Search

Spinal muscular atrophy (SMA) is a rare and devastating disease. New disease-modifying treatments have recently been approved and early treatment has been related to a better outcome. In this context, several newborn screening (NBS) programs have been implemented. The aim of the study was to obtain a global overview on the current situation and perspectives on SMA NBS. We conducted a survey and contacted experts from 152 countries, from which we gathered 87 responses. We identified 9 SMA NBS programs that have so far detected 288 newborns with SMA out of 3,674,277 newborns screened. Funding, screening methods, organisation, and consent process were variable between SMA NBS programs. Many respondents pointed the lack of cost/benefit data as a major obstacle to SMA NBS implementation. In the next four years, our data suggest a 24% coverage of newborns from countries where a disease-modifying drug is available and 8,5% coverage in countries with no diseases-modifying drugs. The annual proportion of newborns to be screened in the coming years is expected to increase steadily. The experts expressed a strong need for the implementation of SMA NBS as means to improve care for patients with SMA.

We aimed to assess the impact of POLG disease on mental health and quality of life in 15 patients using the Symptom Checklist-90-R (SCL-90-R) and Short-Form 36 Health Survey (RAND-36). We found increased scores in all nine subscales of SCL-90-R, particularly phobic anxiety, depression and somatization. Further, patients reported considerably lower scores in all RAND-36 domains. This study revealed a global decline in mental health and poor quality of life in patients with POLG disease and highlights the need for increased awareness and systematic assessment in order to improve their quality of life and mental health. © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license.

We aimed to investigate the epidemiology and natural history of FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) in Norway. We identified 153 genetically confirmed subjects making the overall prevalence 2.84/100,000, the highest reported figure worldwide. Of the 153 subjects, 134 (88 %) were homozygous for FKRP c.826C>A giving a carrier frequency for this variant of 1/101 in Norway. Clinical questionnaires and patient notes from 101 subjects, including 88 c.826C>A homozygotes, were reviewed, and 43/101 subjects examined clinically. Age of onset in c.826C>A homozygotes demonstrated a bimodal distribution. Female subjects showed an increased cumulative probability of wheelchair dependency and need for ventilatory support. Across the cohort, the need for ventilatory support preceded wheelchair dependency in one third of the cases, usually due to sleep apnea. In c.826C>A homozygotes, occurrence of cardiomyopathy correlated positively with male gender but not with age or disease stage. This study highlights novel gender differences in both loss of ambulation, need for ventilatory support and the development of cardiomyopathy. Our results confirm the need for vigilance in order to detect respiratory insufficiency and cardiac involvement, but indicate that these events affect males and females differently. publishedVersion

Background: As new gene-related treatment options for Duchenne muscular dystrophy (DMD) are being developed, precise information about the patients’ genetic diagnosis and knowledge about the diversities of natural history in DMD is vital. Objective: To obtain detailed insight into the genetic and clinical characteristics of paediatric DMD in Norway. Methods: 94 boys with DMD, aged 0–18 years, were identified over a period of 3.5 years, yielding a national prevalence of 13.5×10–5 boys. 73 boys (78%) were recruited to full genetic and clinical or limited (genetic only) evaluation. Results: Molecular analysis disclosed 64% deletions, 18% duplications and 18% point mutations. The mean age of diagnosis was 3.9±2.0 years. 78% were treated with glucocorticoids from age 5.8±1.5 years. 23 boys (35%) had lost ambulation at an age of 10.7±2.0 years. 17% were treated for left ventricular dysfunction from age 12.1±3.0 years and 12% had received night-time non-invasive positive pressure ventilation from age 13.0±2.5 years. Conclusions: The distribution of mutation types and sites was similar to previous studies but with more duplications and fewer point mutations. Any genotype-phenotype correlations were not uncovered. The boys were diagnosed early but there is still diagnostic delay among boys presenting with late motor development. Glucocorticoid treatment was widespread, especially among the younger boys. The clinical results of this comprehensive nationwide study highlight the large variability of disease progression in DMD.

