Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Jungbluth, Heinz; Treves, Susan; Zorzato, Francesco; Sárközy, Anna; Ochala, Julien; Sewry, Caroline A.; Phadke, Rahul; Gautel, Mathias; Muntoni, Francesco

doi:10.1038/nrneurol.2017.191

Cited by 227 publications

(235 citation statements)

References 237 publications

(192 reference statements)

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“…First described as a single entity in 1956 [43], congenital myopathies are now considered a spectrum of rare, slowly-progressive neuromuscular disorders with overlapping symptoms and histopathology [31]. Congenital myopathies have been attributed to pathogenic variants in over 20 genes.…”

Section: Introductionmentioning

confidence: 99%

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.Electronic supplementary materialThe online version of this article (10.1007/s00415-018-9033-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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“…The most distinctive structural abnormality observed in all patients was the presence of multiminicores in the majority of type I fibers. This is the first report of core‐rod pathology in TNNT1 ‐related myopathy …”

Section: Discussionmentioning

confidence: 68%

“…The nemaline myopathies (NMs) are a group of genetically and clinically heterogeneous myopathies defined by the presence of nemaline rod inclusions in skeletal muscle fibers . The phenotypic spectrum ranges from severe congenital forms to milder adult onset presentations .…”

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confidence: 99%

Novel Recessive TNNT1 Congenital Core‐Rod Myopathy in French Canadians

Pellerin

Aykanat

Ellezam

et al. 2020

Annals of Neurology

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Objective Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core‐rod myopathy. Methods Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss‐of‐function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild‐type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype. Results Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb‐girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild‐type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so. Interpretation This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568–583

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“…In addition, electromyography showed subtle features of denervation rather than the silent cramps or myopathic features that have been reported numerous times. The muscle biopsy also showed suggestions of histological features found in some congenital myopathies (Jungbluth et al, ). These findings indicate that Brody myopathy, along with genetic analysis of ATP2A1 , should be considered in patients with clinical myotonia of unclear etiology, as well as patients who have findings suggestive of congenital myopathy on muscle biopsy.…”

Section: Discussionmentioning

confidence: 85%

Identification of a pathogenic mutation in ATP2A1 via in silico analysis of exome data for cryptic aberrant splice sites

Bruels

Mendoza

et al. 2019

Molec Gen & Gen Med

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Background Pathogenic mutations causing aberrant splicing are often difficult to detect. Standard variant analysis of next‐generation sequence (NGS) data focuses on canonical splice sites. Noncanonical splice sites are more difficult to ascertain. Methods We developed a bioinformatics pipeline that screens existing NGS data for potentially aberrant novel essential splice sites (PANESS) and performed a pilot study on a family with a myotonic disorder. Further analyses were performed via qRT‐PCR, immunoblotting, and immunohistochemistry. RNAi knockdown studies were performed in Drosophila to model the gene deficiency. Results The PANESS pipeline identified a homozygous ATP2A1 variant (NC_000016.9:g.28905928G>A; NM_004320.4:c.1287G>A:p.(Glu429=)) that was predicted to cause the omission of exon 11. Aberrant splicing of ATP2A1 was confirmed via qRT‐PCR, and abnormal expression of the protein product sarcoplasmic/endoplasmic reticulum Ca ++ ATPase 1 (SERCA1) was demonstrated in quadriceps femoris tissue from the proband. Ubiquitous knockdown of SERCA led to lethality in Drosophila, as did knockdown targeting differentiating or fusing myoblasts. Conclusions This study confirms the potential of novel in silico algorithms to detect cryptic mutations in existing NGS data; expands the phenotypic spectrum of ATP2A1 mutations beyond classic Brody myopathy; and suggests that genetic testing of ATP2A1 should be considered in patients with clinical myotonia.

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Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

Cited by 227 publications

References 237 publications

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Novel Recessive TNNT1 Congenital Core‐Rod Myopathy in French Canadians

Identification of a pathogenic mutation in ATP2A1 via in silico analysis of exome data for cryptic aberrant splice sites

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