Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder.

We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases. These enzymes form the hexose-1-phosphates crucial for NDP-sugars synthesis and ensuing glycosylation reactions. While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there. Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing. All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally. Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect, but the clinical features observed in this neurodevelopmental disorder point toward an important but still unknown role of glucose-1,6-bisphosphate or other sugar bisphosphates in brain metabolism.

Gait analysis for individually tailored interdisciplinary interventions in children with cerebral palsy: a randomized controlled trial.

AIM: To test the hypothesis that improvements in gait and function following individualized interdisciplinary interventions consisting of physical therapy, orthotics, spasticity management, and orthopaedic surgery using instrumented gait analysis are superior to 'usual care' in children with cerebral palsy (CP). METHOD: This was a prospective, single-blind, parallel-group, randomized controlled trial investigating the effectiveness of interventions based on the use of gait analysis. Primary outcome was gait (Gait Deviation Index) and secondary outcomes were walking and patient-reported outcome measures of function, disability, and health-related quality of life. Follow-ups were done at 26 weeks (questionnaires) and at the primary end point of 52 weeks (all outcomes). RESULTS: Sixty participants with CP (39 males, 21 females, mean age 6y 10mo, standard deviation 1y 3mo, range 5y-9y 1mo) in Gross Motor Function Classification System levels I or II, were randomized to interventions with or without gait analysis. No significant or clinically relevant between-group differences in change scores of the primary or secondary outcomes were found. The recommended categories of interventions were dominated by non-surgical interventions and were applied in 36% to 86% of the participants. INTERPRETATION: Interventions using gait analysis were not superior to 'usual care' on gait, walking, or patient-reported outcomes in a sample of relatively young and independently walking children with CP not expected to need surgery. WHAT THIS PAPER ADDS: Gait analysis in children with cerebral palsy in Gross Motor Function Classification System levels I or II recommends interdisciplinary interventions. Compliance to interventions recommended after gait analysis was low. No statistically significant advantages were identified for the intervention group versus the control group.

ANÁLISIS DE MARCHA PARA LA INTERVENCIÓN INTERDISCIPLINARIA ADAPTADA INDIVIDUALMENTE EN NIÑOS CON PARÁLISIS CEREBRAL: ENSAYO CONTROLADO RANDOMIZADO: OBJETIVO: Comprobar la hipótesis que las mejoras en la marcha y la función luego de las intervenciones interdisciplinarias individualizadas de terapia física, ortésis, tratamiento antiespástico, y cirugía ortopédica son superiores que "tratamiento convencional" en parálisis cerebral (PC) utilizando un análisis de marcha instrumentada METODO: Este fue un ensayo randomizado controlado, prospectivo, ciego, con grupo paralelo que investigó la efectividad de intervenciones basada en el uso de análisis de marcha. El resultado primario fue la marcha (Índice de Desviación de la Marcha) y los resultados secundarios fueron el paso y los resultados reportados por los pacientes de función, discapacidad y calidad de vida relacionada a la salud. Los seguimientos se realizaron a las 26 semanas (cuestionarios) y el punto de fin primario de 52 semanas (todos los resultados). RESULTADOS: Sesenta participantes con PC (39 masculinos, 21 femeninos, edad media de 6 años 10 meses, desviación estándar de 1 años y 3 meses, rango 5 años 0 meses- 9 años y 1 mes) con niveles de GMFCS I o II, fueron asignados al azar intervenciones con y sin análisis de marcha. No se encontraron diferencias significativas o clínicamente relevantes entre los grupos en cuanto a los cambios de los resultados primarios y secundarios. INTERPRETACION: Las intervenciones que usaron análisis de marcha no fueron superiores al tratamiento convencional sobre el paso, la marcha o resultados reportados por los pacientes en una muestra de niños con PC relativamente jóvenes y de marcha independiente que no se espera que necesiten cirugía.

