Nebulin (NEB) mutations in a childhood onset distal myopathy with rods and cores uncovered by next generation sequencing

Scoto, Mariacristina; Cullup, Thomas; Çırak, Sebahattin; Yau, Shu; Manzur, Adnan; Feng, Lucy; Jacques, Thomas S.; Anderson, Glenn; Abbs, Stephen; Sewry, Caroline A.; Jungbluth, Heinz; Muntoni, F.

doi:10.1038/ejhg.2013.31

Cited by 49 publications

(47 citation statements)

References 18 publications

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“…Recently, Scoto et al (2013) reported a childhood-onset distal myopathy with rods and cores, caused by compound heterozygous NEB variants (the Ashkenazi founder deletion of exon 55 and a frameshift mutation in the alternatively spliced exon 172, family CR2, Table 2). In the current paper, we report compound heterozygous NEB variants identified in two French families in which the patients had a similar distal phenotype (F282, F410; Table 2).…”

Section: The Spectrum Of Myopathies Caused By Variants In Nebmentioning

confidence: 99%

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Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

et al. 2014

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A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (~7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB-associated disease.

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Section: The Spectrum Of Myopathies Caused By Variants In Nebmentioning

confidence: 99%

“…Other, less common entities include early-onset distal myopathy without nemaline bodies [Wallgren-Pettersson et al, 2007], a distal form of NM [Lehtokari et al, 2011], core-rod myopathy with generalized muscle weakness [Romero et al, 2009], and a childhood-onset distal myopathy with rods and cores [Scoto et al, 2013]. …”

Section: Introductionmentioning

confidence: 99%

Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

et al. 2014

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“…20 In 2 cases, next-generation sequencing analysis has subsequently allowed comprehensive analysis of NEB. 21 Histologic analysis. Muscle biopsies were reviewed and classified according to criteria suggested by Dubowitz et al 22 : (1) nemaline myopathy (NM); (2) centronuclear myopathy (CNM); (3) "core myopathies," including central core disease and multiminicore disease; (4) FTD; (5) type 1 fiber predominance/ uniformity; and (6) nonspecific myopathic changes (NSMC).…”

Section: Methodsmentioning

confidence: 99%

Congenital myopathies

et al. 2015

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Objective: To assess the natural history of congenital myopathies (CMs) due to different genotypes. Methods:Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012.Results: Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p 5 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchairdependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). Conclusions:We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling. Neurology ® 2015;84:28-35 GLOSSARY ACTA1 5 skeletal muscle a-actin; AD 5 autosomal dominant; AR 5 autosomal recessive; CM 5 congenital myopathy; CNM 5 centronuclear myopathy; DNIV 5 daily noninvasive ventilation; DNM2 5 dynamin 2; FTD 5 fiber type disproportion; G/J 5 gastrostomy/jejunostomy; KLHL40 5 kelch-like family member 40; MTM1 5 myotubularin; NEB 5 nebulin; NGT 5 nasogastric tube; NM 5 nemaline myopathy; NNIV 5 nocturnal noninvasive ventilation; NSMC 5 nonspecific myopathic changes; RYR1 5 ryanodine receptor type 1; SEPN1 5 selenoprotein N; TPM2 5 b-tropomyosin; TPM3 5 tropomyosin 3.

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“…8 Some patients present with a distal myopathy, with their skeletal muscle biopsies containing nemaline bodies, both nemaline bodies and cores, or no nemaline bodies. 9,10 Rare cases of core-rod myopathy with generalised muscle weakness may also be caused by NEB variants. 11 ACTA1: over 200 different variants identified, with the majority causing nemaline myopathy, or nemaline myopathy with other features (eg cores, actin aggregates, intranuclear rods and zebra bodies).…”

Section: Mutational Spectrummentioning

confidence: 99%