Background We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. Methods Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. Results Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. Conclusions Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.

Objective: To develop a new way to interpret Gross Motor Function Measure (GMFM-66) score improvement in studies conducted without control groups in children with cerebral palsy (CP).Design: The curves, which describe the pattern of motor development according to the children's Gross Motor Function Classification System level, were used as historical control to define the GMFM-66 expected natural evolution in children with CP. These curves have been modeled and generalized to fit the curve to particular children characteristics.Setting: Research center.Participants: Not applicable. Interventions: Not applicable.Mean Outcome Measures: Not applicable.Results: Assuming that the GMFM-66 score evolution followed the shape of the Rosenbaum curves, by taking into account the age and GMFM-66 score of children, the expected natural evolution of the GMFM-66 score was predicted for any group of children with CP who were <8 years old. Because the expected natural evolution could be predicted for a specific group of children with CP, the efficacy of a treatment could be determined by comparing the GMFM-66 score evolution measured before and after treatment with the expected natural evolution for the same period. A new index, the Gross Motor Function Measure Evolution Ratio, was defined as follows: Gross Motor Function Measure Evolution Ratio = measured GMFM-66 score change/expected natural evolution.Conclusions: For practical or ethical reasons, it is almost impossible to use control groups in studies evaluating effectiveness of many therapeutic modalities. The Gross Motor Function Measure Evolution Ratio gives the opportunity to take into account the expected natural evolution of the gross motor function of children with CP, which is essential to accurately interpret the therapy effect on the GMFM-66. (C) 2016 by the American Congress of Rehabilitation Medicine

OBJECTIVE:To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD).METHODS:This phase III, double-blind, randomized, placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5-15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995.RESULTS:All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis.CONCLUSIONS:After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED.CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that for boys with DMD, daily use of either DFZ and PRED is effective in preserving muscle strength over a 12-week period.

Background: The aim of the present study was to examine the frequency and the phenotypic manifestations in a FrenchCanadian population with a chromosome 17pl 1.2 duplication (Charcot-Marie-Tooth type 1A, CMT-1 A). Methods: Molecular analysis were performed by Southern blot using pVAW409R3a probe. Clinical evaluation was carried out according to the scale defined by the European HMSN Consortium. Results: The frequency of duplication was found to be similar in the adult (70.8%) and pediatric (72.7%) populations. Onset of symptoms occurred before 20 years of age in 85.7% of adult cases and before the age of 5 in 80% of the pediatric cases. The classical CMT syndrome was observed in 77% of the cases and the syndrome was associated with additional features in 15% of cases in the adult population. All the children presented with classical CMT syndrome with no additional features. There was a significant correlation between the disability score and the duration of the disease but no correlation was found between median nerve conduction velocity and the functional handicap, the age at onset or the duration of the disease. In one family, there was a very conspicuous anticipation over five observed generations. Conclusion: This study reveals that the age at onset, the clinical and electrophysiological variability as well as the functional disability variations in a French-Canadian population did not differ from those reported in other populations. RESUME: Etude clinique et electrophysiologique, dans la population canadienne franchise, de la maladie de Charcot-Marie-Tooth de type 1A associee a une duplication en 17pll.2. Introduction: Le but de cette etude etait d'examiner la frequence et les manifestations phenotypiques de la maladie de Charcot-Marie-Tooth de type 1A (CMT-1 A) associee a une duplication en 17pl 1.2 dans la population canadienne francaise. Methodes: Une analyse moleculaire a 6t6 faite par buvardage de Southern au moyen de la sonde pVAW409R3a. Une evaluation clinique a 6te faite selon I'echelle deTinie par le Consortium European sur la neuropathie sensitivomotrice hereditaire. Resultats: La frequence de la duplication etait la meme chez les adultes (70.8%) et chez les enfants (72.7%). Le debut des symptomes etait survenu avant l'age de 20 ans chez 85.7% des adultes et avant l'age de 5 ans chez 80% des enfants. Le syndrome classique du CMT a etfi observe dans 77% des cas et ce syndrome etait associe a des manifestations additionnelles chez 15% des cas adultes. Tous les enfants presentaient le syndrome CMT classique sans manifestations additionnelles. II existait une correlation significative entre le score a I'echelle d'invalidite et la duree de la maladie, mais aucune correlation entre la vitesse de conduction dans le nerf median et I'invalidite fonctionnelle, l'age de debut ou la dur£e de la maladie. Dans une famille, nous avons observe une anticipation evidente d'une generation a l'autre sur cinq generations. Conclusion: Cette etude revele que l'age de debut, la variabilite clinique et electrophysiologique ainsi que les variations de l'invalidite fonctionnelle sont les memes dans la population canadienne francaise que ce qui a ete rapporte dans d'autres populations. Can. J. Neurol. Sci. 1999; 26: 196-200 Hereditary sensory and motor neuropathies are a clinically and genetically heterogeneous group of neuromuscular disorders. The most common types, the hypertrophic type, are denominated type I hereditary motor and sensory neuropathy (HMSN-I) or type 1 Charcot-Marie-Tooth (CMT-I). Inheritance is usually autosomal dominant although sporadic cases have been reported. HMSN-I is itself genetically heterogeneous, with at least two chromosomal loci involved. The most common form, type la, is due to a dominant allele mapping on chromosome 17 associated with either a 1.5 Mb DNA duplication in 17pl 1.2-pl2, including the peripheral myelin protein-22 (PMP-22) geneor a point mutation of the PMP-22 gene." A much rarer form, type lb, is mapped at lq22-23 and is associated with point mutations in the myelin Po gene;" two more families in which the disease was From the Laboratoire de Recherche en Genetique Humaine, CHU Laval, Quebec, Canada (N.P., L.C., J.P.), Departement des Sciences Neurologiques, Hopital EnfantJesus, Quebec, Canada (J.-P.B., D.B.), Service de Pediatrie, Hopital Marie-Enfant, Montreal, Canada (M.V.), Service de Neurologie Pediatrique, CHU Sherbrooke, Canada (B.L.), Service de Rhumatologie, CHU Laval, Quebec, Canada (G.M.) RECEIVED DECEMBER 1 5 , 1 9 9 8 . ACCEPTED IN FINAL FORM APRIL 7 , 1 9 9 9 . Reprint requests to: Dr Jack Puymirat, Laboratoire de Recherche en Genetique Humaine, CHU Laval, 2705 Blvd Laurier, Ste-Foy, Quebec, Canada Gl V 4G2

