A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain

Carbonell-Corvillo, Pilar; Tristán-Clavijo, Enriqueta; Cabrera‐Serrano, Macarena; Servián‐Morilla, Emilia; Martín, Guillermina García; Villarreal-Pérez, Liliana; Infante, Eloy Rivas; Area-Gomez, Estela; Chamorro-Muñoz, M.I.; Gil-Gálvez, Alejandro; Miranda‐Vizuete, Antonio; Martı́nez-Mir, Amalia; Laing, Nigel G.; Paradas, Carmen

doi:10.1016/j.nmd.2018.07.006

Cited by 11 publications

(9 citation statements)

References 21 publications

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“…Because the human mutation has an autosomal dominant inheritance pattern, we generated transgenic animals expressing UNC-54(mut)::GFP in a wild-type genetic background; worms expressing GFP alone and UNC-54(wt)::GFP fusion protein in the same wild-type background served as controls. Transgenic UNC-54(mut)::GFP animals were indistinguishable from wild-type, GFP or UNC-54(wt)::GFP control worms in terms of their body morphology (not shown) and they had normal muscle cell morphology and longitudinal distribution of the myofilaments (Figure 1B), consistent with the mild alteration seen in patients' muscle biopsies [20].…”

Section: Letter To the Editorsupporting

confidence: 56%

“…Previous studies have shown that introducing proline residues in the MYH7 protein interferes with myosin self-assembly [18,21]. Moreover, most MYH7 mutations associated with distal myopathy are located in the mid-rod region of the protein, within exons 32-36 [22], and this is where the c.4679G>C mutation lies [20]. To test whether the p.R1460P change also causes such alteration, we expressed in worm muscle cells an UNC-54::GFP fusion protein with a corresponding proline change to that identified in the patients (UNC-54(mut)::GFP) (Figure 1A).…”

Section: Letter To the Editormentioning

confidence: 99%

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Cautionary Note on the Use of Caenorhabditis Elegans to Study Muscle Phenotypes Caused by Mutations in the Human MYH7 Gene

et al. 2020

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Mutations in the human MYH7 gene, encoding a slow skeletal muscle/β-cardiac myosin heavy chain, cause different types of myopathies. The nematode model Caenorhabditis elegans has frequently been employed to study the molecular and physiological consequences of MYH7 mutations in muscle function by introducing mutations into the unc-54 gene, the worm MYH7 ortholog. We report here that the C. elegans model is not appropriate for such studies if they involve expression of the UNC-54 protein (wild-type or fused to green fluorescent protein) above endogenous levels.

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Section: Letter To the Editorsupporting

confidence: 56%

Section: Letter To the Editormentioning

confidence: 99%

Cautionary Note on the Use of Caenorhabditis Elegans to Study Muscle Phenotypes Caused by Mutations in the Human MYH7 Gene

et al. 2020

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“…In our series of TK2 patients although no clear pattern of fat infiltration was detected, we have identified some radiological common features, as the involvement of the sartorius muscle in all cases. This muscle is usually spared until late stages in many genetic muscle diseases (is only affected early in some myofibrillar myopathies, in the Laing distal myopathy and in RYR1-related myopathies (encodes for ryanodine receptor 1 protein) [12, 25–27]), so this finding could be helpful for differential diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Late-onset thymidine kinase 2 deficiency: a review of 18 cases

Domínguez‐González

Hernández-Laín

Rivas

et al. 2019

Orphanet J Rare Dis

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Background TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the ‘myopathic form’ of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity. Methods We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12. Results The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients. Conclusions The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency.

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“…This observation has been reported repeatedly, but discrepancies in relation to the muscles preferentially affected in the distinct regions are often left unexplained. For example, some reports have highlighted the involvement of the gluteus maximus in the pelvic region [12], while others have postulated a predominance of the gluteus minimus [11]; in the thighs, an earlier and more severe affectation of the sartorius and vastii was highlighted in some studies [7,12], yet elsewhere the involvement of the adductor magnus and the short head of the biceps, in addition to the sartorius, was emphasized [11]. In the legs, early reports suggested that the calf muscles remained well preserved or that they were only affected at more advanced stages [6,22].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, despite the traditional early onset anterior distal myopathy, alternative phenotypic variants have been successively reported, with axial features such as scoliosis/rigid spine, bent spine or dropped head syndromes, scapulo-peroneal syndromes and disto-proximal myopathies [4,[6][7][8][9][10][11]. Asymptomatic carriers of MYH7 mutations have also been reported [6,12], as well as severe forms complicated with respiratory insufficiency [4,7,11] and cases of associated cardiomyopathy [4,[13][14][15][16][17], widening the spectrum and complexity of this disorder.…”

Section: Introductionmentioning

confidence: 99%

A study of the phenotypic variability and disease progression in Laing myopathy through the evaluation of muscle imaging

Muelas

Frasquet

Más-Estellés

et al. 2020

Euro J of Neurology

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Background Laing myopathy is characterized by broad clinical and pathological variability. They are limited in number and protocol of study. We aimed to delineate muscle imaging profiles and validate imaging analysis as an outcome measure. Methods This was a cross‐sectional and longitudinal cohort study. Data from clinical, functional and semi‐quantitative muscle imaging (60 magnetic resonance imaging [MRI] and six computed tomography scans) were studied. Hierarchical analysis, graphic heatmap representation and correlation between imaging and clinical data using Bayesian statistics were carried out. Results The study cohort comprised 42 patients from 13 families harbouring five MYH7 mutations. The cohort had a wide range of ages, age at onset, disease duration, and myopathy extension and Gardner‐Medwin and Walton (GMW) functional scores. Intramuscular fat was evident in all but two asymptomatic/pauci‐symptomatic patients. Anterior leg compartment muscles were the only affected muscles in 12% of the patients. Widespread extension to the thigh, hip, paravertebral and calf muscles and, less frequently, the scapulohumeral muscles was commonly observed, depicting distinct patterns and rates of progression. Foot muscles were involved in 40% of patients, evolving in parallel to other regions with absence of a disto‐proximal gradient. Whole cumulative imaging score, ranging from 0 to 2.9 out of 4, was associated with disease duration and with myopathy extension and GMW scales. Follow‐up MRI studies in 24 patients showed significant score progression at a variable rate. Conclusions We confirmed that the anterior leg compartment is systematically affected in Laing myopathy and may represent the only manifestation of this disorder. However, widespread muscle involvement in preferential but variable and not distance‐dependent patterns was frequently observed. Imaging score analysis is useful to categorize patients and to follow disease progression over time.

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A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain

Cited by 11 publications

References 21 publications

Cautionary Note on the Use of Caenorhabditis Elegans to Study Muscle Phenotypes Caused by Mutations in the Human MYH7 Gene

Cautionary Note on the Use of Caenorhabditis Elegans to Study Muscle Phenotypes Caused by Mutations in the Human MYH7 Gene

Late-onset thymidine kinase 2 deficiency: a review of 18 cases

A study of the phenotypic variability and disease progression in Laing myopathy through the evaluation of muscle imaging

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