salud y la educación.

Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases.

BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS. METHODS: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype. RESULTS: The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America. CONCLUSIONS: This study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS.

CDKL5 Deficiency Disorder Without Epilepsy.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) has epilepsy as a cardinal feature. Here we report two new female patients and review six previously published patients, one male and five females, with features of CDD but who never developed epilepsy. In contrast with the classical and severe CDD phenotype, they presented with milder gross motor delays, autism spectrum disorder, and no visual cortical impairment. Prolonged video electroencephalography was normal in adult cases but showed interictal frontal-temporal bilateral spikes and sharp waves in sleep in the three-year-old girl. Causative CDKL5 variants included two likely gene damaging (nonsense and frameshift) and six missense variants, being de novo or maternally inherited from asymptomatic females with skewed X-chromosome inactivation (two missense variants). Our data indicate that a milder form of CDD without epilepsy can occur in some cases without clear correlation with specific variants in the CDKL5 gene.

[Neuropsychological deficit, symptom intensity and functional impairment in attention deficit hyperactivity disorder]. / Déficits neuropsicológicos, intensidad sintomática y repercusión funcional en el trastorno por déficit de atención con hiperactividad.

This study aims to contribute to a better understanding of attention deficit hyperactivity disorder (ADHD) by comprehensively examining the relationship between two of the main cognitive deficits of the disorder (attention and inhibitory control), symptomatology (inattention and hyperactivity/impulsivity) and functional impairment in 85 children and adolescents with ADHD without other comorbid disorders. We found, independent of general intellectual functioning and age, that i) greater attentional and inhibitory deficits predicted greater severity of ADHD symptoms, ii) greater attentional and inhibitory deficits predicted greater functional impairment, but not in a direct way but through symptoms, and iii) greater symptomatic severity predicted greater functional impairment. Beginning to explore and understand the complexity of ADHD is key to advance our knowledge of the disorder and for correct clinical decision making.

Este estudio pretende contribuir a una mejor comprensión del trastorno por déficit de atención con hiperactividad (TDAH) examinado de manera exhaustiva la relación entre dos de los principales déficits cognitivos del trastorno (la atención y el control inhibitorio), la sintomatología (falta de atención e hiperactividad / impulsividad) y la repercusión funcional en 85 niños/as y adolescentes con TDAH sin otros trastornos comórbidos. Encontramos, con independencia del funcionamiento intelectual general y de la edad, que i) un mayor déficit atencional e inhibitorio, predijo una mayor gravedad de los síntomas del TDAH, ii) un mayor déficit atencional e inhibitorio predijo un mayor deterioro funcional, pero no de una manera directa sino a través de los síntomas, y iii) una mayor severidad sintomática predijo una mayor repercusión funcional. Comenzar a explorar y comprender la complejidad del TDAH es clave para avanzar en nuestro conocimiento del trastorno y para la correcta toma de decisiones clínicas.

Lower immunglobulin A levels but not lower cortisol or α-amylase activity in children with chronic tension-type headache.

OBJECTIVE: The study was designed to investigate the differences in salivary cortisol (hypothalamic-pituitary-adrenocortical [HPA] axis), immunoglobulin A (IgA) (immune system) concentrations and α-amylase (sympathetic nervous system [SNS]) activity between children with chronic tension-type headache (CTTH) and healthy children. METHODS: Thirty-six children, 10 boys and 26 girls (age: 9 ± 2 years) with CTTH and 36 age- and sex-matched healthy children were recruited. Salivary cortisol, α-amylase activity, salivary flow rate, IgA concentration and IgA rate were collected from non-stimulated saliva. A headache diary was used for collecting data on intensity, frequency and duration of headache for four weeks. RESULTS: Children with CTTH showed lower IgA concentration (p = .008) and IgA rate (p = .039), but not lower cortisol concentration (p = .447), salivary flow rate (p = .289) or α-amylase activity (p = .559), as compared to healthy children. Neither age (p > .582) nor gender (p > .227) influenced salivary markers. A significant association between the number of years with headache and IgA concentration (r(s) = - 0.385; p = .023) was found: the greater the number of years with headache, the lower the IgA concentration. CONCLUSIONS: These results suggest that children with CTTH present with deficits in the immune system, but not dysfunction in the HPA axis or SNS. Future studies are needed to elucidate the direction of these relationships.

Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache.