Background Nusinersen is one of an increasing number of new, expensive orphan drugs to receive authorization. These drugs strain public healthcare budgets and challenge principles for resource allocation. Nusinersen was introduced in the Norwegian public healthcare system in 2018. A national expert group consisting of physicians was formed to oversee the introduction and continuation of treatment in light of specific start and stop criteria. Methods We have studied experiences within the expert group with a special emphasis on their application of the start and stop criteria, rationing of treatment, and experienced moral dilemmas. A research interview with six members of the national expert group was performed, then analysed with manifest content analysis. The analysis was supplemented with publically available sources on priority setting and the process leading up to the introduction of nusinersen and the establishment of the expert group. Results Sixty-six patients have received treatment within the first 25 months since the national expert group’s establishment. Treatment has not been discontinued for any patient. No patients under 18 years of age have been denied treatment, as those who were referred at this age were all deemed to fulfill the start criteria. The expert group has, however, increased geographical treatment equity and facilitated important cooperation at the national level. Furthermore, it has enhanced open and critical discussions of both medical issues and new ethical dilemmas. Conclusion Although facilitating equal access to treatment for SMA patients, the national expert group has not discontinued treatment for any patient. It is suggested that in order for clinicians to be able to ration care for individual patients, they require both adequate support and sufficient formal authority. Start and stop criteria need to be re-evaluated as more knowledge and experience are gained regarding the treatment.

Background Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. Methods A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. Results We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset—onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. Conclusion Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Children with muscular diseases constitute an important group in paediatric neurology. Some of the conditions are very serious and require extensive interdisciplinary treatment and facilitation. There is some degree of optimism regarding the possibility of causal treatment in some of the conditions.

Background CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss) syndrome is caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. Other mutations in this gene can cause a spectrum of overlapping phenotypes including alternating hemiplegia of childhood, rapid onset dystonia parkinsonism, early infantile epileptic encephalopathy and fever induced paroxysmal weakness and encephalopathy. The phenotype is still mistaken for mitochondrial/metabolic disorders and follow up studies are scare. Case presentation We report a 20 year old Norwegian male with ataxia, sensorineural deafness and visual loss. Before the age of five he experienced three fever related episodes of acute neurological deterioration when he temporarily lost his acquired motor skills and developed persistent gait and limb ataxia. In childhood, he developed bilateral optic atrophy and bilateral sensorineural hearing loss. Motor skills improved and at age 20 the patient showed a mild ataxia, hearing loss and reduced vision. A c.2452G > A mutation in the ATP1A3 gene was identified and CAPOS syndrome was confirmed. Conclusions This is the first Norwegian patient reported with CAPOS syndrome. Our patient had a de novo, previously identified ATP1A3 mutation. The combination of recurrent episodes of fever related ataxia, loss of motor skills in early childhood, and early onset hearing and vision loss is typical of CAPOS syndrome. Previous reports suggest a gradual progression of the disease after the initial episodes, while this patient showed a good outcome with improvement of motor skills from adolescence long after the last deterioration episode. Electronic supplementary material The online version of this article (10.1186/s40673-019-0096-3) contains supplementary material, which is available to authorized users.

Contains fulltext : 204157.pdf (Publisher’s version ) (Closed access) BACKGROUND: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. OBJECTIVE: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. METHODS: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results. RESULTS: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. CONCLUSION: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.

BackgroundLow bone mineral density and an increased risk of appendicular and vertebral fractures are well-established consequences of Duchenne muscular dystrophy (DMD) and the risk of fractures is exacerbated by long-term glucocorticoid treatment. Monitoring of endocrine and skeletal health and timely intervention in at-risk patients is important in the management of children with DMD.MethodsAs part of the Norwegian Duchenne muscular dystrophy cohort study, we examined the skeletal maturation of 62 boys less than 18 years old, both currently glucocorticoid treated (n = 44), previously treated (n = 6) and naïve (n = 12). The relationship between bone age, height and bone mineral density (BMD) Z-scores was explored.ResultsThe participants in the glucocorticoid treated group were short in stature and puberty was delayed. Bone age was significantly delayed, and the delay increased with age and duration of treatment. The difference in height between glucocorticoid treated and naïve boys was no longer significant when height was corrected for delayed skeletal maturation. Mean BMD Z-scores fell below − 2 before 12 years of age in the glucocorticoid treated group, with scores significantly correlated with age, duration of treatment and pubertal development. When BMD Z-scores were corrected for by retarded bone age, the increase in BMD Z-scores was significant for all age groups.ConclusionOur results suggest that skeletal maturation should be assessed in the evaluation of short stature and bone health in GC treated boys with DMD, as failing to consider delayed bone age leads to underestimation of BMD Z-scores and potentially overestimation of fracture risk.

