Clinical and electrophysiological evaluation of myasthenic features in an alpha-dystroglycanopathy cohort (FKRP-predominant)

González-Pérez, Paloma; Smith, C. V.; Sebetka, Wendy L.; Gedlinske, Amber M.; Perlman, Seth J.; Mathews, Katherine D.

doi:10.1016/j.nmd.2020.01.002

Cited by 5 publications

(5 citation statements)

References 27 publications

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“…53 Patients affected by dystroglycanopathy often present dysfunctional NMJ, demonstrating the importance of a-DYSTROGLYCAN and the DAPC. 54 a-DYSTROGLYCAN is expressed in both myofibres and satellite cells, suggesting that its lossof-function could affect either cell type, and impact directly or indirectly on the NMJ, especially given the function of a-DYSTROGLYCAN in the nervous system. 55 Satellite cells and NMJ activity could also be compromised in secondary and tertiary dystroglycanopathies, since our analysis confirmed dynamic expression of a-DYSTROGLYCANglycosylating enzymes in early satellite cell myogenesis (Figures 2 and 3).…”

Section: Myopathogenes Encoding Proteins Of the Dapc May Also Affect ...mentioning

confidence: 99%

Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies

Ganassi

Zammit

2022

Eur J Transl Myol

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Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength and motility irreversibly impacts quality of life. In addition to directly affecting skeletal muscle, pathogenesis can also arise from dysfunctional crosstalk between nerves and muscles, and may include cardiac impairment. Muscular weakness is often progressive and paralleled by continuous decline in the ability of skeletal muscle to functionally adapt and regenerate. Normally, the skeletal muscle resident stem cells, named satellite cells, ensure tissue homeostasis by providing myoblasts for growth, maintenance, repair and regeneration. We recently defined 'Satellite Cell-opathies’ as those inherited neuromuscular conditions presenting satellite cell dysfunction in muscular dystrophies and myopathies (doi:10.1016/j.yexcr.2021.112906). Here, we expand the portfolio of Satellite Cell-opathies by evaluating the potential impairment of satellite cell function across all 16 categories of neuromuscular disorders, including those with mainly neurogenic and cardiac involvement. We explore the expression dynamics of myopathogenes, genes whose mutation leads to skeletal muscle pathogenesis, using transcriptomic analysis. This revealed that 45% of myopathogenes are differentially expressed during early satellite cell activation (0 - 5 hours). Of these 271 myopathogenes, 83 respond to Pax7, a master regulator of satellite cells. Our analysis suggests possible perturbation of satellite cell function in many neuromuscular disorders across all categories, including those where skeletal muscle pathology is not predominant. This characterisation further aids understanding of pathomechanisms and informs on development of prognostic and diagnostic tools, and ultimately, new therapeutics.

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Section: Myopathogenes Encoding Proteins Of the Dapc May Also Affect ...mentioning

confidence: 99%

Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies

Ganassi

Zammit

2022

Eur J Transl Myol

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“…It has been validated in patients with neuromuscular diseases 8–10 . The PROMIS‐57 includes 57 questions covering seven domains: physical function, social functioning, etc, and has been validated in several LGMD studies 11–13 . The total raw PROMIS score for each participant is converted to standardized T‐score with a mean = 50 (US general population average) and standard deviation (SD) of 10.…”

Section: Subjects/materials and Methodsmentioning

confidence: 99%

“… 8 , 9 , 10 The PROMIS‐57 includes 57 questions covering seven domains: physical function, social functioning, etc, and has been validated in several LGMD studies. 11 , 12 , 13 The total raw PROMIS score for each participant is converted to standardized T‐score with a mean = 50 (US general population average) and standard deviation (SD) of 10. The customized LGMDD1 questionnaire was collaboratively developed by neuromuscular physicians with LGMDD1 patient input.…”

Section: Subjects/materials and Methodsmentioning

confidence: 99%

LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials

Findlay

Robinson

Poelker

et al. 2022

Ann Clin Transl Neurol

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Objective To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). Methods We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross‐sectional observational study using previously validated patient‐reported outcome assessments (ACTIVLIM, PROMIS‐57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. Results A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5‐1 lb/year). Cross‐sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. Interpretation This study is the largest description of LGMDD1 patients to date and highlights potential genotype‐dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients.

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“…4 The DG complex is essential for neuronal migration, axon guidance, neuromuscular junction formation in the nervous system, and the formation of optic tissue; which explains optic and central nervous system involvement in some patients with dystroglyconopathies. 5,6 Mutations in the gene encoding the fukutin-related protein (FKRP) represent the most common cause of dystroglycanopathies, 3,7 with highly variable phenotypes, ranging from severe CMD with or without compromise to the central nervous system to mild limb-girdle muscular dystrophy type 2I (LGMD2I). 5 FKRP is a type II transmembrane protein that is targeted to the Golgi apparatus through an N-terminal signal anchor.…”

Section: Introductionmentioning

confidence: 99%

Novel Radiological Brain Anomalies in a Patient with Congenital Muscular Dystrophy due to FKRP Mexican Founder Mutation c.1387A > G: Review of the Literature

Cervera-Gaviria¹,

Enterría-Rosales

Juárez-Vignon-Whaley

et al. 2021

J Pediatr Genet

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Mutations in the FKRP gene result in phenotypes with severe forms of congenital muscular dystrophies (CMD) and limb-girdle muscular dystrophies. We present a Mexican patient with a pathogenic homozygous mutation in the FKRP gene (c.1387A > G, p.Asn463Asp) and CMD with radiological brain anomalies as disseminated hyperintensity lesions and discrete generalized cortical atrophy. These findings have not been reported to the best of our knowledge in other patients with the same mutation. The mutation c.1387A > G, p.Asn463Asp in the FKRP gene has been described to have a founder effect in central Mexico, since all the patients described to date are of Hispanic origin. Therefore, we emphasize studying mutations in the FKRP gene in Hispanic pediatric patients with clinical suspicion of CMD. Clinical and molecular diagnosis of specific CMD subtypes is needed to help clarify the prognosis, management, and genetic counseling to the patient and families.

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Clinical and electrophysiological evaluation of myasthenic features in an alpha-dystroglycanopathy cohort (FKRP-predominant)

Cited by 5 publications

References 27 publications

Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies

Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies

LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials

Novel Radiological Brain Anomalies in a Patient with Congenital Muscular Dystrophy due to FKRP Mexican Founder Mutation c.1387A > G: Review of the Literature

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