Our aim was to investigate the relationship between Val158Met polymorphisms, headache, and pressure hypersensitivity in children with chronic tension-type headache (CTTH). A case-control study with blinded assessor was conducted. Seventy children with CTTH associated with pericranial tenderness and 70 healthy children participated. After amplifying Val158Met polymorphism by polymerase chain reactions, we assessed genotype frequencies and allele distributions. We classified children according to their Val158Met polymorphism: Val/Val, Val/Met, Met/Met. Pressure pain thresholds (PPT) were bilaterally assessed over the temporalis, upper trapezius, second metacarpal, and tibialis anterior muscles. The distribution of Val158Met genotypes was not significantly different (p = 0.335), between children with CTTH and healthy children, and between boys and girls (p = 0.872). Children with CTTH with the Met/Met genotype showed a longer headache history compared with those with Met/Val (p = 0.001) or Val/Val (p = 0.002) genotype. Children with CTTH with Met/Met genotype showed lower PPT over upper trapezius and temporalis muscles than children with CTTH with Met/Val or Val/Val genotype (p < 0.01). The Val158Met catechol-O-methyltransferase (COMT) polymorphism does not appear to be involved in predisposition to suffer from CTTH in children; nevertheless, this genetic factor may be involved in the phenotypic expression, as pressure hypersensitivity was greater in those CTTH children with the Met/Met genotype.

Prevalence and anatomical localization of muscle referred pain from active trigger points in head and neck musculature in adults and children with chronic tension-type headache.

OBJECTIVE: To compare differences in the prevalence and the anatomical localization of the referred pain areas of active trigger points (TrPs) in head and neck musculature between adults and children with chronic tension-type headache (CTTH). DESIGN: A cross-sectional study. SETTING: Some studies had found that referred pain from active TrPs reproduce the head pain pattern in adults. No study has compared clinical differences between referred pain patterns elicited by active TrPs between adults and children with CTTH. PATIENTS: Twenty adults (10 men, 10 women, mean age: 41 ± 11 years) and 20 children (10 boys, 10 girls, mean age: 8 ± 2 years) with CTTH were included. OUTCOME MEASURES: Bilateral temporalis, sternocleidomastoid, upper trapezius, and suboccipital muscles were examined for TrPs. TrPs were identified by palpation and considered active when local and referred pains reproduce the headache pain attacks. The referred pain areas were drawn on anatomical maps, digitalized, and also measured. An analysis technique based on a center of gravity (COG) method was used to provide a quantitative estimate of the localization of the TrP referred pain areas. RESULTS: Adults with CTTH exhibited a greater years with headache, higher intensity, and longer headache duration (P < 0.05) compared with children. The COG coordinates of the spontaneous pain on the dominant side were located more anterior (higher X-value), and spontaneous pain in the frontal and posterior areas was located more inferior (lower Y-value) in adults than in children. The number of active muscle TrPs was significantly higher (P = 0.001) in adults with CTTH (mean ± standard deviation [SD]: 4 ± 0.8) as compared with children (mean ± SD: 3 ± 0.7). Children with CTTH had larger referred pain areas than adults for upper trapezius, sternocleidomastoid, and temporalis (P < 0.001) muscles. The COG coordinates of the referred pain areas of temporalis and sternocleidomastoid muscle TrPs were more inferior (lower Y-values) in adults than in children with CTTH. CONCLUSIONS: This study showed that the referred pain elicited from active TrPs shared similar pain patterns as spontaneous CTTH in adults and children. Differences in TrP prevalence and location of the referred pain areas can be observed between adults and children with CTTH.

Salivary cortisol and melatonin levels in children with frequent episodic tension-type headache do not differ from healthy children.

AIM: To investigate the differences in cortisol and melatonin concentrations between children with frequent episodic tension-type headache (FETTH) and healthy children. METHODS: Forty-four children, 12 boys/32 girls (age: 9 ± 2 years) with FETTH associated to peri-cranial tenderness and 44 age- and sex- matched healthy children participated. Both salivary cortisol and melatonin concentrations were collected from non-stimulated saliva following standardized guidelines. A headache diary for 4 weeks was used for collecting intensity, frequency and duration of headache. RESULTS: No significant differences for cortisol (t = -0.431; p = 0.668), and melatonin (z = -1.564; p = 0.118) concentrations and salivary flow rate (z = -1.190; p = 0.234) were found between both groups. No significant effect of age or gender was found. In addition, no significant association between cortisol-melatonin concentrations and between cortisol-melatonin concentrations and headache clinical parameters were found. CONCLUSION: These results suggest that children with FETTH, at first instance, do not present deficits in the secretion of these cortisol and melatonin. Prospective longitudinal studies are needed to further elucidate the direction of current findings, particularly the synchronism of cortisol and melatonin and the course of the headache.