Mitochondrial DNA depletion syndromes (MTDPS) represent a clinically and genetically heterogeneous group of autosomal recessive disorders, caused by mutations in genes involved in maintenance of mitochondrial DNA (mtDNA). Biallelic mutations in FBXL4 were recently described to cause encephalomyopathic MTDPS13. The syndrome has infantile onset and presents with hypotonia, feeding difficulties, a pattern of mild facial dysmorphisms, global developmental delay and brain atrophy. Laboratory investigations reveal elevated blood lactate levels, unspecific mitochondrial respiratory chain (MRC) enzyme deficiencies and mtDNA depletion. We report a novel missense variant, c.1442T > C (p.Leu481Pro), in FBXL4 (NM_012160.4) in a Norwegian boy with clinical, biochemical and cerebral MRI characteristics consistent with MTDPS13. The FBXL4 c.1442T > C (p.Leu481Pro) variant was not present in public databases, 149 Norwegian controls nor an in-house database containing whole exome sequencing data from 440 individuals, and it was predicted in silico to be deleterious to the protein function. Activities of MRC enzymes were normal in muscle tissue (complexes I-IV) and cultured skin fibroblasts (complexes I-V) from the patient, but mtDNA depletion was confirmed in muscle, thus supporting the predicted pathogenicity of the FBXL4 c.1442T > C (p.Leu481Pro) variant. On clinical indication of mitochondrial encephalomyopathy, sequencing of FBXL4 should be performed, even when the activity levels of the MRC enzymes are normal.

To describe the group of patients under the age of 18 who have neuromuscular disorders and are from a region with 1.65 million inhabitants in South-Eastern Norway. Patients with known or suspected neuromuscular disorders were identified by neuropediatricians/rehabilitation teams in the region. We registered a total of 141 patients under the age of 18 who had a neu- romuscular diagnosis, giving a prevalence of 35.6 × 10 −5 in this population. It was possible to check the diagnoses of 122 pa- tients. Duchenne muscular dystrophy was the largest group, followed by peripheral neuropathies, myotonic dystrophy and spinal muscular atrophy. The prevalence figures for the different diagnostic entities are discussed on the basis of previously reported studies from the same area, from a comparable Swedish area and from other countries. We registered patients with a broad spectrum of neuromuscular diagnoses in our health region. The classical, well-known entities were the most prevalent condi- tions. It was difficult to make a very specific diagnosis in quite a few cases.

We describe the case of a six year old boy with findings consistent with myotonia congenita: muscular hypertrophy, stiffness when commencing movements and typical warm-up signs. The most prominent symptom was myotonia of the eyelid muscles with apparent swelling around the eyes. Even though the pronounced warm-up phenomena in our patient suggested a chloride channel-associated myotonia congenita, the myotonia of his eyelid muscles indicated an involvement of sodium channels. Screening for mutations in the underlying CLCN1 gene was negative, however, in the SCN4A gene, we identified the missense mutation c.2108T>C; p.Leu703Pro for which there is strong evidence of pathogenicity because it arose de novo in the index patient.

AIM Duchenne muscular dystrophy (DMD) is an X-linked myopathy affecting one in 3600-6000 live male births. The aim of this study was to gain further insight into how parents experience caring for boys with DMD. METHODS Using a qualitative design, parents in 12 families with boys with DMD, whereof two pairs of siblings, were interviewed in 2014 and 2015. Participants were parents of boys followed at Oslo University Hospital or other hospitals in the south-eastern health region of Norway. Mean age of the boys was 13 years, range 7-17. RESULTS Parents expressed the importance of obtaining good information about the diagnosis, supplied with sensitivity for them as clients, and the parents must be involved in timing of interventions. Meeting with others in the same situation was highly appreciated. Many of the parents expressed their own need for support to cope with the difficult situation. Continuity of support in the boys' transition to adulthood was pointed out as important, as well as the need for professional help to talk to the boys about their diagnosis. CONCLUSION Our study suggests that professional teams should expand the parental perspective and emphasise a holistic approach in their work with patients with DMD.

