Acquisition of Developmental Milestones in Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum and Other TUBB4A-Related Leukoencephalopathy.

Mutations in TUBB4A are associated with a spectrum of neurologic disorders categorized as TUBB4A-related leukoencephalopathy. Affected children can present with global developmental delay or normal early development, followed by a variable loss of skills over time. Further research is needed to characterize the factors associated with the divergent developmental trajectories in this rare monogenic disorder because this phenotypic spectrum is not fully explained by genotype alone.To characterize early psychomotor features, developmental milestones and age of disease onset were collected from medical records (n=54 individuals). Three subcohorts were identified: individuals with the common p.Asp249Asn variant vs all other genotypes with either early (<12 months of age) or late onset of presentation. Individuals with the p.Asp249Asn variant or those with non-p.Asp249Asn genotypes with later disease onset attained key milestones, including head control, sitting, and independent walking. Subjects with early-onset, non-p.Asp249Asn-associated disease were less likely to achieve developmental milestones. Next, we defined the developmental severity as the percentage of milestones attained by age 2 years. The mild form was defined as attaining at least 75% of key developmental milestones. Among cohort categorized as mild, individuals with p.Asp249Asn variant were more likely to lose acquired abilities when compared with non-p.Asp249Asn individuals.Our results suggest multiple influences on developmental trajectory, including a strong contribution from genotype and age of onset. Further studies are needed to identify additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10.

PYCR2 pathogenic variants lead to an autosomal recessive hypomyelinating leukodystrophy 10 (HLD10), characterized by global developmental delay, microcephaly, facial dysmorphism, movement disorder, and hypomyelination. This study identified the first two unrelated Thai patients with HLD10. Patient 1 harbored the novel compound heterozygous variants, c.257T>G (p.Val86Gly) and c.400G>A (p.Val134Met), whereas patient 2 possessed the homozygous variant, c.400G>A (p.Val134Met), in PYCR2. Haplotype analysis revealed that the two families' members shared a 2.3 Mb region covering the c.400G>A variant, indicating a common ancestry. The variant was estimated to age 1450 years ago. Since the c.400G>A was detected in three out of four mutant alleles and with a common ancestry, this variant might be common in Thai patients. We also reviewed the phenotype and genotype of all 35 previously reported PYCR2 patients and found that majorities of cases were homozygous with a consanguineous family history, except patient 1 and another reported case who were compound heterozygous. All patients had microcephaly and developmental delay. Hypotonia and peripheral spasticity were common. Hypomyelination or delayed myelination was a typical radiographic feature. Here, we report the first two Thai patients with HLD10 with the novel PYCR2 variants expanding the genotypic spectrum and suggest that the c.400G>A might be a common mutation in Thai patients.

Dynamic disequilibrium of macromolecular transport as possible mechanism for hydrocephalus associated with long-term spaceflight.

Hydrocephalus associated with long term spaceflight (HALS) for missions lasting over five months is well described but poorly understood. While structural changes of the brain due to microgravitational forces affecting the circulation of cerebrospinal fluid (CSF) have been described as one potential cause, we propose an alternative hypothesis based on dynamic disequilibrium of macromolecular transport across the blood brain barrier. We propose that factors altering physiology under conditions of spaceflight such as microgravity, hypercapnia, venous hypertension, medications, and dietary substances contribute to increased protein load in the ventricles and/or contribute to impairment of transport out of the ventricles that results in HALS. Individual variation in the genetic expression of efflux transporters (p-glycoprotein) has been shown to correlate with the presence and degree of hydrocephalus in animal studies. We describe the evidence behind this concept and propose how these factors can be studied in order to determine the underlying pathogenesis which is imperative in order to cure or prevent HALS.

