Abstract A paediatric and adult whole-body MRI (WB-MRI) protocol using a 1.5-T MRI system was used to examine 117 individuals (106 patients, 11 asymptomatic relatives). Genetic diagnosis was obtained ...in 38 subjects ( RYR1 , LMNA , COL6 , DNM2 , GAA , TPM2 , SGCA , MYH7 , NEB , SMN , FKBP14 ). T1-TSE WB-MRI sequences were abnormal in 67% of patients and 27% of asymptomatic relatives. Multiple striped signal abnormalities (‘tiger-like’) were very specific for COLVI-related myopathy. Distinct involvement of muscles in the head, neck, trunk, girdles and limbs was observed in patients with RYR1 , SEPN1 , GAA , LMNA or TPM2 mutations. Abnormalities and pattern recognition were more frequent in patients studied due to rigid spine syndrome (80% abnormal, recognisable in 75% of cases), hyperlaxity syndrome (75%; 50%) or with confirmed myopathy but absence of these markers (71%; 40%). Pattern was consistent with the molecular diagnosis in 97%. Mild clinical involvement was revealed by muscle testing in three parents with abnormal WB-MRI. The Garches WB-MRI protocol is suitable for a large spectrum of adults and children with early-onset neuromuscular disorders and can be used as an effective screening test in relatives. Recognition of characteristic patterns of abnormalities is improved by whole-body scanning compared with sequential MRI and, therefore, diagnostic impact is greater.
Duchenne and Becker muscular dystrophies (DMD and BMD) are muscle-wasting diseases caused by mutations in the DMD gene-encoding dystrophin. Usually, out-of-frame deletions give rise to DMD, whereas ...in-frame deletions result in BMD. BMD patients exhibit a less severe disease because an abnormal but functional dystrophin is produced. This is the rationale for attempts to correct the reading frame by using an exon-skipping strategy. In order to apply this approach to a larger number of patients, a multi-exon skipping strategy of exons 45-55 has been proposed, because it should correct the mRNA reading frame in almost 75% of DMD patients with a deletion. The resulting dystrophin lacks part of the binding site for the neuronal nitric oxide synthase (nNOSμ), which normally binds to spectrin-like repeats 16 and 17 of the dystrophin. Since these domains are encoded by exons 42-45, we investigated the nNOSμ status in muscle biopsies from 12 BMD patients carrying spontaneous deletions spaning exons 45-55. We found a wide spectrum of nNOSμ expression and localization. The strictly cytosolic mislocalization of nNOSμ was associated with the more severe phenotypes. Cytosolic NO production correlated with both hypernitrosylation of the sarcoplasmic reticulum calcium-release-channel ryanodine receptor type-1 (RyR1) and release of calstabin-1, a central hub of Ca(2+) signaling and contraction in muscle. Finally, this study shows that the terminal truncation of the nNOS-binding domain in the 'therapeutic' del45-55 dystrophin is not innocuous, since it can perturb the nNOS-dependent stability of the RyR1/calstabin-1 complex.
The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers ...followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.
Genetics of laminopathies Ben Yaou, Rabah; Muchir, Antoine; Arimura, Takuro ...
Novartis Foundation symposium,
2005, Letnik:
264
Journal Article
Laminopathies are now recognized as a group of disorders due to mutations of the LMNA gene, which encodes A-type lamins. Primarily, mutations in LMNA have been associated to the autosomal forms of ...Emery-Dreifuss muscular dystrophy, a rare slowly progressive humero-peroneal muscular dystrophy accompanied by early contractures and dilated cardiomyopathy with conduction defects. LMNA mutations have been reported to be responsible for up to 10 distinct phenotypes that affect specifically either the skeletal and/or cardiac muscle, the adipose tissue, the peripheral nervous tissue, the bone tissue or more recently premature ageing. So far more than 180 different LMNA mutations have been identified in 903 individuals. The first studies of phenotype/genotype relationships revealed no dear relation between the phenotype and the type and/or the localization of the mutation, except perhaps for the globular tail domain of lamins A/C. Studies of the consequences of LMNA mutations in the skin cultured fibroblasts from the patients reveal abnormal nuclei in variable proportions, with dysmorphic nuclei exhibiting abnormal patterns of expression of B-type lamins and emerin. Finally, the development of KO and KI LMNA mice, will certainly give further insight into the pathophysiological mechanisms associated with LMNA mutations. For example, Lmna(H222P/H222P) mice harbour phenotypes reminiscent of Emery-Dreifuss muscular dystrophy.
To study the genetic and phenotypic spectrum of patients harboring recessive mutations in
.
We performed whole-exome sequencing in a multicenter cohort of 1929 patients with a suspected hereditary ...myopathy, showing unexplained limb-girdle muscular weakness and/or elevated creatine kinase levels. Immunohistochemistry and mRNA experiments on patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in
.
We identified 4 individuals from 3 families harboring homozygous LOF variants in
, the gene that encodes for Popeye domain containing protein 1 (POPDC1). Patients showed skeletal muscle involvement and cardiac conduction abnormalities of varying nature and severity, but all exhibited at least subclinical signs of both skeletal muscle and cardiac disease. All identified mutations lead to a partial or complete loss of function of
through nonsense-mediated decay or through functional changes to the POPDC1 protein.
We report the identification of homozygous LOF mutations in
, causal in a young adult-onset myopathy with concomitant cardiac conduction disorders in the absence of structural heart disease. These findings underline the role of POPDC1, and by extension, other members of this protein family, in striated muscle physiology and disease. This disorder appears to have a low prevalence, although it is probably underdiagnosed because of its striking phenotypic variability and often subtle yet clinically relevant manifestations, particularly concerning the cardiac conduction abnormalities.
Abstract
Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period ...to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0–2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8–4.0) and age of ambulation loss (median: 7 years, range: 1.2–38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype–phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.
Abbreviated summary
Ben Yaou et al. report the largest cohort of LMNA-congenital muscular dystrophy. They identified phenotypic subgroups based on walking status and specific mutation and defined age range where most clinical progression occurs (5–15 years ago). This will help subject stratification and clinical endpoints designing for future clinical trials
Graphical Abstract
Graphical Abstract
TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are ...poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.
We show that TSPEAR variants cause a frequent recessive ectodermal dysplasia characterized by dental anomalies and multiple founder variants that originated around the end of the last ice age; pathogenic variants destabilize the TSPEAR β-propeller; and TSPEAR is a likely wnt10a-interacting extracellular matrix-dependent signaling regulator with highly restricted expression.
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