En rekke genetiske skjelettmuskeldystrofier er assosiert med kardiomyopati med hjertesviktutvikling og risiko for plutselig død. Grad av kardial affeksjon er ikke nødvendigvis relatert til grad av skjelettmuskelaffeksjon, og plutselig hjertedød kan være første tegn på kardiomyopati. For å iverksette behandling og forebyggende tiltak mot livstruende kardiale hendelser er det nødvendig med økt oppmerksomhet blant allmennleger og spesialister.

En rekke genetiske skjelettmuskeldystrofier er assosiert med kardiomyopati med hjertesviktutvikling og risiko for plutselig dod. Grad av kardial affeksjon er ikke nodvendigvis relatert til grad av skjelettmuskelaffeksjon, og plutselig hjertedod kan vaere forste tegn pa kardiomyopati. For a iverksette behandling og forebyggende tiltak mot livstruende kardiale hendelser er det nodvendig med okt oppmerksomhet blant allmennleger og spesialister.

Background Mitochondria play an important role in iron metabolism and haematopoietic cell homeostasis. Recent studies in mice showed that a mutation in the catalytic subunit of polymerase gamma (POLG) was associated with haematopoietic dysfunction including anaemia. The aim of this study was to analyse the frequency of anaemia in a large cohort of patients with POLG related disease. Methods We conducted a multi-national, retrospective study of 61 patients with confirmed, pathogenic biallelic POLG mutations from six centres, four in Norway and two in the United Kingdom. Clinical, laboratory and genetic data were collected using a structured questionnaire. Anaemia was defined as an abnormally low haemoglobin value adjusted for age and sex. Univariate survival analysis was performed using log-rank test to compare differences in survival time between categories. Results Anaemia occurred in 67% (41/61) of patients and in 23% (14/61) it was already present at clinical presentation. The frequency of anaemia in patients with early onset disease including Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) was high (72%) and 35% (8/23) of these had anaemia at presentation. Survival analysis showed that the presence of anaemia was associated with a significantly worse survival (P = 0.004). Conclusion Our study reveals that anaemia can be a feature of POLG-related disease. Further, we show that its presence is associated with significantly worse prognosis either because anaemia itself is impacting survival or because it reflects the presence of more serious disease. In either case, our data suggests anaemia is a marker for negative prognosis.

Aim To describe patients diagnosed with limb girdle muscular dystrophy 2I (LGMD2I) in our paediatric departments between 2004 and 2012. Methods The hospital charts of 17 patients presenting for evaluation at a mean age of 7.8 years (range 1–13 years) were retrospectively reviewed. Results With one exception, all patients were homozygous for the common mutation c.826C>A in the FKRP gene. Three patients experienced transient pronounced weakness as toddlers. Fatigue and muscle pain were most prominent, weakness less so, in children presenting at an older age. The degree of severity varied substantially. In certain cases, increased creatine kinase was an incidental finding. All walked independently by 18 months. When last evaluated at a mean age of 14.3 years (range 3.5–18 years), five patients were part-time wheelchair users. One patient was then treated for a cardiomyopathy. Creatine kinase was consistently increased, except presymptomatic in one patient. Muscle biopsies showed focal acute and chronic myopathic changes and pathological expression of α-dystroglycan. No consistent relationship between clinical function and the degree of morphological pathology was found. Conclusion LGMD2I is a relevant differential diagnosis when creatine kinase is increased in children presenting with fatigue, muscle pain and sometimes weakness.

Background Duchenne muscular dystrophy is one of the most severe muscle diseases to affect children. In the last twenty years, treatments have been established that have significantly improved patients' quality of life and life expectancy. The purpose of this article is to outline the main features of the disease and its treatment, and to examine possible future treatment options. Method The article is based on a literature search in PubMed, current international guidelines and our own clinical experience. Results Close monitoring by an interdisciplinary rehabilitation team forms the basis of treatment. Treatment with glucocorticoids can slow disease progression and improve motor function in the short term. The treatment may cause side effects, which must be monitored and which may require intervention. A not insignificant proportion of patients have cognitive and neuropsychiatric problems that must be addressed. Active intervention in response to signs of respiratory or cardiac failure is important. More causal treatment of Duchenne muscular dystrophy is under testing and offers cautious hope for future patients. Interpretation With improved treatment and increased life expectancy come new challenges for patients with Duchenne muscular dystrophy and their families, as well as new demands on the support services. This patient group requires close and comprehensive follow-up, also in the transition from child to adult.