Seguimiento fisioterápico a lo largo de 14 meses a niño con síndrome de Sandifer / A 14-month physiotherapy follow up to a child with Sandifer syndrome

INTRODUCCIÓN: El síndrome de Sandifer fue descrito en 1964 por el neurólogo Paul Sandifer cuando detectó un trastorno del tracto gastrointestinal superior, que generaba enfermedad de reflujo gastroesofágico, especialmente en bebés y recién nacidos. Suele presentarse con esofagitis, anemia ferropénica y movimientos posturales paroxísticos relacionados con la ingesta, que remiten durante el sueño. Puede provocar en el niño un retraso psicomotor y, por lo tanto, la detección y la identificación precoz de los signos son fundamentales. Con respeto al tratamiento no farmacológico, la estimulación precoz resulta imprescindible en el proceso de aprendizaje y la consolidación de hitos psicomotrices. El tratamiento consiste en estimular al niño mediante el juego activo para la progresión psicomotora y trabajar las alteraciones perceptivas y sensoriales evitando el dolor. CASO CLÍNICO: Lactante de ocho meses con retraso psicomotor derivado a Atención Temprana desde el ámbito hospitalario. Presenta hiperextensión de cuello, hipotonía cervicoaxial, rechazo del decúbito prono, opistótonos en decúbito supino y regurgitaciones esporádicas. A nivel motriz no tiene ninguna vía de desplazamiento y tampoco mantiene la sedestación; en cuanto a la manipulación, aún no choca juguetes. A nivel comunicativo, el contacto es bueno, pero no señala objetos ni emite bisílabos. COMENTARIOS: Después de catorce meses de Atención Temprana (Fisioterapia), el niño sube y baja escaleras cogido de la barandilla con una mano y puede levantarse del suelo casi solo. Además, puede realizar encajes complejos, con dominancia de la mano derecha. A nivel cognitivo-comunicativo comprende los conceptos de permanencia y de acción-reacción, repite muchas palabras y emite de forma espontánea más de diez palabras. La colaboración familiar aplicando las pautas recomendadas ha sido una pieza clave en el tratamiento. Así, las pautas aplicadas en diversos entornos facilitaron la consecución de hitos motrices y el afianzamiento de etapas

INTRODUCTION: The Sandifer's Syndrome was described in 1964 by the neurologist Paul Sandifer when detected a disorder of the upper gastrointestinal tract that generated gastroesophageal reflux disease, especially in new-borns and children. It tends to present with esophagitis, iron deficiency anemia and paroxysmal postural movements. These symptoms are related with the ingestion and they use to remit during the sleep. This syndrome generates to the child a psychomotor delay and, therefore, the Early Care is essential to detect and to identify all the signs early; always focusing on the process of learning and consolidation of psychomotor achievements. Thus, the treatment consists of stimulating the child trough the active game to get the psychomotor progression, working on perceptual and sensory changes, and avoiding pain during the intervention. CASE REPORT: 8-month-old lactating child with psycmotor delay referred to Early Care from Hospital. The baby presents neck hyperextension, cervicoaxial hypotonia, rejection of the prone position, opisthotonus in supine position and sporadic regurgitations. The child can not move neither maintains the sedestation. Furthermore, he does not hit toys; he has good contact but does not point out objects and does not emit bisyllables. COMMENTS: After fourteen months of Early Care (Physiotherapy), the toddler can up and down the stairs grabbed to the railing with one hand and he gets up from the ground practically alone. He can make more complex lace with dominance of the right hand. The toddler understands concepts of permanence and of action-reaction; and he repeats many words and emits more than ten words spontaneously. The family collaboration by applying the recommended patterns has been a key piece in the treatment. The guidelines applied in various settings facilitated the achievement of motor skills and the consolidation of stages

A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism.