AIM:Lacosamide is an antiepileptic drug approved for the treatment of focal epilepsy in adult patients. The aim of this observational study was to review our centre's experience with lacosamide and to characterize its effectiveness and tolerability as an adjunctive antiepileptic drug in a retrospective cohort of children with refractory focal epilepsy.METHODS:We retrospectively reviewed the medical records of 22 patients who received lacosamide from November 2009 to April 2014 at the CHU Ste-Justine, University of Montreal. Treatment responders were defined as children with a ≥50% reduction in seizure frequency compared to baseline, and this was determined three months after the initiation of treatment and at the last follow-up visit.RESULTS:We included 14 boys and eight girls with a mean age of 12.9 years (SD: 5.2; range: 5.2-20.7 years) at the initiation of treatment. The average length of follow-up was 11.9 months. Patients had previously received an average of 7.5 antiepileptic drugs. The mean number of concomitant antiepileptic drugs was 2.3. The mean initial and maintenance doses were 2.9 and 8.4 mg/kg/d, respectively. Thirteen (59%) and ten (45%) patients were responders after three months of treatment and at the last follow-up visit, respectively. One became seizure-free. Adverse effects were reported in 11 patients and none were severe. Responders and non-responders were identical with respect to all studied parameters except gender, with the proportion of responders being greater in girls than in boys (75% vs 29%; p=0.035).CONCLUSION:Our study adds evidence that lacosamide appears to be a safe and effective adjunctive therapy for children with refractory focal epilepsy.

Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47), and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK) levels up to 300,000 U/L (normal, 30 to 200). Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency.

Allan-Herndon-Dudley syndrome is an X-linked disease caused by mutations in the solute carrier family 16 member 2 (SLC16A2) gene. As SLC16A2 encodes the monocarboxylate transporter 8 (MCT8), a thyroid hormone transporter, patients with Allan-Herndon-Dudley syndrome present a specific altered thyroid hormone profile. Allan-Herndon-Dudley syndrome has been associated with myelination delay on the brain magnetic resonance imaging (MRI) of affected subjects. We report a patient with Allan-Herndon-Dudley syndrome characterized by developmental delay, hypotonia, and delayed myelination caused by a novel SLC16A2 mutation (p.L291R). The thyroid hormones profile in our patient was atypical for Allan-Herndon-Dudley syndrome. The follow-up examinations showed that the progression of the myelination was not accompanied by a clinical improvement. Our paper suggests that SLC16A2 mutations should be investigated in patients with myelination delay even when the thyroid function is not conclusively altered.