Children with muscular diseases constitute an important group in paediatric neurology. Some of the conditions are very serious and require extensive interdisciplinary treatment and facilitation. There is some degree of optimism regarding the possibility of causal treatment in some of the conditions.

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context., European Research Council (GA 309449: Fellowship to Y.J.C.), ERA-NET Neuron (MR/M501803/1), and a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” (ANR-10-IAHU-01)

Mutations in the FKRP (Fukutin Related Protein) gene produce a range of phenotypes including Limb Girdle Muscular Dystrophy Type 2I (LGMD2I). In order to investigate the prevalence, the mutation spectrum and possible genotype-phenotype correlation, we studied a cohort of Norwegian patients with LGMD2I, ascertained in a 4-year period. In this retrospective study of genetically tested patients, we identified 88 patients from 69 families, who were either homozygous or compound heterozygous for FKRP mutations. This gives a minimum prevalence of 1/54,000 and a corresponding carrier frequency of 1/116 in the Norwegian population. Seven different FKRP mutations, including three novel changes, were detected. Seventy-six patients were homozygous for the common c.826C>A mutation. These patients had later disease onset than patients who were compound heterozygous - 14.0 vs. 6.1 years. We detected substantial variability in disease severity among homozygous patients.

Background: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Patients and results: Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38 % of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14 % of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12 % of SUCLA2 and in 10 % of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of SUCLA2 and 80 % of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. Conclusions: To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.

Contains fulltext : 167925.pdf (Publisher’s version ) (Open Access) See Cannon (doi:10.1093/brain/awv400) for a scientific commentary on this article.Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the alpha-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy.

