Background: Developmental coordination disorder (DCD) is a neurodevelopmental disorder encountered in about 6% of children at school age. DCD mostly affects motor task automatization and it persists in adulthood. Several brain structures were supposed to be involved in DCD pathophysiology. Quantitative imaging techniques have the potential to investigate these connected brain regions associated with motor tasks. Methods: In the present work, we studied with 18F-fluorodeoxyglucose (18F-FDG) and positron emission tomography imaging (PET) brain metabolism in subjects with DCD versus control in resting state and during repetitive and standardized finger movements of the left non-dominant hand. We analyzed 42 brain structures in the right and left hemispheres and the data were statistically assessed by the Ward clustering approach to detect the activated/non-activated/deactivated brain regions. Results: The images obtained with PET clearly showed different uptake of 18F-FDG in subjects with DCD with respect to control subjects. The statistics showed less brain regions activated and more deactivated in subjects with DCD than in control. Among other differences, the right thalamus was activated in DCD subjects as both caudate nuclei were deactivated for a possible compensation for basal ganglia dysfunction or deficit. Conclusions: This first PET study of DCD found significant thalamus activation as previous studies on finger movement tasks comparing PET and fMRI in normal subjects. The Ward clustering in DCD images allowed to identify activated/non-activated/deactivated brain structures in subjects with DCD versus control.

AimTo describe the clinico‐radiological phenotype of children with a CACNA1A mutation and to precisely evaluate their learning ability and cognitive status.MethodChildren between the ages of 3 and 18 years harboring a pathogenic CACNA1A mutation associated with episodic ataxia, hemiplegic migraine, benign paroxysmal torticollis, benign paroxysmal vertigo, or benign paroxysmal tonic upgaze, were enrolled in this cross‐sectional study. Data concerning psychomotor development, academic performance, educational management, clinical examination at inclusion, and brain imaging were collected. Cognitive assessment was performed using age‐standardized scales.ResultsEighteen patients (nine males, nine females; mean age at inclusion: 11y 7mo [SD 4y 5mo; range 3y–17y 11mo]) from 14 families were enrolled. Eleven patients displayed the coexistence or consecutive occurrence of more than one type of episodic event. Nine patients exhibited abnormal neurological examination at inclusion. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy in five patients. Psychomotor development was delayed in nine patients and academic difficulties were reported by the parents in 15 patients; nine patients were in special education. Impairment of intellectual function was assessed in six of the 12 patients with interpretable Full‐scale IQ scores and was more frequent when cerebellar atrophy was present on MRI.InterpretationCognitive impairment is commonly associated with CACNA1A mutations. We suggest that CACNA1A‐associated phenotype should be considered a neurodevelopmental disorder.What this paper adds Cognitive disabilities and academic difficulties are common in children with CACNA1A mutations associated with episodic syndromes. Cognitive function ranges from normal to moderate intellectual disorder in wheelchair‐dependent children. Patients with vermian atrophy are at a higher risk of cognitive impairment.

Objective To describe the clinico-radiological phenotype of 3 patients harboring a homozygous novel AP4M1 pathogenic mutation. Methods The 3 patients from an inbred family who exhibited early-onset developmental delay, tetraparesis, juvenile motor function deterioration, and intellectual deficiency were investigated by magnetic brain imaging using T1-weighted, T2-weighted, T2*-weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging (SWI) sequences. Whole-exome sequencing was performed on the 3 patients. Results In the 3 patients, brain imaging identified the same pattern of bilateral SWI hyposignal of the globus pallidus, concordant with iron accumulation. A novel homozygous nonsense mutation was identified in AP4M1, segregating with the disease and leading to truncation of half of the adap domain of the protein. Conclusions Our results suggest that AP4M1 represents a new candidate gene that should be considered in the neurodegeneration with brain iron accumulation (NBIA) spectrum of disorders and highlight the intersections between hereditary spastic paraplegia and NBIA clinical presentations.

The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.

OBJECTIVE:To describe the clinico-radiological phenotype of 3 patients harboring a homozygous novel AP4M1 pathogenic mutation.METHODS:The 3 patients from an inbred family who exhibited early-onset developmental delay, tetraparesis, juvenile motor function deterioration, and intellectual deficiency were investigated by magnetic brain imaging using T1-weighted, T2-weighted, T2*-weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging (SWI) sequences. Whole-exome sequencing was performed on the 3 patients.RESULTS:In the 3 patients, brain imaging identified the same pattern of bilateral SWI hyposignal of the globus pallidus, concordant with iron accumulation. A novel homozygous nonsense mutation was identified in AP4M1, segregating with the disease and leading to truncation of half of the adap domain of the protein.CONCLUSIONS:Our results suggest that AP4M1 represents a new candidate gene that should be considered in the neurodegeneration with brain iron accumulation (NBIA) spectrum of disorders and highlight the intersections between hereditary spastic paraplegia and NBIA clinical presentations.