The giant 532 kDa HERC1 protein is a ubiquitin ligase that interacts with tuberous sclerosis complex subunit 2 (TSC2), a negative upstream regulator of the mammalian target of rapamycin complex 1 (mTORC1). TSC2 regulates anabolic cell growth through its influence on protein synthesis, cell growth, proliferation, autophagy, and differentiation. TSC subunit 1 (TSC1) stabilizes TSC2 by inhibiting the interaction between TSC2 and HERC1, forming a TSC1-TSC2 complex that negatively regulates mTORC1. HERC1-TSC2 interaction destabilizes and degrades TSC2. Recessive mutations in HERC1 have been reported in patients with intellectual disability. Some patients exhibit epilepsy, macrocephaly, somatic overgrowth, and dysmorphic facial features as well. Here we describe two sisters from a consanguineous marriage with a novel homozygous missense variant in the C-terminal HECT domain of HERC1 [chr15:g63,907,989C>G GRCh37.p11 | c.14,072G>C NM_003922 | p.(Arg4,691Pro)]. Symptoms compris global developmental delay, macrocephaly, somatic overgrowth, intellectual disability, seizures, schizoaffective disorder, and pyramidal tract signs. We functionally assessed the HERC1 mutation by investigation of patient and control fibroblasts under normal and nutrient starving conditions. During catabolic state, mTORC1 activity remained high in patient fibroblasts, which stands in stark contrast to its downregulation in controls. This was corroborated by an abnormally high phosphorylation of S6K1-kinase, a direct downstream target of mTORC1, in patients. Moreover, autophagy, usually enhanced in catabolic states, was down-regulated in patient fibroblasts. These data confirm that the missense variant found in both patients results in a gain-of-function for the mutant HERC1 protein.

Long-term observation of a Japanese mucolipidosis IV patient with a novel homozygous p.F313del variant of MCOLN1.

Mucolipidosis type IV (MLIV) is an autosomal recessively inherited lysosomal storage disorder characterized by progressive psychomotor delay and retinal degeneration that is associated with biallelic variants in the MCOLN1 gene. The gene, which is expressed in late endosomes and lysosomes of various tissue cells, encodes the transient receptor potential channel mucolipin 1 consisting of six transmembrane domains. Here, we described 14-year follow-up observation of a 4-year-old Japanese male MLIV patient with a novel homozygous in-frame deletion variant p.(F313del), which was identified by whole-exome sequencing analysis. Neurological examination revealed progressive psychomotor delay, and atrophy of the corpus callosum and cerebellum was observed on brain magnetic resonance images. Ophthalmologically, corneal clouding has remained unchanged during the follow-up period, whereas optic nerve pallor and retinal degenerative changes exhibited progressive disease courses. Light-adapted electroretinography was non-recordable. Transmission electron microscopy of granulocytes revealed characteristic concentric multiple lamellar structures and an electron-dense inclusion in lysosomes. The in-frame deletion variant was located within the second transmembrane domain, which is of putative functional importance for channel properties.

Common vs. Distinct Visuomotor Control Deficits in Autism Spectrum Disorder and Schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are neurodevelopmental disorders with partly overlapping clinical phenotypes including sensorimotor impairments. However, direct comparative studies on sensorimotor control across these two disorders are lacking. We set out to compare visuomotor upper limb impairment, quantitatively, in ASD and SCZ. Patients with ASD (N = 24) were compared to previously published data from healthy control participants (N = 24) and patients with SCZ (N = 24). All participants performed a visuomotor grip force-tracking task in single and dual-task conditions. The dual-task (high cognitive load) presented either visual distractors or required mental addition during grip force-tracking. Motor inhibition was measured by duration of force release and from principal component analysis (PCA) of the participant's force-trajectory. Common impairments in patients with ASD and SCZ included increased force-tracking error in single-task condition compared to controls, a further increase in error in dual-task conditions, and prolonged duration of force release. These three sensorimotor impairments were found in both patient groups. In contrast, distinct impairments in patients with ASD included greater error under high cognitive load and delayed onset of force release compared to SCZ. The PCA inhibition component was higher in ASD than SCZ and controls, correlated to duration of force release, and explained group differences in tracking error. In conclusion, sensorimotor impairments related to motor inhibition are common to ASD and SCZ, but more severe in ASD, consistent with enhanced neurodevelopmental load in ASD. Furthermore, impaired motor anticipation may represent a further specific impairment in ASD. Autism Res 2020, 13: 885-896. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism spectrum disorder (ASD) and schizophrenia (SCZ) are neurodevelopmental disorders with partly overlapping and partly distinct clinical symptoms. Sensorimotor impairments rank among these symptoms, but it is less clear whether they are shared or distinct. In this study, we showed using a grip force task that sensorimotor impairments related to motor inhibition are common to ASD and SCZ, but more severe in ASD. Impaired motor anticipation may represent a further specific impairment in ASD.