Referred pain from myofascial trigger points in head and neck-shoulder muscles reproduces head pain features in children with chronic tension type headache.

Our aim was to describe the referred pain pattern and areas from trigger points (TrPs) in head, neck, and shoulder muscles in children with chronic tension type headache (CTTH). Fifty children (14 boys, 36 girls, mean age: 8 ± 2) with CTTH and 50 age- and sex- matched children participated. Bilateral temporalis, masseter, superior oblique, upper trapezius, sternocleidomastoid, suboccipital, and levator scapula muscles were examined for TrPs by an assessor blinded to the children's condition. TrPs were identified with palpation and considered active when local and referred pains reproduce headache pain attacks. The referred pain areas were drawn on anatomical maps, digitalized, and also measured. The total number of TrPs was significantly greater in children with CTTH as compared to healthy children (P < 0.001). Active TrPs were only present in children with CTTH (P < 0.001). Within children with CTTH, a significant positive association between the number of active TrPs and headache duration (r (s) = 0.315; P = 0.026) was observed: the greater the number of active TrPs, the longer the duration of headache attack. Significant differences in referred pain areas between groups (P < 0.001) and muscles (P < 0.001) were found: the referred pain areas were larger in CTTH children (P < 0.001), and the referred pain area elicited by suboccipital TrPs was larger than the referred pain from the remaining TrPs (P < 0.001). Significant positive correlations between some headache clinical parameters and the size of the referred pain area were found. Our results showed that the local and referred pains elicited from active TrPs in head, neck and shoulder shared similar pain pattern as spontaneous CTTH in children, supporting a relevant role of active TrPs in CTTH in children.

[Attention deficit hyperactivity disorder and its relation to social skills and leadership evaluated with an evaluation system of the behavior of children and adolescents (BASC)]. / Trastorno por déficit de atención/hiperactividad y su relación con las habilidades sociales y de liderazgo evaluadas a través de un sistema de evaluación de la conducta de niños y adolescentes (BASC).

INTRODUCTION: Numerous studies have documented that children with attention deficit hyperactivity disorder (ADHD) show a low social competence. OBJECTIVE: To compare the symptomatic severity of ADHD, as well as associations to different subtypes, sex and comorbidities, with social functioning ("ability" and "leadership") estimated through a Behavior Assessment System for Children (BASC) for parents and teachers. PATIENTS AND METHODS: We have retrospectively analyzed 170 patients with ADHD, diagnosed between 2007 and 2010. Social "ability," "leadership," "hyperactivity" and "attention deficit" sections of BASC and cardinal symptoms of ADHD measured through a Spanish scale for de evaluation of DHD (E-DHD) were registered. Results of these variables are analyzed according to the normative data by age and sex, and processed in Z values. RESULTS: The ratings for social skills were significantly lower in patients with conduct disorder or oppositional defiant disorder as informed by parents (p<0.05). Symptomatic intensity of ADHD showed significant (p<0,001) and inverse relation with social "ability" as parents. "Attention-deficit" scores were related with social "ability" and "leadership" as parents and teachers. CONCLUSIONS: Intensity of attention deficit was the only variable that showed a significant relation with the social skills and leadership according to the BASC scores, independently of the informer.

Bilateral, wide-spread, mechanical pain sensitivity in children with frequent episodic tension-type headache suggesting impairment in central nociceptive processing.

INTRODUCTION: The aim was to investigate bilateral, wide-spread pressure pain hyperalgesia in symptomatic (trigeminocervical) and non-symptomatic (pain-free distant) regions in children with frequent episodic tension-type headache (FETTH). METHODS: Twenty-five children, 6 boys and 19 girls (mean age, 8.9 +/- 1.8 years) with FETTH and 50 age- and sex-matched healthy children (12 boys, 38 girls; mean age: 8.8 +/- 1.7 years) were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over temporalis muscle, upper trapezius muscle, second metacarpal and tibialis anterior muscles in a blinded design. RESULTS: The results showed that PPT levels were significantly decreased bilaterally over the temporalis, upper trapezius and tibialis muscles, and the second metacarpal in children with FETTH as compared to controls (all sites, P < 0.001). No significant differences in the magnitude of PPT decrease between the upper trapezius muscle, second metacarpal and tibialis anterior muscles were found. PPT over both upper trapezius muscles were negatively correlated with the history and intensity of headache (r(s) = -0.415; P = 0.045). CONCLUSIONS: The findings revealed bilateral, wide-spread pressure pain hypersensitivity in children with FETTH suggesting that wide-spread central sensitisation is involved in children with this headache pain condition.

