A novel MYH2 mutation in family members presenting with congenital myopathy, ophthalmoplegia and facial weakness

Willis, Tracey; Hedberg‐Oldfors, Carola; Alhaswani, Zoya; Kulshrestha, Richa; Sewry, Caroline A.; Oldfors, Anders

doi:10.1007/s00415-016-8154-8

Cited by 15 publications

(19 citation statements)

References 15 publications

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“…They are thought to cause disease through reduction or absence of MyHCIIa expression, or loss of function due to involvement of the myosin motor domain. [4,6] The majority of AD mutations involve the coiled coil rod domain (Figure 3) and are thought to exert a dominant negative effect by altering proper assembly of myosin homodimers. [10,11] The E706K mutation impacts the SH1 helix critical for the lever arm swing and is thought to cause a dominant negative effect on muscle via perturbation of conformational changes during ATP hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

“…Table summarizing key clinical characteristics seen in patients with AR or AD MYH2 mutations (A). [3,4,6,10,11,15–17] Mutation map for AR and AD MYH2 mutations. Bolded mutation indicates proband (B).…”

Section: Figurementioning

confidence: 99%

“…[2] Autosomal recessive (AR) mutations in MYH2 also cause external ophthalmoplegia but distinct from AD associated MYH2 myopathy, have mild, diffuse weakness that presents in early childhood and is largely non-progressive. [1,4–6] Unlike AD associated MYH2 myopathy, patient muscle has small or absent type 2A fibers without vacuoles or protein inclusions. [4–6] In the present report we describe a family with a previously unreported c.737 G>A p.(Arg246Thr) homozygous MYH2 variant.…”

Section: Introductionmentioning

confidence: 99%

“…[1,4–6] Unlike AD associated MYH2 myopathy, patient muscle has small or absent type 2A fibers without vacuoles or protein inclusions. [4–6] In the present report we describe a family with a previously unreported c.737 G>A p.(Arg246Thr) homozygous MYH2 variant.…”

Section: Introductionmentioning

confidence: 99%

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Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy

Findlay

Harms

Pestronk

et al. 2018

Neuromuscular Disorders

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Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy

Findlay

Harms

Pestronk

et al. 2018

Neuromuscular Disorders

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“…Facial weakness and ophthalmoplegia are typical clinical features, causing diagnostic difficulties with RYR1 ‐related myopathies. Histopathological abnormalities include core‐like areas, fatty infiltration, fibrosis, excess internal nuclei, rimmed vacuoles and, in particular, a reduction or absence of 2A fibres in recessive cases .…”

Section: Myosin‐related Myopathiesmentioning

confidence: 99%

Myopathology in congenital myopathies

Sewry

Wallgren‐Pettersson

2017

Neuropathology Appl Neurobio

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Congenital myopathies are clinically and genetically a heterogeneous group of early onset neuromuscular disorders, characterized by hypotonia and muscle weakness. Clinical severity and age of onset are variable. Many patients are severely affected at birth while others have a milder, moderately progressive or nonprogressive phenotype. Respiratory weakness is a major clinical aspect that requires regular monitoring. Causative mutations in several genes have been identified that are inherited in a dominant, recessive or X-linked manner, or arise de novo. Muscle biopsies show characteristic pathological features such as nemaline rods/bodies, cores, central nuclei or caps. Small type 1 fibres expressing slow myosin are a common feature and may sometimes be the only abnormality. Small cores (minicores) devoid of mitochondria and areas showing variable myofibrillar disruption occur in several neuromuscular disorders including several forms of congenital myopathy. Muscle biopsies can also show more than one structural defect. There is considerable clinical, pathological and genetic overlap with mutations in one gene resulting in more than one pathological feature, and the same pathological feature being associated with defects in more than one gene. Increasing application of whole exome sequencing is broadening the clinical and pathological spectra in congenital myopathies, but pathology still has a role in clarifying the pathogenicity of gene variants as well as directing molecular analysis.

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MYH2 myopathy, a new case expands the clinical and pathological spectrum of the recessive form

Telese

Pagliarani

Lerario

et al. 2020

Molec Gen & Gen Med

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Background Hereditary myosin myopathies are a group of rare muscle disorders, caused by mutations in genes encoding for skeletal myosin heavy chains (MyHCs). MyHCIIa is encoded by MYH2 and is expressed in fast type 2A and 2B muscle fibers. MYH2 mutations are responsible for an autosomal dominant (AD) progressive myopathy, characterized by the presence of rimmed vacuoles and by a reduction in the number and size of type 2A fibers, and a recessive early onset myopathy characterized by complete loss of type 2A fibers. Recently, a patient with a homozygous mutation but presenting a dominant phenotype has been reported. Methods The patient was examined thoroughly and two muscle biopsies were performed through the years. NGS followed by confirmation in Sanger sequencing was used to identify the genetic cause. Results We describe the second case presenting with late‐onset ophthalmoparesis, ptosis, diffuse muscle weakness, and histopathological features typical for AD forms but with a recessive MYH2 genotype. Conclusion This report contributes to expand the clinical and genetic spectrum of MYH2 myopathies and to increase the awareness of these very rare diseases.

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A novel MYH2 mutation in family members presenting with congenital myopathy, ophthalmoplegia and facial weakness

Cited by 15 publications

References 15 publications

Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy

Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy

Myopathology in congenital myopathies

MYH2 myopathy, a new case expands the clinical and pathological spectrum of the recessive form

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