The clinical, histologic, and genotypic spectrum of -related myopathy: A case series.

Objective: To clarify the prevalence, long-term natural history, and severity determinants of -related myopathy (SEPN1-RM), we analyzed a large international case series.

Methods: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades.

Results: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.

Effect of Salbutamol on Respiratory Muscle Strength in Spinal Muscular Atrophy.

Background: Oral salbutamol has shown clinical benefits in spinal muscular atrophy (SMA). We studied its effect on the respiratory muscle strength in children with different types of SMA.

Methods: Lung and respiratory muscle functions were assessed in children receiving daily oral salbutamol for at least one year.

Diaphragmatic dysfunction in SEPN1-related myopathy.

SEPN1-related myopathy (SEPN1-RM) is characterized by predominant axial muscle weakness, early scoliosis, rigid spine and severe respiratory insufficiency. The aim of the study was to characterize the mechanisms of respiratory dysfunction in SEPN1-RM patients. Breathing pattern and respiratory muscle strength were measured by means of esophageal (Pes) and gastric (Pgas) pressures.

Orthopedic Management of Scoliosis by Garches Brace and Spinal Fusion in SMA Type 2 Children.

Background: Scoliosis is the most debilitating issue in SMA type 2 patients. No evidence confirms the efficacy of Garches braces (GB) to delay definitive spinal fusion.

Objective: Compare orthopedic and pulmonary outcomes in children with SMA type 2 function to management.

Pediatric laminopathies: Whole-body magnetic resonance imaging fingerprint and comparison with Sepn1 myopathy.

Introduction: We sought to define the whole-body MRI (WB-MRI) fingerprint of muscle involvement in pediatric LMNA-related dystrophy (LMNA-RD) and to compare it with SEPN1-related myopathy (SEPN1-RM).

Methods: Signal abnormality and atrophy in 109 muscles were scored by semiquantitative scales in 8 children with LMNA-RD and represented by heatmaps. These features were compared with those from 9 SEPN1-RM patients by random forests.

Whole-body muscle magnetic resonance imaging in SEPN1-related myopathy shows a homogeneous and recognizable pattern.

Introduction: The aim of this study was to delineate the spectrum of muscle involvement in patients with a myopathy due to mutations in SEPN1 (SEPN1-RM).

Methods: Whole-body magnetic resonance imaging (WBMRI) was used in 9 patients using T1-weighted turbo spin-echo (T1-TSE) sequences and short tau inversion recovery (STIR) in 5 patients.

Results: Analysis of signal and volume abnormalities by T1-TSE sequences in 109 muscles showed a homogeneous pattern characterized by a recognizable combination of atrophy and signal abnormalities in selected muscles of the neck, trunk, pelvic girdle, and lower limbs.

Congenital muscular dystrophy phenotype with neuromuscular spindles excess in a 5-year-old girl caused by HRAS mutation.

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene.

Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype.

Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype.

[What a tracheostomy changes in a child with a neuromuscular disease].

Introduction: The severe course of certain early onset neuromuscular disorders may lead to the indication of a tracheostomy for a child, a step that parents dread. Previous publications report that families in this situation face particular difficulties and need to develop new strategies of organization and adaptation in order to cope with the new context of life.

Objectives: The aim of this study is identifying, through the mother's eye, what changes implies tracheostomy for the child and his family.

Congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. The characterization of CMS comprises two complementary steps: establishing the diagnosis and identifying the pathophysiological type of CMS. The combination of clinical, electrophysiological, and morphological studies allows the physician to refer a given CMS to mutation(s) in one of the 18 causative genes discovered to date and, in turn, to classify the CMS according to the location of the mutated proteins at the neuromuscular junction into presynaptic compartment, synaptic basal lamina, and postsynaptic compartment CMS.

Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families.

Background: Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD.

The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis.

Distal arthrogryposis (DA) is a heterogeneous subgroup of arthrogryposis multiplex congenita (AMC), a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. DA is mainly characterized by contractures afflicting especially the distal extremities without overt muscular or neurological signs. Although a limited number of genes mostly implicated in the contractile apparatus have been identified in DA, most patients failed to show mutations in currently known genes.

Whole-Body muscle MRI in a series of patients with congenital myopathy related to TPM2 gene mutations.