Novel variants in AP4B1 cause spastic tetraplegia, moderate psychomotor development delay and febrile seizures in a Chinese patient: a case report.

INTRODUCTION: The AP4B1 gene encodes a subunit of adaptor protein complex-4 (AP4), a component of intracellular transportation of proteins which plays important roles in neurons. Bi-allelic mutations in AP4B1 cause autosomal recessive spastic paraplegia-47(SPG47). CASE PRESENTATION: Here we present a Chinese patient with spastic tetraplegia, moderate psychomotor development delay and febrile seizures plus. Brain MRIs showed dilated supratentorial ventricle, thin posterior and splenium part of corpus callosum. The patient had little progress through medical treatments and rehabilitating regimens. Whole exome sequencing identified novel compound heterozygous truncating variants c.1207C > T (p.Gln403*) and c.52_53delAC (p.Cys18Glnfs*7) in AP4B1 gene. Causal mutations in AP4B1 have been reported in 29 individuals from 22 families so far, most of which are homozygous mutations. CONCLUSIONS: Our study enriched the genetic and phenotypic spectrum of SPG47. Early discovery, diagnosis and proper treatment on the conditions generally increase chances of improvement on the quality of life for patients.

Phosphoserine aminotransferase deficiency: imaging findings in a child with congenital microcephaly.

Serine deficiency disorders can result from deficiency in one of three enzymes. Deficiency of the second enzyme, 3-phosphoserine aminotransferase (PSAT), has been reported in two siblings; the eldest investigated for acquired microcephaly, spasticity and epilepsy. Our patient had neurological symptoms at birth. Fetal magnetic resonance imaging (MRI) at 35-week gestation demonstrated microencephaly and gyral simplification (anterior > posterior) which was confirmed upon postnatal MRI. Congenital microcephaly was apparent at birth. PSAT deficiency was confirmed when exome sequencing identified biallelic mutations in PSAT1 and biochemical testing noted low plasma serine and cerebral spinal fluid serine. Despite oral serine and glycine supplementation at 4 months old, the patient showed little neurodevelopmental progress and developed epileptic spasms at 10 months old. PSAT deficiency should be considered for patients with congenital microcephaly. Although further characterization of MRI findings in other patients is required, microencephaly with simplified gyral pattern could provide imaging clues for this rare metabolic disorder.

Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease.

OBJECTIVE: To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients. METHODS: Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long-term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) improvement (63 patients). RESULTS: Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R2 = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R2 = 9%) and its sensorimotor subpart (R2 = 10%). In the second independent cohort, sweet spot overlap explained R2 = 20% of the variance in long-term UPDRS-III improvement, which was equivalent to the variance explained by overlap with the STN (R2 = 21%) and sensorimotor STN (R2 = 19%). INTERPRETATION: This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short- and long-term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527-538.

[Sensory-psychomotor evaluation in Autism: A new tool for functional diagnosis]. / L'évaluation sensori-psychomotrice dans l'autisme : un nouvel outil d'aide au diagnostic fonctionnel.