Restricted neck mobility in children with chronic tension type headache: a blinded, controlled study.

The main purpose of this study was to analyze the differences in neck mobility between children with chronic tension type headache (CTTH) and healthy children, and to determine the influence of cervical mobility on headache intensity, frequency and duration. Fifty children, 13 boys and 37 girls (mean age 8.5 ± 1.6 years) with CTTH associated to peri-cranial tenderness (IHS 2.3.1) and 50 age- and sex matched children without headache (13 boys, 37 girls, mean age 8.5 ± 1.8 years, P = 0.955) participated. Cervical range of motion (CROM) was objectively assessed with a cervical goniometer by an assessor blinded to the children's condition. Children completed a headache diary for 4 weeks to confirm the diagnosis. Children with CTTH showed decreased CROM as compared to children without headache for flexion (z = -6.170; P < 0.001), extension (z = -4.230; P < 0.001), right (z = -4.505; P < 0.001) and left (z = -4.768; P < 0.001) lateral-flexions, but not for rotation (right z = -0.802; P = 0.425; left z = -1.254; P = 0.213) and also for total range of motion for flexion-extension (z = -4.267; P < 0.001) and lateral-flexion (z = -4.801; P < 0.001), but not for rotation (z = -1.058; P = 0.293). Within CTTH children, CROM was not correlated with headache intensity, frequency or duration. Additionally, age (P > 0.125) or gender (P > 0.250) did not influence CROM in either children with CTTH or without headache. Current results support the hypothesis that the cervical spine should be explored in children with headache. Further research is also needed to clearly define the potential role of the cervical spine in the genesis or maintenance of CTTH.

[Genetic studies and neurodevelopment. From effectiveness to genetic models]. / Estudios genéticos y neurodesarrollo. De la utilidad al modelo genético.

Advances in genetics have been able to support the clinical suspicion on the large hereditary component of most of these neurodevelopmental disorders (NDD). Initial studies on heritability, linkage or association showed from the beginning the great contribution of genotypic variation to the clinic in general, and to NDD in particular. The effectiveness of genetic studies in clinical practice, targeted to aetiological diagnosis, should not be ignored. Most of these are protocolized in the study of disorders such as intellectual disability and autism; within these, the array comparative genomic hybridization have supported a greater diagnostic effectiveness with respect to historical cytogenetic techniques (3 vs. 10% respectively). However, the irruption and success of molecular genetic sequencing techniques, particularly the exome and genome in trio, analyzing the parents (diagnostic rates of 30-50%), are conditioning the modification of the genetic algorithms in the diagnosis of different NDD. The greater knowledge of causal variants in intellectual disability and autism is also modifying the polygenic theoretical models established to date.

Los avances en la genética han podido apoyar la sospecha que aportaba la experiencia clínica sobre el gran componente hereditario de la mayor parte de estos trastornos del neurodesarrollo (TND). Los estudios iniciales de heredabilidad, ligamiento o asociación evidenciaron desde los inicios la gran contribución de la variación genotípica a la clínica en general, y a los TND en particular. No debe obviarse la utilidad de los estudios genéticos en el ejercicio clínico, encaminados al diagnóstico etiológico. La mayor parte de los mismos están protocolizados en el estudio de trastornos como la discapacidad intelectual y el autismo; dentro de éstos, la hibridación por arrays cromosómicos ha aportado una mayor rentabilidad diagnóstica respecto a técnicas citogenéticas históricas (3 vs. 10% respectivamente). Sin embargo, la irrupción y rentabilidad de técnicas de genética molecular por secuenciación, particularmente la exómica y genómica en trío, analizando a padres, (tasas diagnósticas del 30-50%), están condicionando la modificación de los algoritmos genéticos en el diagnóstico de trastornos graves del neurodesarrollo. El mayor conocimiento de variantes causales de discapacidad intelectual y autismo está igualmente modificando los modelos teóricos poligénicos establecidos hasta la fecha.

[Rett syndrome: 50 years' history of a still not well known condition]. / Síndrome de Rett: 50 años de historia de un trastorno aun no bien conocido.