Background Serious heart and pulmonary failure may be treated with extracorporeal membrane oxygenation (ECMO). The aim of this follow-up study was a multimodal assessment of outcome in children surviving ECMO at our hospital from 1991 to 2004. Methods Twenty-two children were, on average, 1.18 years old (SD = 1.92; range, 0.1 to 7.8) when ECMO was initiated. Average age at follow-up was 7.2 years (range, 1.8 to 13.9). Thirteen children were treated for cardiac and nine for pulmonary failure. Venoarterial ECMO was performed in 21 patients and venovenous ECMO in one patient. The protocol included a review of patients records, clinical, neurologic and neuropsychologic, and radiological examinations, electroencephalogram, and interviews with the parents. Results Moderate or severe impairment in at least two clinical assessments were found in 16 (72.7%) children. Five (22.7%) children had cerebral palsy and 15 (68.2%) had moderate or severe cognitive impairment. Eight (36%) children had pathological radiologic findings. Pathological electroencephalograms were found in 11 (50%) patients including four (18.2%) with epileptic activity. Children with radiologic findings had a slightly worse cognitive outcome. There was no association between the neurophysiologic findings and the neuropsycohologic performance or the radiologic findings. Based on parental assessment, only four children had pathological scores. Conclusions All children, except for two, came walking to the follow-up visit. All parents were positive to the ECMO treatment, and reported a good or slightly reduced quality of life for their child. Cerebral sequelae were frequently found in children treated with ECMO. The need for treatment and support should be assessed in order to optimize their physical and psychosocial functioning.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:22:37Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:33:38Z : No. of bitstreams: 1 2-s2.0-35349019691.pdf: 4144234 bytes, checksum: 9b86846640bd2e66375c65e289357bd0 (MD5) Made available in DSpace on 2014-05-27T11:22:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-10-24 Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P = .001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified. © 2007 by The American Society of Human Genetics. All rights reserved. Leeds Institute of Molecular Medicine, Leeds DNA Laboratory Department of Clinical Genetics St. James's University Hospital, Leeds Cancer Research UK Mutation Detection Facility, Leeds Department of Paediatric Neurology Leeds General Infirmary, Leeds Department of Paediatric Neurology Erasme Hospital, Brussels Children's Hospital Queen Fabiola, Brussels Service de Neuropédiatrie Hôpital Trousseau Department of Paediatric Neurology Hôpital Trousseau Pediatric Neurology Department Hôpital Bicêtre Institut de Myologie Groupe Hospitalier Pitié-Salpêtrière Service de Virologie Hôpital Cochin-St. Vincent de Paul, Paris Department of Clinical Biochemistry Hospital Sant Joan de Déu-Ciberer, Barcelona Department of Barcelona Pediatric Neurology Hospital Sant Joan de Déu-Ciberer, Barcelona Department of Paediatrics St. Luke's Hospital, Guardamangia Department of Molecular and Human Genetics Baylor College of Medicine, Houston Serive de Neurologie Centre Hospitalier, Pau Department of Paediatrics Children's Hospital, Sheffield Developmental and Metabolic Neurology Branch National Institute of Neurological Disorders and Stroke National Institutes of Health, Bethesda Department of Human Genetics Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen Unit of Molecular Medicine Bambino Gesù Children's Research Hospital, Rome Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Casa Sollievo Della Sofferenza Mendel Institute, Rome Muscular and Neurodegenerative Disease Unit G. Gaslini Institute, Genova Department of Clinical Genetics Churchill Hospital, Oxford Division of Clinical Chemistry and Biochemistry University Children's Hospital, Zurich Clinical Genetics Unit Birmingham Women's Hospital, Birmingham Department of Paediatrics Sandwell and West Birmingham NHS Trust, Birmingham Neurology Department Birmingham Children's Hospital, Birmingham Department of Human Genetics Radboud University, Nijmegen Department of Pediatric Neurology Radboud University, Nijmegen Department of Paediatric Neurology Royal Children's Hospital, Brisbane, QLD Genetic Health Queensland Royal Children's Hospital, Brisbane, QLD Serviço de Aconselhamento Genético Universidade Estadual de São Paulo, Botucatu Academic Unit of Medical Genetics St. Mary's Hospital, Manchester Kinderkrankenhaus Auf der Bult, Hannover Department of Paediatrics Bradford National Health Service (NHS) Trust, Bradford Developmental Neurology Department Fondazione Istituto Neurologico C. Besta, Milan Grampian Clinical Genetics Centre, Aberdeen Department of Neonatology University Hospital, Ghent Department of Pediatrics University Hospital, Ghent Department of Clinical Genetics Maastricht University Hospital, Maastricht Department of Neurology Maastricht University Hospital, Maastricht Department of Paediatrics and Imaging Sciences Imperial College Great Ormond Street Hospital, London St. Mary's NHS Trust Great Ormond Street Hospital, London Department of Ophthalmology Great Ormond Street Hospital, London North East Thames Regional Genetics Service Great Ormond Street Hospital, London Evelina Children's Hospital Guy's and St. Thomas' NHS Trust, London Department of Paediatrics Université Laval Medical School, Québec Clinical Genetics Unit Hospital de Cruces, Baracaldo Service de Génétique Médicale Centre Hospitalier Universitaire Pellegrin Enfants, Bordeaux Unité de Neurologie de l'Enfant et de l'Adolescent Centre Hospitalier Universitaire Pellegrin Enfants, Bordeaux National Centre for Medical Genetics Our Lady's Hospital, Dublin Department of Paediatric Neurology Children's University Hospital, Dublin Department of Medical Genetics Rikshospitalet-Radiumhospitalet, Oslo Department of Paediatrics Rikshospitalet-Radiumhospitalet, Oslo Rikshospitalet-Radiumhospitalet, Oslo Department of Pediatrics Academic Medical Center, Amsterdam Department of Child Neurology Vrije Universiteit Medical Center, Amsterdam Medical Research Council Human Genetics Unit Western General Hospital, Edinburgh Department of Clinical Genetics Leiden University Medical Center, Leiden Division of Pediatric Neurology Oregon Health and Science University, Portland, OR Pediatric Neurology Klinikum Aschaffenburg, Aschaffenburg Department of Neurology Royal Children's Hospital, Parkville, Vic. Division of Clinical Genetics Department for Medical Genetics Medical University Innsbruck, Innsbruck Department of Pediatrics Division of Pediatric Neurology and Inborn Errors of Metabolism Children's Hospital Innsbruck, Innsbruck Klinik für Kinder und Jugendliche, Konstanz Paediatric Neurology University Hospitals of Gasthuisberg, Leuven Department of Child Neurology and Psychiatry IRCCS Casimiro Mondino Institute of Neurology, Pavia Department of Neurogenetics School of Medicine of Ribeirao Preto, Ribeirao Preto Greenwood Genetic Center, Greenwood, SC Raphael Recanati Genetic Institute Rabin Medical Center, Petach-Tikva Department of Paediatrics Crosshouse Hospital, Ayr Fraser of Allander Neurosciences Unit Royal Hospital for Sick Children, Glasgow Duncan Guthrie Institute of Medical Genetics Royal Hospital for Sick Children, Glasgow Division of Medical Genetics Montreal Children's Hospital, Montreal Department of Paediatric Neurology University Hospitals of Leicester NHS Trust, Leicester University Hospital of Aarhus, Aarhus Division of Pediatric Dermatology British Columbia's Children's Hospital, Vancouver, BC Institut de Pathologie et de Génétique, Gosselies Pediatric Neurology Department Guide Chauliac Hospital, Montpellier Servicio de Pediatría Hospital Universitario Doctor Peset, Valencia Genetic Institute Ha'Emek Medical Center, Afula Rappaport Faculty of Medicine Technion, Haifa Neuropediatrics Unit Complejo Hospitalario de Jean, Jean Department of Paediatrics Manor Hospital, Walsall Division of Neuropediatrics University Hospital, Freiburg Genetic Health Services Victoria Royal Children's Hospital, Vic. Service de Génétique Hôpital Debrousse, Lyon Lancashire Teaching Hospitals Trust, Preston Neonatal Intensive Care Unit Arcispedale Santa Maria Nuova, Reggio Emilia Center for Medical Genetics, Antwerp Department of Neurology Children's National Medical Center, Washington, DC Department of Neuropediatrics Humboldt University, Berlin Leeds Institute of Molecular Medicine St. James's University Hospital Wellcome Trust Brenner Building, Leeds LS9 7TF Serviço de Aconselhamento Genético Universidade Estadual de São Paulo, Botucatu

Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. (c) 2015 Wiley Periodicals, Inc

Duchenne muscular dystrophy is one of the most severe muscle diseases to affect children. In the last twenty years, treatments have been established that have significantly improved patients' quality of life and life expectancy. The purpose of this article is to outline the main features of the disease and its treatment, and to examine possible future treatment options.The article is based on a literature search in PubMed, current international guidelines and our own clinical experience.Close monitoring by an interdisciplinary rehabilitation team forms the basis of treatment. Treatment with glucocorticoids can slow disease progression and improve motor function in the short term. The treatment may cause side effects, which must be monitored and which may require intervention. A not insignificant proportion of patients have cognitive and neuropsychiatric problems that must be addressed. Active intervention in response to signs of respiratory or cardiac failure is important. More causal treatment of Duchenne muscular dystrophy is under testing and offers cautious hope for future patients.With improved treatment and increased life expectancy come new challenges for patients with Duchenne muscular dystrophy and their families, as well as new demands on the support services. This patient group requires close and comprehensive follow-up, also in the transition from child to adult.

Of the 12 children who represent the complete cohort of Norwegian patients surviving the complete palliative operative programme for hypoplastic left heart syndrome, 10 were studied by a pediatric cardiologist, a pediatric neurologist, a neuropsychologist and a child psychiatrist. We found significant morbidity. Hemodynamic function was relatively uncompromised in eight of the patients, but one had significant cyanosis due to use of an operative technique subsequently abandoned and one had obstruction of the flow of blood from the left to the right atrium. Five children had disturbances of rhythm, with one requiring insertion of a pacemaker. One child had epilepsy. Delayed motor development, most often to mild degree, was found in seven children, while six had attention problems. Mental retardation was found in two children and autistic traits in one. Despite these various problems, the parents were seemingly satisfied with their own lives, and the quality of life of their children.

Purpose To determine physical function and activity level in children and adolescents with neuromuscular disorders. Methods Seventeen children and adolescents aged 10 to 18 years with neuromuscular disorders who were ambulatory participated. Physical function was measured using the Hammersmith Motor Ability Scale and the Six-Minute Walk Test. Physical activity (PA) level was measured using the SenseWear Armband activity monitor. Activities were recorded using a questionnaire. Results were compared with previous data published for peers who are healthy and public recommendations. Results Hammersmith Motor Ability Scale scores were lower than normal values. Results of the Six-Minute Walk Test were considerably lower than results for peers who are healthy. Time in PA and the number of steps were considerably lower on holidays and slightly lower on weekdays compared with the values for peers who are healthy. No vigorous activity was registered. Conclusions The participants had lower physical function and PA levels than peers who are healthy. The small, heterogeneous sample makes generalizations challenging and multicenter studies are recommended.