INTRODUCTION: Psychomotor impairments in Autism Spectrum Disorders (ASD) have frequently been described in scientific literature. Such deficits impact upon the development of social motor function and interfere with the ability to adjust to everyday life. The inclusion of sensory-motor signs in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) confirms their importance in the diagnosis of ASD. Previous literature has shown the presence precocity of these signs, sometimes before the alteration of the social communication. To our knowledge, there are no existing clinical tools to measure sensory-psychomotor deficit, specifically in ASD. The current paper presents the construction and validation of a new scale, designed to evaluate sensory-psychomotor signs in Autism: 'the Sensory-psychomotor Particularities Scale in Autism' (SPSA). METHOD: The scale is composed of 160 items describing common sensory-psychomotor signs in autism. These items are grouped into 20 variables: touch, nociception, vestibular sensitivity, proprioceptive sensitivity, vision, auditory, multimodality, tone, posture, balance, global coordination, manual dexterity, body schema, bodily self-consciousness, relational adjustment, emotional expression, use of objects, space, time and tonico-emotional regulation. For each item, the psychomotor therapist evaluated sensori-psychomotor signs according to a five-level Likert scale (0="the sign is never expressed by the person", 1="weakly expressed", 2="moderately expressed", 3="severely expressed" and 4="the sign is very characteristic of the person and very severely expressed"). This is completed by a family interview in order to assess the impact of these signs on everyday situations. The study included 111 children with autism. The presence of neurological and genetic diseases was exclusion criteria. For each child, a global developmental evaluation was carried out by an expert clinical team specializing in ASD. Standardized clinical tools were used: Autism Diagnostic Observation Schedule (ADOS), Childhood Autism Rating Scale (CARS), Behavior Summarized Evaluation scale (BSE-R), Repeated and Restricted Behavior scale (RRB), Movement Assessment Battery for Children (M-ABC), Motor Development Rating scale (MDR), Sensory Profile (SP). Developmental quotients (DQ) were evaluated using various tests depending on age and ability. RESULTS: Factor analysis produced three clinically relevant factors: F1: "sensory-emotional synchronization", F2: "multisensory integration" and F3: "motor skills": each containing a similar quantity of items. They account for roughly equal percentages of variance (18.9%, 18.0%, 16.8%, respectively). The factorial structure does not change if the 26 children with comorbid developmental coordination disorder are removed. The three factors show good internal consistency and excellent inter-rater reliability. F1 is comprised of 6 items: touch, nociception, proprioceptive sensitivity, vision, emotional expression and tonico-emotional regulation. This factor is significantly associated with items of the Sensory Profile (touch processing, poor registration, sensory seeking). F2 is comprised of 5 items: multimodality, bodily self-consciousness, relational adjustment, use of objects and space. This factor is associated with ADOS, BSE-R and RRB scores, and the item "touch processing" of the Sensory Profile. F3 is comprised of 4 items: tone, posture, global coordination, manual dexterity. This factor is associated with the M-ABC, the MDR and the item "low endurance" of the Sensory Profile. CONCLUSION: The SPSA is a relevant clinical tool to assess the severity of sensory-psychomotor clinical signs in order to describe the individual profiles of children with ASD. It represents a critical step in advancing knowledge of the complex and heterogeneous pattern of psychomotor development in autism. It could make a valuable contribution to the field, both in research and clinical practice.

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi-allelic missense mutations in DDX41.

DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD-box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA-sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA-sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi-allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.

5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination.

Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.

Supporting a comprehensive and coordinated evaluation of the elderly with diabetes by integrating cognitive and physical assessment in the evaluation process.

BACKGROUND: Successful ageing with diabetes is challenged by co-morbidities, which may present barriers to self-care. Currently, measurement of physical and cognitive status is not part of routine care of the older person with diabetes, and these are not taken into account when devising the treatment plan. OBJECTIVE: To describe a novel approach that integrates cognitive and physical assessment into the routine evaluation of the older person with diabetes and the tailor-made treatment plan devised accordingly. To provide estimates of the relative contribution of cognitive and physical disabilities in this population. METHODS: Cognitive and physical assessments were added to the standard evaluation. A composite measure of cognitive and of physical status categorizing each individual to intact, mild, or severe impairment was generated. In addition, all recommendations provided were categorized and tabulated. RESULTS: Of 119 individuals, over the age of 60 with type 2 diabetes who were referred because of difficulties in managing their disease, 16% and 3% of individuals met the criteria for severe cognitive/physical impairment, respectively, and 42% and 21% met the criteria for mild cognitive/physical impairment; 72%, 12.5%, 61% received recommendations related to intensification of physical activity, cognitive treatment, change in pharmacological agents, respectively. 25% were referred for further emotional treatment. CONCLUSIONS: These data suggest that a substantial proportion of individuals with diabetes over the age of 60 may have cognitive/physical impairment. It highlights the importance of measuring these as part of the multidisciplinary evaluation and being able to provide a tailor made treatment plan.