Most neuromuscular diseases (NMD) are rare inherited conditions presenting a relentlessly progressive course. Some NMD are associated with intellectual impairment and many are complicated by musculoskeletal, cardiac, or respiratory problems. Rehabilitation care of NMD is thus best provided by a team of medical specialists and health professionals working closely together in an interdisciplinary fashion. Rehabilitation for patients with NMD should include physical evaluation but also assessment of their ability to manage their daily activities or work and their need for assistive devices. With appropriate physical, psychological, and social support, those patients can maintain a good quality of life and an adequate level of well-being. Surgical management of musculoskeletal problems in children related to neuromuscular disorders remains a highly controversial subject. This review is based mainly on the author's personal experience with conservative and periopeporative rehabilitation care for neuromuscular diseases. A multidisciplinary approach is advocated. The importance of proactive respiratory care is emphasized. Rehabilitation after surgical treatment of spinal deformities is analyzed outlining the particular aspects in spinal muscular atrophy, Duchenne's muscular dystrophy, congenital muscular dystrophy, and congenital myopathies. A disease- specific approach is recommended as the wide variety of different neuromuscular pathologies requires careful planning of treatment strategies best managed in a team approach.

OBJECTIVE: To describe the atypical clinical presentation of a patient with an SCN9A mutation.

Objectives This study sought to determine the impact of steroid therapy on cardiomyopathy and mortality in patients with Duchenne muscular dystrophy (DMD).Background DMD is a debilitating X-linked disease that afflicts as many as 1 in 3,500 boys. Although steroids slow musculoskeletal impairment, the effects on cardiac function and mortality remain unknown.Methods We conducted a cohort study on patients with DMD treated with renin-angiotensin-aldosterone system antagonists with or without steroid therapy.Results Eighty-six patients, 9.1 +/- 3.5 years of age, were followed for 11.3 +/- 4.1 years. Seven of 63 patients (11%) receiving steroid therapy died compared with 10 of 23 (43%) not receiving steroid therapy (p = 0.0010). Overall survival rates at 5, 10, and 15 years of follow-up were 100%, 98.0%, and 78.6%, respectively, for patients receiving steroid therapy versus 100%, 72.1%, and 27.9%, respectively, for patients not receiving steroid therapy (log-rank p = 0.0005). In multivariate propensity-adjusted analyses, steroid use was associated with a 76% lower mortality rate (hazard ratio: 0.24; 95% confidence interval: 0.07 to 0.91; p = 0.0351). The mortality reduction was driven by fewer heart failure-related deaths (0% vs. 22%, p = 0.0010). In multivariate analyses, steroids were associated with a 62% lower rate of new-onset cardiomyopathy (hazard ratio: 0.38; 95% confidence interval: 0.16 to 0.90; p = 0.0270). Annual rates of decline in left ventricular ejection fraction (-0.43% vs. -1.09%, p = 0.0101) and shortening fraction (-0.32% vs. -0.65%, p = 0.0025) were less steep in steroid-treated patients. Consistently, the increase in left ventricular end-diastolic dimension was of lesser magnitude (-0.47 vs. -0.92 mm per year, p = 0.0105).Conclusions In patients with DMD, steroid therapy is associated with a substantial reduction in all-cause mortality and new-onset and progressive cardiomyopathy. (J Am Coll Cardiol 2013;61:948-54) (C) 2013 by the American College of Cardiology Foundation

INTRODUCTION:Erythromelalgia due to heterozygous gain-of-function SCN9A mutations usually presents as a pure sensory-autonomic disorder characterized by recurrent episodes of burning pain and redness of the extremities. METHODS:We describe a patient with an unusual phenotypic presentation of gross motor delay, childhood-onset erythromelalgia, extreme visceral pain episodes, hypesthesia, and self-mutilation. The investigation of the patient's motor delay included various biochemical analyses, a comparative genomic hybridization array (CGH), electromyogram (EMG), and muscle biopsy. Once erythromelalgia was suspected clinically, the SCN9A gene was sequenced. RESULTS:The EMG, CGH, and biochemical tests were negative. The biopsy showed an axonal neuropathy and neurogenic atrophy. Sequencing of SCN9A revealed a heterozygous missense mutation in exon 7; p.I234T. CONCLUSIONS:This is a case of global motor delay and erythromelalgia associated with SCN9A. The motor delay may be attributed to the extreme pain episodes or to a developmental perturbation of proprioceptive inputs.