Since it was first described by Andrea Rett 50 years ago, Rett syndrome (RS) has been the subject of further investigations, nonetheless it continues to be a not well known condition. Our own experience and an updated literature review on RS is presented. RS is a severe dominant X chromosome-linked neurodevelopmental disorder with a characteristic clinical picture that mostly occurs in girls, most of the cases are sporadic and genetically determined. The diagnosis of RS is made based on observation and clinical assessment. Main clinical features are mental retardation, behavioural changes, stereotypes, loss of speech and hand skills, gait apraxia, irregular breathing with hyperventilation while awake, and frequent seizures. The internationally established criteria are reviewed. RS is caused by mutations in MECP2 in the majority of cases, but a proportion of atypical cases may result from mutations in CDKL5, particularly the early onset seizure variant. However, the molecular pathogenesis of this disorder remains unclear, as well as the relation between the mutations in MECP2 and other neurodevelopmental disorders. Neuroimaging, neuropathological and biochemical findings in RS are reviewed. Besides symptomatic treatment, no therapeutic trials have shown effectiveness. Some perspectives in the treatment of RS have been provided by a recent work showing a phenotypic reversal by activation of MeCP2 expression in a mouse model.

Déficits neuropsicológicos, intensidad sintomática y repercusión funcional en el trastorno por déficit de atención con hiperactividad / Neuropsychological deficits, symptom intensity and functional impairment in attention deficit hyperactivity disorder

Resumen Este estudio pretende contribuir a una mejor comprensión del trastorno por déficit de atención con hiperactividad (TDAH) examinado de manera exhaustiva la relación entre dos de los principales déficits cognitivos del trastorno (la atención y el control inhibitorio), la sintomatología (falta de atención e hipe ractividad/impulsividad) y la repercusión funcional en 85 niños/as y adolescentes con TDAH sin otros trastornos comórbidos. Encontramos, con independencia del funcionamiento intelectual general y de la edad, que i) un mayor déficit atencional e inhibitorio, predijo una mayor gravedad de los síntomas del TDAH, ii) un mayor déficit atencional e inhibitorio predijo un mayor deterioro funcional, pero no de una manera directa sino a través de los síntomas, y iii) una mayor severidad sintomática predijo una mayor repercusión funcional. Comenzar a explorar y comprender la complejidad del TDAH es clave para avanzar en nuestro conocimiento del trastorno y para la correcta toma de decisiones clínicas.

Abstract This study aims to contribute to a better understanding of at tention deficit hyperactivity disorder (ADHD) by comprehensively examining the relationship between two of the main cognitive deficits of the disorder (attention and inhibitory control), symptomatology (inattention and hyperactivity/impulsivity) and functional impairment in 85 children and adolescents with ADHD without other comorbid disorders. We found, independent of general intellectual functioning and age, that i) greater atten tional and inhibitory deficits predicted greater severity of ADHD symptoms, ii) greater attentional and inhibitory deficits predicted greater functional impairment, but not in a direct way but through symptoms, and iii) greater symptomatic severity predicted greater functional impairment. Beginning to explore and understand the com plexity of ADHD is key to advance our knowledge of the disorder and for correct clinical decision making.

Estudios genéticos y neurodesarrollo: De la utilidad al modelo genético / Genetic studies and neurodevelopment. From effectiveness to genetic models]

Los avances en la genética han podido apoyar la sospecha que aportaba la experiencia clínica sobre el gran componente hereditario de la mayor parte de estos trastornos del neurodesarrollo (TND). Los estudios iniciales de heredabilidad, ligamiento o asociación evidenciaron desde los inicios la gran contribución de la variación genotípica a la clínica en general, y a los TND en particular. No debe obviarse la utilidad de los estudios genéticos en el ejercicio clínico, encaminados al diagnóstico etiológico. La mayor parte de los mismos están protocolizados en el estudio de trastornos como la discapacidad intelectual y el autismo; dentro de éstos, la hibridación por arrays cromosómicos ha aportado una mayor rentabilidad diagnóstica respecto a técnicas citogenéticas históricas (3 vs. 10% respectivamente). Sin embargo, la irrupción y rentabilidad de técnicas de genética molecular por secuenciación, particularmente la exómica y genómica en trío, analizando a padres, (tasas diagnósticas del 30-50%), están condicionando la modificación de los algoritmos genéticos en el diagnóstico de trastornos graves del neurodesarrollo. El mayor conocimiento de variantes causales de discapacidad intelectual y autismo está igualmente modificando los modelos teóricos poligénicos establecidos hasta la fecha.