BACKGROUND:Developmental Coordination Disorder (DCD) is a neurological impairment occurring in nearly 6% of general population, and sometimes mimics other developmental disorders like Attention Deficit Hyperactivity Disorder (ADHD) or, in the most severe cases, intellectual deficiency.OBJECTIVES:To review the general portrait of DCD, the physiology, the clinical assessments, and to provide an overview of functional studies on the subject. We finally report some proposed DCD managements which vary depending on the manifestation of the disorder and on the goals of the therapy.RESULTS:DCD can be stated as a sum of fine motor, perceptual visual and executive difficulties, emerging during childhood brain development and lasting throughout adulthood. Even if DCD can be isolated from other co-morbidities in certain individuals, it is still difficult to categorize it in delimited subclasses of characteristics, e.g. problems of vision or language. The findings in functional imaging also diverge in locating the cerebral deficit for a given motor task.CONCLUSION:Finding a single explanation seems difficult as many cerebral regions are associated with DCD and many clinical aspects are involved, but, further studies could explore genetic (or epigenetic) explanation for the prevalence of DCD in population.

Background Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. Objectives To better characterise the natural history of PMM2-CDG. Methods Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. Results The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. Conclusions PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

OBJECTIVE:To determine the molecular basis of a complex phenotype of congenital muscle weakness observed in an isolated but consanguineous patient.METHODS:The proband was evaluated clinically and neurophysiologically over a period of 15 years. Genetic testing of candidate genes was performed. Functional characterization of the candidate mutation was done in mammalian cell background using whole cell patch clamp technique.RESULTS:The proband had fatigable muscle weakness characteristic of congenital myasthenic syndrome with acute and reversible attacks of most severe muscle weakness as observed in periodic paralysis. We identified a novel homozygous SCN4A mutation (p.R1454W) linked to this recessively inherited phenotype. The p.R1454W substitution induced an important enhancement of fast and slow inactivation, a slower recovery for these inactivated states, and a frequency-dependent regulation of Nav1.4 channels in the heterologous expression system.CONCLUSION:We identified a novel loss-of-function mutation of Nav1.4 that leads to a recessive phenotype combining clinical symptoms and signs of congenital myasthenic syndrome and periodic paralysis, probably by decreasing channel availability for muscle action potential genesis at the neuromuscular junction and propagation along the sarcolemma.

Background Developmental Coordination Disorder (DCD) is a chronic neurological disorder observed in children. DCD is characterized by slowness in activities and motor impairment that affects the children’s daily living and academic achievements, and later their professional and social behavior. Our aim in this work was to report characteristics frequencies in a group of children with DCD and to propose a subtyping of DCD characteristics. Methods Thirty three clinical DCD characteristics, the mostly reported in the literature, were assessed in 129 patients, boys and girls aged from 4 years to 18 years, and their subtyping was proposed. The statistical analyses were carried out with the Chi square, the t-test and the correlation for the statistical differences, and with the Ward clustering method for subtyping. Results We found that there were 3.17 boys for one girl, all patients were characterized as slow, 47% were left-handers or ambidextrous, 36% and 26% had orofacial and verbal dyspraxia, respectively, 83% were found anxious, and 84% were described as being clumsy. Conclusions It appears from these results that a child with DCD expresses more than a single difficulty. Three subtypes emerged from the statistical analysis in this study: (1) clumsiness and other characteristics except language difficulties; (2) self-esteem and peer relation without clumsiness and language difficulties; (3) language difficulties and orofacial dyspraxia.

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2‐weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <−2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM . The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non‐specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype–phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA , L1CAM , or IKBKG , respectively, in the duplicated segment. © 2015 Wiley Periodicals, Inc.