OBJECTIVE: To describe the atypical clinical presentation of a patient with an SCN9A mutation.

An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues. We further observed that these mutants display defects in oxidative phosphorylation, increased Reactive Oxygen Species (ROS), and an upregulated mitochondrial Unfolded Protein Response. With the aid of this knowledge, we identified MARS2 to be mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy (ARSAL) patients. We uncovered complex rearrangements in the MARS2 gene in all ARSAL patients. Analysis of patient cells revealed decreased levels of MARS2 protein and a reduced rate of mitochondrial protein synthesis. Patient cells also exhibited reduced Complex I activity, increased ROS, and a slower cell proliferation rate, similar to Drosophila Aats-met mutants.

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.

STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of secretory vesicles to the presynaptic membrane for the release of neurotransmitters. De novo missense mutations in STXBP1 were recently reported in patients with Ohtahara syndrome, a form of encephalopathy with severe early-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in 95 patients with non-syndromic intellectual disability (NSID) revealed de novo truncating mutations in two patients who also showed severe non-specific epilepsy, suggesting that STXBP1 disruption has the potential of causing a wide spectrum of epileptic disorders in association with intellectual disability. Here, we report on the mutational screening of STXBP1 in a different series of 50 patients with NSID and the identification of a novel de novo truncating mutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no history of epilepsy. This is the first report of a patient with a truncating mutation in STXBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption.

Objectives To determine the etiologies and evolution of rhabdomyolysis in children.Study design We performed a retrospective study of patients with rhabdomyolysis who were seen in our tertiary care university-affiliated pediatric hospital. Patients in outpatient clinics, seen in the emergency department, or admitted from 2001 to 2002 were selected. With a standardized case report form, we collected predetermined data from each patient's chart.Results A total of 130 patients with rhabdomyolysis were included in the study (male, 56%; mean age, 7.5 +/- 5.9 years). The median elevation of creatine phosphokinase was 2207 IU/L (range, 1003 to 811 428 IU/L). The most frequent diagnoses were viral myositis (29, 22.3%), trauma (24, 18.4%), surgery (24, 18.4%), hypoxia (12, 9.2%), and drug reaction (8, 6.2%). Metabolic myopathy was found only in one patient (0.8%). In 17 patients (13.1%), no definite diagnosis could be made.Conclusions Etiologies of rhabdomyolysis in children are varied and differ from those reported in adults. In most patients, rhabdomyolysis is benign and without recurrence. In our series, rhabdomyolysis was the initial symptom of a metabolic myopathy in only one patient. (J Pediatr 2011;159:682-5).

Leukodystrophies are a heterogeneous group of disorders associated with abnormal central nervous system white matter. The clinical features invariably include upper motor neuron signs and developmental regression with or without other neurological manifestations. The objective of this study was to characterize clinically and genetically a new form of childhood-onset leukodystrophy with ataxia and tremor. We recruited seven French-Canadian cases belonging to five families affected by an unknown form of childhood-onset leukodystrophy. Genome-wide scans (GWS) were performed using the Illumina Hap310 or Hap610 Bead Chip to identify regions of shared homozygosity that were further studied for linkage with STS markers. All cases presented between the ages of 1 and 5 years with spasticity along with other upper motor neuron signs, prominent postural tremor, and cerebellar signs. Though motor regression is a constant feature, cognitive functions are relatively preserved, even late in the course of the disease. The higher frequency of founder diseases in the French-Canadian population and the segregation in pedigrees are suggestive of a recessive mode of inheritance. By homozygosity mapping, we established linkage to a 12.6-Mb SNP-haplotyped region on chromosome 10q22.3–10q23.31 (maximum LOD score: 5.47). We describe an autosomal recessive childhood-onset leukodystrophy with ataxia and tremor mapping to a 12.6 Mb interval on chromosome 10q22.3–10q23.31. Identification of the mutated gene will allow precise diagnosis and genetic counseling and shed light on how its perturbed function leads to white matter abnormalities.