Novel Mutations Widen the Phenotypic Spectrum of Slow Skeletal/β-Cardiac Myosin (<i>MYH7</i>) Distal Myopathy

Lamont, Phillipa; Wallefeld, William; Hilton‐Jones, David; Udd, Bjarne; Argov, Zohar; Barboi, Alexandru; Bönneman, Carsten; Boycott, Kym M.; Bushby, Kate; Connolly, Anne M.; Davies, Nicholas; Beggs, Alan H.; Cox, Gerald F.; Dastgir, Jahannaz; DeChene, Elizabeth T.; Gooding, Rebecca; Jungbluth, Heinz; Muelas, Nuria; Palmio, Johanna; Penttilä, Sini; Schmedding, Eric; Suominen, Tiina; Straub, Volker; Staples, Christopher; Bergh, Peter Van den; Vilchez, Juan J.; Wagner, Kathryn R.; Wheeler, Patricia G.; Wraige, Elizabeth; Laing, Nigel G.

doi:10.1002/humu.22553

Cited by 85 publications

(104 citation statements)

References 48 publications

(82 reference statements)

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“…Laing early-onset myopathy (MPD1), caused by dominant variants in the slow/beta cardiac myosin heavy chain gene (MYH7), frequently presents as walking difficulties due to problems with ankle dorsiflexion in early childhood. 21,22 A dominantly inherited myopathy caused by a variant of the Kelch-like homolog 9 gene (KLHL9) was reported by Cirak et al 23 In this family, the muscle weakness started between the age of 8 and 16 years with weakness of ankle extensors and foot drop.…”

Section: Discussionmentioning

confidence: 96%

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

et al. 2016

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We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder -but in contrast, no kyphoscoliosis.

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Section: Discussionmentioning

confidence: 96%

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

et al. 2016

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“…The association of cardiac and skeletal muscle involvement has often been reported in MYH7 mutations [10]. However the specific LVNC has always been described in absence of skeletal muscle impairment [9].…”

Section: Discussionmentioning

confidence: 98%

“…The specific molecular pathobiological processes that cause these different phenotypes remains unexplained [10].…”

Section: Introductionmentioning

confidence: 99%

A rare mutation in MYH7 gene occurs with overlapping phenotype

Ruggiero¹,

Gibertini²,

Stefano³

et al. 2015

Biochemical and Biophysical Research Communications

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“…The subsequent lack of 32 amino acids in the myosin tail (p.1854_1885del) may probably hamper the correct assembly of the myosin filament as suggested [21]. Albeit they presented a similar pathobiological mechanism, the two patients, showed different phenotypes: a dropped head due to axial involvement together with heart dysfunction in case 7 and an early infantile onset of respiratory muscle impairment in case 18.. [22]. Most important in the muscle biopsies of case 7 and 18 there were no features of FTD which characterized the Estonian boy identified by exome sequencing reported in [22].…”

Section: Novel Mutations and Genotype-phenotype Correlation In Comparmentioning

confidence: 97%

MYH7-related myopathies: Clinical, histopathological and imaging findings in a cohort of Italian patients

Savarese

Astrea

Cassandrini

et al. 2015

Neuromuscular Disorders

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Background: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. Results: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. Conclusion: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.

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Novel Mutations Widen the Phenotypic Spectrum of Slow Skeletal/β-Cardiac Myosin (MYH7) Distal Myopathy

Cited by 85 publications

References 48 publications

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

A rare mutation in MYH7 gene occurs with overlapping phenotype

MYH7-related myopathies: Clinical, histopathological and imaging findings in a cohort of Italian patients

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