ANÁLISE DE MARCHA PARA INTERVENÇÕES INDIVIDUALMENTE PLANEJADAS EM CRIANÇAS COM PARALISIA CEREBRAL: UM ENSAIO CONTROLADO RANDOMIZADO: OBJETIVO: Testar a hipótese de que melhoras na marcha e função após intervenções interdisciplinares individualizadas consistindo de fisioterapia, órteses, manejo da espasticidade, e cirurgia ortopédica usando análise de marcha instrumentalizada são superiors comparadas ao "cuidado usual" em crianças com paralisia cerebral (PC). MÉTODO: Este foi um estudo randomizado controlado prospectivo, único cego, com grupos paralelos, investigando a efetividade de intervenções baseadas no uso da análise de marcha. O desfecho primário foi a marcha (Índice de Desvio da Marcha) e os desfechos secundários foram o caminhar e medidas relatadas pelo paciente da função, incapacidade, e qualidade de vida relacionada à saúde. Acompanhamentos foram feitos com 26 semanas (questionários) e o encerramento primário foi 52 semanas (todos os resultados). RESULTADOS: Sessenta participantes com PC (39 do sexo masculino, 21 do sexo feminino, média de idade 6a 10 m, desvio padrão 1a 3 m, variação 5a 0 m- 9a 1 m) nos níveis do Sistema de Classificação da Função Motora Grossa (GMFCS) I ou II foram fandomizados para intervenções com ou sem análise de marcha. Nenhuma diferença significativa ou clinicamente relevante entre grupos nos escores de mudança dos desfechos primários e secundários foram encontradas. As categorias de intervenção recomendadas foram dominadas pelas intervenções não-cirúrgicas e foram aplicadas em 36% a 86% dos participantes. INTERPRETAÇÃO: Intervenções usando análise de marcha não foram superiores ao "cuidado usual" para a marcha, o caminhar, ou resultados reportados por pacientes em ma amostra de crianças com PC relativamente jovens e com deambulação indepente, para a qual não se espera a necessidade de cirurgia.

The use of instrumented gait analysis for individually tailored interdisciplinary interventions in children with cerebral palsy: a randomised controlled trial protocol.

BACKGROUND: Children with cerebral palsy (CP) often have an altered gait. Orthopaedic surgery, spasticity management, physical therapy and orthotics are used to improve the gait. Interventions are individually tailored and are planned on the basis of clinical examinations and standardised measurements to assess walking ('care as usual'). However, these measurements do not describe features in the gait that reflect underlying neuro-musculoskeletal impairments. This can be done with 3-dimensional instrumented gait analysis (IGA). The aim of this study is to test the hypothesis that improvements in gait following individually tailored interventions when IGA is used are superior to those following 'care as usual'. METHODS/DESIGN: A prospective, single blind, randomised, parallel group study will be conducted. Children aged 5 to 8 years with spastic CP, classified at Gross Motor Function Classification System levels I or II, will be included. The interventions under investigation are: 1) individually tailored interdisciplinary interventions based on the use of IGA, and 2) 'care as usual'. The primary outcome is gait measured by the Gait Deviation Index. Secondary outcome measures are: walking performance (1-min walk test) and patient-reported outcomes of functional mobility (Pediatric Evaluation of Disability Inventory), health-related quality of life (The Pediatric Quality of Life Inventory Cerebral Palsy Module) and overall health, pain and participation (The Pediatric Outcome Data Collection Instrument). The primary endpoint for assessing the outcome of the two interventions will be 52 weeks after start of intervention. A follow up will also be performed at 26 weeks; however, exclusively for the patient-reported outcomes. DISCUSSION: To our knowledge, this is the first randomised controlled trial comparing the effects of an individually tailored interdisciplinary intervention based on the use of IGA versus 'care as usual' in children with CP. Consequently, the study will provide novel evidence for the use of IGA. TRIAL REGISTRATION: ClinicalTrials.gov NCT02160457 . Registered June 2, 2014.

Ryanodine receptor 1 related myasthenia like myopathy responsive to pyridostigmine.

Disease causing variants in the Ryanodine receptor 1 (RYR1) gene are a common cause for congenital myopathy and for malignant hyperthermia susceptibility. We report a 17 year old boy with congenital muscle weakness progressing to a myasthenia like myopathy with muscle weakness, fatigability, ptosis, and ophthalmoplegia. Muscle biopsy showed predominance and atrophy of type 1 fibers. Whole-exome trio sequencing revealed three variants in the RYR1-gene in the patient: c.6721C > T,p.(Arg2241*) and c.2122G > A,p.(Asp708Asn) in cis position, and the c.325C > T,p.(Arg109Trp) variant in trans. Treatment with pyridostigmine improved symptoms. This case supports that a myasthenia like phenotype is part of the phenotypic spectrum of RYR1 related disorders, and that treatment with pyridostigmine can be beneficial for patients with this phenotype.

Predictors of physical activity levels in children and adolescents with cerebral palsy: clinical cohort study protocol.

