Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

Schnitzler, L; Schreckenbach, Tobias; Nadaj‐Pakleza, Aleksandra; Stenzel, Werner; Rushing, Elisabeth J.; Damme, Philip Van; Ferbert, A.; Petri, Susanne; Hartmann, Christian; Bornemann, Antje; Meisel, Andreas; Petersen, Jens A.; Tousseyn, Thomas; Thal, Dietmar Rudolf; Reimann, Jens; Jonghe, Peter De; Martin, Jean‐Jacques; Bergh, Peter Y. Van den; Schulz, Jörg B.; Weis, Joachim; Claeys, Kristl G.

doi:10.1186/s13023-017-0640-2

Cited by 81 publications

(148 citation statements)

References 54 publications

(69 reference statements)

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“…Other affected family members had difficulty in maintaining an erect posture, which correlated with fatty degeneration of spinal muscles on radiological imaging. In the biopsy of P23, nemaline bodies were found repeatedly, albeit not as frequent as usually seen in sporadic late‐onset nemaline myopathy (SLONM) (78). In addition, muscle weakness was only slowly progressive in this case; there was no rapid progression leading to respiratory weakness within 1–5 years after onset or axial weakness or dysphagia which is often encountered in SLONM cases (78).…”

Section: Resultsmentioning

confidence: 90%

Differential diagnosis of vacuolar myopathies in the NGS era

et al. 2020

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Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.

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Section: Resultsmentioning

confidence: 90%

Differential diagnosis of vacuolar myopathies in the NGS era

et al. 2020

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“…Historically, three muscle diseases have been classified with the congenital myopathies but are currently no longer considered part of this group: (1) sporadic late‐onset nemaline myopathy because of a late onset, rapidly progressive course, lack of clarity concerning a genetic or rather an acquired cause, since some cases are associated with a monoclonal gammopathy or human immunodeficiency virus infection; (2) spheroid body myopathy and sarcotubular myopathy caused by pathogenic variants in the tripartite motif containing 32 ( TRIM32 ) and myotilin ( MYOT ) gene. These entities are now classified with the limb‐girdle muscular dystrophies and myofibrillar myopathies respectively; and (3) reducing body myopathy caused by mutations in the four‐and‐a‐half LIM domains 1 ( FHL1 ) gene, because of a rapid progression and severe disease course …”

Section: Myopathies Excluded From the Initial Congenital Myopathies Cmentioning

confidence: 99%

“…These entities are now classified with the limb-girdle muscular dystrophies and myofibrillar myopathies respectively; and (3) reducing body myopathy caused by mutations in the four-and-a-half LIM domains 1 (FHL1) gene, because of a rapid progression and severe disease course. 2,13,14 DIFFERENTIAL DIAGNOSES OF CONGENITAL MYOPATHIES The most important differential diagnoses of congenital myopathies are congenital muscular dystrophies, congenital myotonic dystrophy type 1, metabolic myopathies including Pompe disease, congenital myasthenic syndromes, and spinal muscular atrophy, which can all occur at neonatal age with severe weakness and/or hypotonia.…”

Section: Myopathies Excluded From the Initial Congenital Myopathies Cmentioning

confidence: 99%

Congenital myopathies: an update

Claeys

2019

Develop Med Child Neuro

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ABBREVIATION MHS Malignant hyperthermia susceptibilityCongenital myopathies comprise a clinical, histopathological, and genetic heterogeneous group of rare hereditary muscle diseases that are defined by architectural abnormalities in the muscle fibres. They are subdivided by the predominant structural pathological change on muscle biopsy, resulting in five subgroups: (1) core myopathies;(2) nemaline myopathies; (3) centronuclear myopathies; (4) congenital fibre type disproportion myopathy; and (5) myosin storage myopathy. Besides the clinical features, muscle biopsy, muscle imaging, and genetic analyses are essential in the diagnosis of congenital myopathies. Using next-generation sequencing techniques, a large number of new genes are being identified as the cause of congenital myopathies as well as new mutations in known genes, broadening the phenotype-genotype spectrum of congenital myopathies. Management is performed by a multidisciplinary team specialized in neuromuscular disorders, where the (paediatric) neurologist has an essential role. To date, only supportive treatment is available, but novel pathomechanisms are being discovered and gene therapies are being explored.

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“…The congenital type comprises approximately 16% of all NM cases (Ryan et al, ) and classically presents with decreased fetal movements, severe hypotonia, muscle weakness, feeding difficulties, and respiratory insufficiency in the neonatal period (Ryan et al, ). In contrast to earlier‐onset forms, adult‐onset forms typically occur sporadically and may be associated with monoclonal gammopathy of unknown significance (Schnitzler et al, ).…”

Section: Introductionmentioning

confidence: 99%

Neonatal fractures as a presenting feature of LMOD3‐associated congenital myopathy

Abbott

Jain

Pferdehirt

et al. 2017

American J of Med Genetics Pt A

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Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in twelve genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory failure requiring ventilator support in three siblings from a consanguineous family. All exhibited perinatal fractures, and thus, a skeletal dysplasia was considered as possibly contributing to the phenotype. However, whole exome sequencing revealed a homozygous, loss-of-function pathogenic variant in LMOD3, which has recently been associated with nemaline myopathy and, in a subset of patients, perinatal fractures. This case demonstrates the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures.

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Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

Cited by 81 publications

References 54 publications

Differential diagnosis of vacuolar myopathies in the NGS era

Differential diagnosis of vacuolar myopathies in the NGS era

Congenital myopathies: an update

Neonatal fractures as a presenting feature of LMOD3‐associated congenital myopathy

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