Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimise quality of life. ...Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne Muscular Dystrophy module of the Pediatric Quality of Life Inventory (PedsQL.sup.TMDMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQL.sup.TMDMD for paediatric patients with DMD, using French multicentre descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatment dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQL.sup.TMDMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice. Keywords: Neuromuscular disorder, Duchenne Muscular Dystrophy, Pediatric Quality of Life (PedsQL)
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major ...role in DMD as well as intracellular calcium (Ca
) mishandling. Ca
release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca
release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing
expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca
concentration was increased, but RYR1-mediated Ca
release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca
concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca
concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca
leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.
Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe ...multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS).
Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies).
We identified causative mutations in 17 out of the 40 patients (43%). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes.
Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects.
Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these ...short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called "Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)" was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989-2009). In the latest period studied, median age at diagnosis was 3 months 0.6-10.4. Seventy-seven patients died at a median 6 months of age1-27: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8).
Congenital myopathies are clinically and genetically heterogeneous, and are classified based on typical structural abnormalities on muscle sections. Recessive mutations in the striated muscle ...preferentially expressed protein kinase (SPEG) were recently reported in patients with centronuclear myopathy (CNM) associated in most cases with dilated cardiomyopathy. Here we report the identification of novel biallelic truncating SPEG mutations in a patient with moderate congenital myopathy without clinical and histological hallmarks of CNM and without cardiomyopathy. This study expands the phenotypic spectrum of SPEG-related myopathy and prompts to consider SPEG for congenital myopathies without specific histological features.
A 5-year-old girl with hereditary spherocytosis presented with two episodes of transient ischemic attacks within a month. Cranial magnetic resonance imaging angiography revealed a left internal ...carotid artery and middle cerebral artery stenosis, with an extensive vascular mesh in the thalamic area indicative of moyamoya disease. Treatment consisted of supporting cerebral perfusion with blood transfusions, and splenectomy to prevent recurrence. Moyamoya disease is a very unusual cerebrovascular disorder in childhood and its association with hereditary spherocytosis is rarely reported.
An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable ...cardioverter-defibrillator implantation.
We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians interquartile range.
We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 1.0-7.2 and 5.1 2.0-9.3 years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach.
In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.
Hemiplegic migraine (HM) is a rare subtype of migraine with aura that occurs as a familial or sporadic condition. The 3 culprit genes identified so far do not account for all familial forms of HM. ...PRRT2 mutations have recently been shown to cause various childhood-onset episodic syndromes including paroxysmal kinesigenic dyskinesia, infantile convulsions with choreoathetosis syndrome, and benign familial infantile epilepsy. Our objective was to test the possible implication of PRRT2 in HM, another episodic disorder with early onset in most cases.
The whole genomic coding region of PRRT2 was sequenced in 101 index cases with HM that started before age 20 years and for whom no mutation was found in the 3 known HM genes. Affected relatives of mutated patients were analyzed when available.
PRRT2 mutations were identified in 4 patients: the previously reported c.649dupC mutation was found in 2 cases, and a novel mutation, c.649delC, was found in the other 2. One patient with mutation subsequently developed paroxysmal dyskinesia, as well as generalized epileptic seizures.
PRRT2 mutations can occasionally cause HM. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.
To clarify the phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathies.
We screened for TRPV4 mutations in 169 French unrelated patients with inherited ...axonal peripheral neuropathy. Ninety-five patients had dominant Charcot-Marie-Tooth type 2 (CMT2) disease, and 74 patients, including 39 patients with distal hereditary motor neuropathy, 14 with congenital spinal muscular atrophy and arthrogryposis, 13 with CMT2, and 8 with scapuloperoneal spinal muscular atrophy, presented with additional vocal cord paralysis and/or skeletal dysplasia.
No deleterious TRPV4 mutation was identified in the 95 patients with "pure" CMT2 (0/95). In contrast, 12 of 74 patients (16%) with neuropathy and vocal cord paralysis and/or skeletal dysplasia presented pathogenic TRPV4 mutations, including 7 patients with distal hereditary motor neuropathy, 2 with scapuloperoneal spinal muscular atrophy, 2 with congenital spinal muscular atrophy and arthrogryposis, and one with CMT2. Investigation of affected relatives allowed us to study 17 patients. All patients had childhood-onset motor neuropathy and showed a variety of associated findings, including foot deformities (100% of cases), kyphoscoliosis (100%), elevated serum creatine kinase levels (100%), vocal cord paralysis (94%), scapular winging (53%), respiratory insufficiency (29%), hearing loss (24%), skeletal dysplasia (18%), and arthrogryposis (12%). Eight missense mutations were observed in these 12 families, including 2 previously unreported. Six mutations were de novo events, and 2 asymptomatic carriers were identified.
With 16% of patients affected in our series, this study demonstrates that TRPV4 mutations are a major cause of inherited axonal neuropathy associated with a large spectrum of additional features.
Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating ...Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype–genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3.
•RECA is defined by recurring episodes of hypotonia and ataxia triggered by fever.•RECA symptoms can be mistaken for recurrent decompensations of metabolic disorders.•RECA is consistently associated with mutations of the Arg756 in the ATP1A3 protein.•Different ATP1A3 ion pump dysfunctions lead to different clinical phenotypes.
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