Health-related quality of life and peer relationships in adolescents with developmental coordination disorder and attention-deficit-hyperactivity disorder.

AIM: Health-related quality of life (HRQoL) and peer relationships were investigated in adolescents with developmental coordination disorder (DCD) and attention-deficit-hyperactivity disorder (ADHD). METHOD: Adolescents with DCD (n=9), ADHD (n=9), DCD and ADHD (n=10), and typically developing adolescents (n=16) completed the following questionnaires: KIDSCREEN-52 Health-Related Quality of Life Questionnaire and Peer Relations Questionnaire for Children. Twenty-five participants took part in semi-structured interviews. RESULTS: Adolescents with DCD and ADHD had lower HRQoL on the mood and emotions, school environment, and financial resources scales of the KIDSCREEN-52 than adolescents in the DCD and typically developing groups (all p<0.05). On the Peer Relations Questionnaire for Children, the DCD and ADHD group reported significantly higher victimization compared with those in the typically developing (p=0.030) and DCD (p=0.010) groups. Qualitative interviews among young people with DCD and ADHD revealed feelings of marginalization and victimization. Descriptors such as 'misfits', 'oddballs', 'weird', and 'the rejects' were used to describe themselves. INTERPRETATION: HRQoL and peer relationships are negatively affected in adolescents with DCD and ADHD. WHAT THIS PAPER ADDS?: Children with developmental coordination disorder (DCD) do not display poorer overall health-related quality of life (HRQoL) versus typically developing controls. Having DCD and attention-deficit-hyperactivity disorder (ADHD) was associated with poorer HRQoL. Adolescents with DCD and ADHD experience significantly higher levels of peer victimization than typically developing adolescents. HRQoL and peer relationships are significantly associated in adolescent respondents.

[Frequency, semiology and prognosis of benign infantile epilepsy]. / Frecuencia, semiologia y pronostico de la epilepsia infantil benigna.

INTRODUCTION: Benign infantile epilepsy is an epileptic syndrome of infancy. Until now, only a small number of case-series have been published. AIM: To study the frequency, semiology and prognosis of benign infantile epilepsy. PATIENTS AND METHODS: The 827 patients with one or more epileptic seizures seen at our hospital between 1 June 1994 and 1 March 2011 were included and prospectively followed. A diagnosis of benign infantile epilepsy was made in patients that fulfilled the following criteria at six month of evolution: one or more focal and/or generalised seizures, onset before 24 months, no neurological deficit and normal neuroimaging and interictal EEG. RESULTS: 77 cases (9%) met the diagnostic criteria. Semiology of the seizures was similar to that of other focal seizures in children under 24 months. 25% of the patients remained as isolated seizures. Among those with two or more seizures, the probability of achieving a 3 year initial remission without antiepileptic treatment was 86%. In the subgroup of patients with focal seizures without family history the probability was 74% and in five cases a global developmental delay/intellectual disability was detected thereafter. CONCLUSIONS: Benign infantile epilepsy is a frequent epileptic syndrome. Semiology of seizures is not useful to characterize the syndrome. A diagnosis of benign infantile epilepsy at six month of evolution implies a reasonably good prognosis, but possibly not as good as for other self-limited epilepsies of infancy.