Advances in genetics have been able to support the clinical suspicion on the large hereditary component of most of these neurodevelopmental disorders (NDD). Initial studies on heritability, linkage or association showed from the beginning the great contribution of genotypic variation to the clinic in general, and to NDD in particular. The effectiveness of genetic studies in clinical practice, targeted to aetiological diagnosis, should not be ignored. Most of these are protocolized in the study of disorders such as intellectual disability and autism; within these, the array comparative genomic hybridization have supported a greater diagnostic effectiveness with respect to historical cytogenetic techniques (3 vs. 10% respectively). However, the irruption and success of molecular genetic sequencing techniques, particularly the exome and genome in trio, analyzing the parents (diagnostic rates of 30-50%), are conditioning the modification of the genetic algorithms in the diagnosis of different NDD. The greater knowledge of causal variants in intellectual disability and autism is also modifying the polygenic theoretical models established to date.

Trastorno por déficit de atención/hiperactividad: Hábitos de estudio / Attention deficit/hyperactivity disorder. Study habits

El trastorno por déficit de atención/hiperactividad (TDAH) es uno de los trastornos más prevalentes en la población infanto-juvenil, con un impacto ya conocido sobre el aprendizaje y rendimiento escolar. La falta de atención, la disfunción ejecutiva asociada y los problemas comórbidos -particularmente los relacionados con el aprendizaje y la ansiedad-, condicionan marcadamente este dominio conceptual. Los jóvenes afectos, tienen más problemas para la toma de apuntes, finalización de trabajos, programación escolar y menor motivación al estudio. A pesar de una mayor dedicación al estudio y mayor uso de recursos de apoyo, el fracaso escolar y la no consecución de objetivos curriculares son más frecuentes en estos pacientes. El diagnóstico temprano del TDAH y sus comorbilidades, la intervención psicoeducativa y farmacológica adecuada e individualizada, han demostrado mejorar el pronóstico académico a corto y largo plazo. Para este propósito, es imprescindible la participación activa de profesionales de la salud y la educación.

Attention deficit / hyperactivity disorder (ADHD) is one of the most prevalent disorders in the child-youth population, with a known impact on learning and school performance. Lack of attention, associated executive dysfunction and comorbid problems -particularly those related to learning and anxiety-, strongly determine this conceptual domain. Affected youths have more problems for taking notes, completion of homework, school programming and less motivation to study. Despite greater dedication to homework and greater use of support resources, school failure and non-achievement of curricular objectives are more frequent in these patients. The early diagnosis of ADHD and its comorbidities, the adequate and individualized psychoeducational and pharmacological intervention, have been shown to improve academic prognosis in the short and long term. For this purpose, the active participation of health and education professionals is essential.

Generalized mechanical nerve pain hypersensitivity in children with episodic tension-type headache.

OBJECTIVES: The objective of this study was to analyze the presence of generalized pressure pain hypersensitivity over nerve tissues in trigeminal and nontrigeminal regions in children with frequent episodic tension-type headache (FETTH). METHODS: Thirty children, 7 boys and 23 girls (mean age: 8.8 +/- 1.7 years) with FETTH and 50 age- and gender-matched healthy children (14 boys, 36 girls; mean age: 8.5 +/- 2.1 years; P = .743) were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over supra-orbital (V1), infra-orbital (V2), mental (V3), median (C5), radial (C6), and ulnar (C7) nerves by an assessor who was blinded to the patient's condition. RESULTS: The analysis of variance showed that PPT levels were significantly bilaterally decreased over both trigeminal (supra-orbital, infra-orbital, and mental) and nontrigeminal (median, ulnar, and radial) nerves in children with FETTH as compared with control subjects (all sites, P < .001). There was a greater magnitude of PPT decrease within trigeminal nerves as compared with nontrigeminal nerves (P < .03). PPTs over infra-orbital (r(s) = -0.4, P < .05) and radial (r(s) = -0.5, P < .01) nerves were negatively correlated with the duration of headache attacks (P < .05). CONCLUSIONS: Our study revealed bilateral and generalized pressure hypersensitivity over both trigeminal and nontrigeminal nerves in children with FETTH. Diffuse hypersensitivity of peripheral nerves evidences the presence of hyperexcitability of the central nervous system in children with FETTH.