Beta-tropomyosin 2 (TPM2) gene mutations are a rare cause of congenital myopathy with variable clinical and histological features. We describe muscle involvement using Whole-Body muscle Magnetic Resonance Imaging (WBMRI) in 8 individuals with genetically proven TPM2 mutations and different clinical and histological features (nemaline myopathy, 'cap disease', Bethlem-like phenotype, arthrogryposis). Most patients shared a recognizable MRI pattern with the involvement of masticatory and distal lower leg muscles.

Tracheotomy and children with spinal muscular atrophy type 1: ethical considerations in the French context.

Spinal muscular atrophy (SMA) type 1 is a genetic neuromuscular disease in children that leads to degeneration of spinal cord motor neurons. This sometimes results in severe muscular paralysis requiring mechanical ventilation to sustain the child's life. The onset of SMA type 1, the most severe form of the disease, is during the first year of life.

Riluzole pharmacokinetics in young patients with spinal muscular atrophy.

Aims: The objective of the present study was to assess the pharmacokinetics of riluzole in patients with spinal muscular atrophy (SMA).

Methods: Fourteen patients were enrolled in an open-label, nonrandomized and repeat-dose pharmacokinetic study. All participants were assigned to receive 50mg riluzole orally for 5 days.

Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation.

Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia.

Early onset collagen VI myopathies: Genetic and clinical correlations.

Objective: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.

Methods: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%).

Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression.

The presence of variable degrees of cognitive impairment, extending from severe mental retardation to specific deficits, in patients with dystrophinopathies is a well-recognized problem. However, molecular basis underlying mental retardation and its severity remain poorly understood and still a matter of debate. Here, we report one of the largest study based on the comparison of clinical, cognitive, molecular and expression data in a large cohort of 81 patients affected with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) bearing mutations predicted to affect either all dystrophin products, including Dp71 or all dystrophin products, except Dp71.

De novo LMNA mutations cause a new form of congenital muscular dystrophy.

Objective: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations.

Methods: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients.

Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores.

Mutations of the ryanodine receptor cause dominant and recessive forms of congenital myopathies with cores. Quantitative defects of RYR1 have been reported in families presenting with recessive forms of the disease and epigenic regulation has been recently proposed to explain potential maternal monoallelic silencing of the RYR1 gene. We investigated nine families presenting with a recessive form of the disease and showing a quantitative defect of RYR1 expression.

Protein O-mannosyltransferase activities in lymphoblasts from patients with alpha-dystroglycanopathies.

Defects in O-mannosylation of alpha-dystroglycan cause some forms of congenital muscular dystrophy (CMD), the so-called alpha-dystroglycanopathies. Six genes are responsible for these diseases with overlapping phenotypes. We investigated the usefulness of a biochemical approach for the diagnosis and investigation of the alpha-dystroglycanopathies using immortalized lymphoblasts prepared from genetically diagnosed and undiagnosed CMD patients and from control subjects.

C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy.

Objective: The giant protein titin is essential for striated muscle development, structure, and elasticity. All titin mutations reported to date cause late-onset, dominant disorders involving either skeletal muscle or the heart. Our aim was to delineate the phenotype and determine the genetic defects in two consanguineous families with an early-onset, recessive muscle and cardiac disorder.

Brain MRI abnormalities in muscular dystrophy due to FKRP mutations.

Introduction: FKRP mutations cause a muscular dystrophy which may present in the neonatal period (MDC1C) or later in life (LGMD2I). Intelligence and brain imaging have been previously reported as being normal in FKRP-associated muscular dystrophy, except in rare cases presenting with mental retardation associated with structural brain abnormalities.

Patients And Methods: We studied cerebral MRIs in twelve patients with FKRP-associated muscular dystrophy presenting in infancy or early childhood, at ages between 14 months and 43 years.

SEPN1: associated with congenital fiber-type disproportion and insulin resistance.

Objective: Our first objective was to determine whether SEPN1 gene mutations are a cause of congenital fiber-type disproportion (CFTD), a rare form of congenital myopathy in which relative hypotrophy of type 1 (slow twitch) muscle fibers is the principal abnormality on histology. Second, we investigated an association between SEPN1-related myopathy and insulin resistance.

Methods: We sequenced SEPN1 in five unrelated CFTD patients with scoliosis and respiratory muscle weakness and screened an additional 22 CFTD patients for abnormalities in SEPN1 by Western blotting and restriction digest for the 943G-->A mutation.