Objective The aim of the study was to propose a means to select a cohort of patients affected by Coordination Developmental Disorder (DCD) based on their phenotypes. Methods The study was carried out in 129 paediatric patients addressed to our outpatient 3rd line clinic dedicated to DCD. A questionnaire with 34 items concerning the developmental stages, education, social interactions and specific clinical examination was developed according to an exhaustive review of the literature. This questionnaire was administered to each new patient. The results of the responses to the 34 items were then compiled. To confirm DCD diagnoses, complementary measurements were performed with magnetic resonance imaging, electroencephalography and other usual psychological tests. Results Among the 200 patients, 129 were confirmed having DCD including 47% who were treated for Attention Deficit Hyperactivity Disorder, in conformation with DSM-5 definitions. In these DCD subjects, among other results, 100% had a slow implementation of actions in requested tasks, 47% were left-handed or ambidextrous, 76% were male, 95% showed handwriting difficulties, 56% moved in a sitting position before acquiring normal walking. Conclusion In our study, DCD subjects divided into 3 categories: 1) slow and clumsy; 2) slow without awkwardness; and 3) slow with “language impairment” (verbal dyspraxia and/or oral-facial dyspraxia). The aim of the study was to propose a means to select a cohort of patients affected by Coordination Developmental Disorder (DCD) based on their phenotypes. The study was carried out in 129 paediatric patients addressed to our outpatient 3rd line clinic dedicated to DCD. A questionnaire with 34 items concerning the developmental stages, education, social interactions and specific clinical examination was developed according to an exhaustive review of the literature. This questionnaire was administered to each new patient. The results of the responses to the 34 items were then compiled. To confirm DCD diagnoses, complementary measurements were performed with magnetic resonance imaging, electroencephalography and other usual psychological tests. Among the 200 patients, 129 were confirmed having DCD including 47% who were treated for Attention Deficit Hyperactivity Disorder, in conformation with DSM-5 definitions. In these DCD subjects, among other results, 100% had a slow implementation of actions in requested tasks, 47% were left-handed or ambidextrous, 76% were male, 95% showed handwriting difficulties, 56% moved in a sitting position before acquiring normal walking. In our study, DCD subjects divided into 3 categories: 1) slow and clumsy; 2) slow without awkwardness; and 3) slow with “language impairment” (verbal dyspraxia and/or oral-facial dyspraxia).

BACKGROUND:Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported.METHODS:PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus.RESULTS:Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2.CONCLUSIONS:Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Congenital muscular dystrophies (CMD) are a large group of genetically determined muscular diseases, initially defined by an early onset before the age of walking and dystrophic changes on myopathologic analyses. Currently, their definition is less restrictive with, a clinical continuum with limb-girdle muscular dystrophies, and closer histomorphological aspects with congenital myopathies. We distinguish 9 different forms of DMC, classified in 6 different groups depending on the location and/or function of the protein involved, on the control of 26 different genes. Ullrich's disease, UCMD (collagenopathy involving three different genes: COL6A1, COL6A2, COL6A3); secondary dystroglycanopathies (by abnormal glycosylation of alpha-dystroglycan involving 16 different genes); and DMC merosin negative, MDC1A, (merosinopathy secondary to mutations in a unique gene, LAMA2); represent the three most common forms. Rigid spine syndrome type 1, RSMD1 (selenopathy secondary to SEPN1 gene mutation) and L-CMD (laminopathy involving LMNA gene) are also part of the most current forms. Clinical features, plasmatic creatine kinase elevation or not, the presence or absence of clinical signs of central nervous system involvement, allow a first level of diagnostic pathway. According to these elements, muscle and/or cerebral MRI, muscle and/or skin biopsy will be discussed to guide the molecular investigations that will allow accurate diagnosis.

MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria ( S.pneumoniae , H.influenzae ) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG 2 -deficiency was detected – in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG 1 -levels were detected in 11/21 patients and supra-normal IgG 3 -levels were seen in 8/21 patients – in 6 of the patients as combined elevation of IgG 1 and IgG 3 . Three of the four patients with IgA/IgG 2 -deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG 2 -deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG 2 may benefit from prophylactic substitution of sIgA and IgG.

Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv7.2 (KCNQ2; Q2) and Kv7.3 (KCNQ3; Q3) voltage-dependent K+ channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named “KCNQ2 encephalopathy.” In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

Background: Acute transverse myelitis (ATM) in children is a rare and often severe disease for which there are few known prognostic factors, particularly the subsequent risk of multiple sclerosis (MS) diagnosis. Objectives: To determine the clinical course and prognostic factors after a first episode of ATM in children. Methods: Thirty children below 16 years of age diagnosed with a first neurological episode of ATM were included retrospectively. Clinical evaluation, treatment, laboratory, and MRI data were collected. Results: Median age at onset was 11 years (range 3–15 years). Follow-up data were available for a median of 4 years (range 0.5–16.7 years). Five patients subsequently had a diagnosis of MS (17%), which was associated with acute partial transverse myelitis (odds ratio 5; 95% confidence interval 2.3–11), with a 60% probability of having a relapse at five years ( p < 0.01). The 2011 Verhey criteria correctly identified MS in children with the highest specificity (96%) and sensitivity (80%). Conclusion: Acute partial transverse myelitis and brain MRI abnormalities at initial presentation are significantly predictive of a subsequent diagnosis of MS in children with ATM. These findings suggest that closer brain MRI monitoring after acute partial transverse myelitis might make the earlier introduction of disease-modifying therapies possible.