INTRODUCTION: Children and adolescents with cerebral palsy may be trapped in a vicious circle of low physical fitness, resulting in deconditioning that causes a further decrease in physical activity (PA), a lower quality of life and an increased risk of developing non-communicable diseases. Therefore, establishing a healthy and active lifestyle during childhood is even more important for individuals with a disability. However, the factors that influence habitual PA in children and adolescents with cerebral palsy remain unknown.The present protocol outlines a prospective cohort study with the aim of investigating potential predictors of habitual PA in children and adolescents with cerebral palsy in order to provide evidence for optimising PA levels and associated overall health. METHODS AND ANALYSIS: This prospective cohort study will enrol participants with cerebral palsy between the ages of 8 and 15 years at Gross Motor Function Classification System levels I-III. Using a modified version of the International Classification of Functioning, Disability and Health model as a conceptual analytical framework, the analysis will be divided into six components and will provide predictors for habitual PA measured by accelerometry. The potential predictive variables are registry data on physical function (Danish Cerebral Palsy Follow-Up Programme); validated proxy-reported questionnaires on quality of life (Paediatric Quality of Life Inventory), overall health, pain and participation in daily activities (Paediatric Outcomes Data Collection Instrument) and supplementary questions regarding sleep, screen time and socioeconomic status. ETHICS AND DISSEMINATION: The project is approved by the Danish Data Protection Agency (19/16396) and has been declared not notifiable by the Regional Committee on Health Research Ethics, cf. Committee Act Art. 14, paragraph 1 (S-20192000-23). The study results will be published in international peer-reviewed journals, presented at international conferences, and published in a PhD dissertation. TRIAL REGISTRATION NUMBER: NCT04614207.

Is MED13L-related intellectual disability a recognizable syndrome?

INTRODUCTION: MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients. MATERIALS AND METHODS: In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing. RESULTS: All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations. CONCLUSIONS: Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance.

Epidemiology of cerebral palsy in Southern Denmark.

INTRODUCTION: The aim of this study was to describe the prevalence, subtypes, severity and neuroimaging findings of cerebral palsy (CP) in a cohort of children born in Southern Denmark. Risk factors were analysed and aetiology considered. METHODS: A population-based cohort study covering 17,580 live births from 2003 to 2008. RESULTS: The study included 43 children diagnosed with CP. The overall prevalence of CP was 2.4 per 1,000 live births (95% confidence interval (CI): 1.8-3.2). The gestational age (GA)-specific prevalence ranged from 63.5 per 1,000 live births for GA < 32 weeks to 1.3 for GA ≥ 37 weeks. Almost half of the children were born preterm and 28% were from multiple pregnancies. The prevalence of CP was 1.8 per 1,000 in singletons and 15.4 per 1,000 in multiples. Low GA and birth weight were risk factors for CP, also after stratification for multiple births. Spastic CP was the predominating subtype of CP, and 24 children (56%) were able to walk independently. White-matter lesions were the most common magnetic resonance imaging finding, and the aetiology of CP was known in 37% of cases. CONCLUSION: The overall prevalence of CP was slightly higher than that found in other Scandinavian studies due to its higher prevalence in the preterm group. Possible explanations include the high rate of multiple births in the background population. Neuroimaging findings were abnormal in the majority of children with CP, but aetiology could only be established in one third of the children. Primary prevention of CP is possible if the numbers of preterm births and multiple pregnancies can be reduced. FUNDING: The Danish Cerebral Palsy Follow-up Programme is supported by the foundation "Ludvig og Sara Elsass Fond". TRIAL REGISTRATION: 2008-58-0034.

Post-varicella angiopathy: a series of 4 patients with focus on virologic and neuroimaging findings.

BACKGROUND: Post-varicella angiopathy is an important cause of childhood stroke and follows a particular pattern. Specific treatment guidelines have not been developed because of a lack of epidemiological, laboratory, and neuroimaging data. Prospective randomized controlled trials evaluating different treatment strategies have not been performed, and expert opinions on diagnostic criteria, prognosis, and treatment are diverging. METHODS: This case series describes the clinical course, laboratory, and neuroimaging findings of four children with post-varicella angiopathy, who all underwent cerebrospinal fluid assessment and received antiviral, immunosuppressive, and antiplatelet treatment. RESULTS: Cerebrospinal fluid analysis was positive for varicella-zoster virus markers in three children. At follow-up, three children had a mild hemiparesis and one child had no neurological symptoms. Neuroimaging showed complete vascular remission in three patients and improvement in one. CONCLUSIONS: Systematic search for virologic markers in cerebrospinal fluid will contribute to the understanding of the pathogenesis of idiopathic childhood stroke and can be considered as a prerequisite for the development of clear diagnostic criteria and relevant treatment strategies for post-varicella angiopathy. The role of antiviral and immunosuppressive medication needs to be clarified.

[Acute hemiparesis after chickenpox]. / Akut hemiparese efter skoldkoppesygdom.

Varicella is a common infectious disease; it is usually benign and self-limited, and complications are believed to be rare. A case is presented of a two-year-old girl who developed a left hemiparesis four weeks after the onset of chickenpox. Laboratory studies ruled out all known causes of stroke. MRI revealed the infarction, and MRA showed segmental narrowing of the right internal carotid artery, compatible with focal vasculitis. Based on the presumed diagnosis of varicella-associated cerebral vasculitis, the patient was treated with acyclovir, methylprednisolone and aspirin.