TITLE: Frecuencia, semiologia y pronostico de la epilepsia infantil benigna.Introduccion. La epilepsia infantil benigna es un sindrome epileptico sobre el que hasta ahora se ha publicado tan solo un pequeño numero de series de casos. Objetivo. Estudiar la frecuencia, semiologia y pronostico de la epilepsia infantil benigna. Pacientes y metodos. Los 827 pacientes con una o mas crisis epilepticas no provocadas que consultaron en nuestro hospital entre el 1 de junio de 1994 y el 1 de marzo de 2011 fueron incluidos y seguidos prospectivamente. Se diagnosticaron de epilepsia infantil benigna los pacientes que cumplieron los siguientes criterios a los seis meses de evolucion: una o mas crisis focales o generalizadas, inicio antes de los 24 meses, ausencia de deficits neurologicos y electroencefalograma y neuroimagen normales. Resultados. Cumplieron los criterios diagnosticos 77 casos (9%). La semiologia de las crisis fue similar a la de otras crisis focales en niños menores de 24 meses. Un 25% de los pacientes permanecio como con crisis aisladas. Entre los de dos o mas crisis epilepticas, la probabilidad de alcanzar una remision inicial de tres años sin tratamiento antiepileptico fue del 86%. En el subgrupo de pacientes con crisis focales sin antecedentes familiares, la probabilidad fue del 74%, y en cinco casos se detecto posteriormente un retraso psicomotor o discapacidad intelectual. Conclusiones. La epilepsia infantil benigna es un sindrome epileptico frecuente. La semiologia de las crisis no es util para caracterizar el sindrome. El diagnostico de epilepsia infantil benigna a los seis meses de evolucion implica un pronostico razonablemente bueno, pero posiblemente no tanto como el de otras epilepsias autolimitadas de la infancia.

Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a rare autosomal dominant disease caused by germline mutations in the fumarate hydratase (FH) gene. Affected individuals develop cutaneous and uterine leiomyomas and aggressive RCC. To date, only few publications described the frequency and morphology of FH-deficient uterine leiomyomas. We reviewed 22 cases collected over 8 years from routine and consultation files based on distinctive histological features. In addition, we screened 580 consecutive uterine leiomyomas from 484 patients, 23 extra-uterine and 8 uterine leiomyosarcomas, and 6 leiomyomas with bizarre nuclei for FH loss using immunohistochemistry (IHC) on tissue microarrays (TMAs). All 22 FH-deficient cases were suspected on H&E sections and confirmed by FH IHC. Patients' ages ranged from 25 to 70 years (median 36). Seventeen patients had multiple nodules (2-14) measuring up to 11.8 cm. None of the patients had stigmata or family history of the HLRCC syndrome. Histologically, all FH-deficient tumors showed consistent and reproducible features as reported previously. FH loss was detected in 2/534 evaluable leiomyomas (0.4%), but in none of leiomyosarcomas. Two of six leiomyomas with bizarre nuclei were FH-deficient. FH-deficient uterine leiomyomas are rare in routine material (= 0.4%). They can be reliably identified or suspected by consistent morphological features. Our data showed predictive morphology to be superior to blind IHC screening for detecting them. The relationship of FH-deficient uterine smooth muscle tumors to the HLRCC syndrome needs further clarification.

Executive functions in children with developmental coordination disorder: a 2-year follow-up study.

AIM: Executive function impairments have been identified in children with poor motor skills, with and without a diagnosis of developmental coordination disorder (DCD). However, most studies are cross-sectional. This study investigates the development of executive function in children with poor motor skills over 2 years. METHOD: Children aged 7 to 11 years (n=51) were assessed twice, 2 years apart, on verbal and nonverbal measures of executive functions: executive-loaded working memory (ELWM); fluency; response inhibition; planning; and cognitive flexibility. Typically developing children (n=17) were compared with those with a clinical diagnosis of DCD (n=17) and those with identified motor difficulties (n=17) but no formal diagnosis of DCD. RESULTS: Developmental gains in executive function were similar between groups, although a gap between children with poor motor skills and typically developing children on nonverbal executive functions persisted. Specifically, children with DCD performed significantly more poorly than typically developing children on all nonverbal executive function tasks and verbal fluency tasks at both time points; and children with motor difficulties but no diagnosis of DCD showed persistent executive function problems in nonverbal tasks of ELWM and fluency. INTERPRETATION: Children with DCD and motor difficulties demonstrated executive function difficulties over 2 years, which may affect activities of daily living and academic achievement, in addition to their motor deficit. WHAT THIS PAPER ADDS: Executive function difficulties in children with poor motor skills persist throughout middle childhood. Children with motor difficulties, without a developmental coordination disorder (DCD) diagnosis, demonstrate less pervasive executive function difficulties than those with DCD. Executive function problems in the groups with motor difficulties and DCD affect mostly nonverbal domains. All groups showed similar developmental gains in executive function.