Limb girdle muscular dystrophy type 2I: No correlation between clinical severity, histopathology and glycosylated α-dystroglycan levels in patients homozygous for common FKRP mutation

Alhamidi, M.; Brox, Vigdis; Stensland, Eva; Liset, Merete; Lindal, Sigurd; Nilssen, Øivind

doi:10.1016/j.nmd.2017.02.015

Cited by 31 publications

(32 citation statements)

References 29 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some previous studies found higher proportion of females with sarcoglycanopathies, while other studies did not; and male predominance in LGMD2I/LGMD‐R9‐FKRP‐related was not previously reported. Further larger cohorts on these subtypes should clarify if there are sex differences in these autosomal recessive diseases or whether these findings reflect selection bias. The finding of male predominance in LGMD2L/LGMD‐R12‐anoctamin5‐related is well established, although little is understood …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinicogenetic lessons from 370 patients with autosomal recessive limb‐girdle muscular dystrophy

et al. 2019

View full text Add to dashboard Cite

Limb‐girdle muscular dystrophies (LGMD) are a group of genetically heterogeneous disorders characterized by predominantly proximal muscle weakness. We aimed to characterize epidemiological, clinical and molecular data of patients with autosomal recessive LGMD2/LGMD‐R in Brazil. A multicenter historical cohort study was performed at 13 centers, in which index cases and their affected relatives' data from consecutive families with genetic or pathological diagnosis of LGMD2/LGMD‐R were reviewed from July 2017 to August 2018. Survival curves to major handicap for LGMD2A/LGMD‐R1‐calpain3‐related, LGMD2B/LGMD‐R2‐dysferlin‐related and sarcoglycanopathies were built and progressions according to sex and genotype were estimated. In 370 patients (305 families) with LGMD2/LGMD‐R, most frequent subtypes were LGMD2A/LGMD‐R1‐calpain3‐related and LGMD2B/LGMD‐R2‐dysferlin‐related, each representing around 30% of families. Sarcoglycanopathies were the most frequent childhood‐onset subtype, representing 21% of families. Five percent of families had LGMD2G/LGMD‐R7‐telethonin‐related, an ultra‐rare subtype worldwide. Females with LGMD2B/LGMD‐R2‐dysferlin‐related had less severe progression to handicap than males and LGMD2A/LGMD‐R1‐calpain3‐related patients with truncating variants had earlier disease onset and more severe progression to handicap than patients without truncating variants. We have provided paramount epidemiological data of LGMD2/LGMD‐R in Brazil that might help on differential diagnosis, better patient care and guiding future collaborative clinical trials and natural history studies in the field.

show abstract

Section: Discussionmentioning

confidence: 99%

“…LGMD-R9-FKRP-related was not previously reported. 35,36 Further larger cohorts on these subtypes should clarify if there are sex differences in these autosomal recessive diseases or whether these findings reflect selection bias. The finding of male predominance in LGMD2L/…”

Section: Sex Effectmentioning

confidence: 99%

Clinicogenetic lessons from 370 patients with autosomal recessive limb‐girdle muscular dystrophy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In both LGMD2I and WWS/MEB, FKRP protein is expressed at relatively normal levels; however, the amount of glycosylation of α-dystroglycan is somewhat reflective of the disease severity and classification (45). There are conflicting reports as to whether or not the levels and complexity of α-dystroglycan glycosylation are faithfully representative of disease severity and classification of FKRP pathogenic variants (16). Recent work in gene therapy has shown that overexpression of full-length FKRP protein using systemic AAV delivery can block muscle wasting and cardiac symptoms associated with LGMD2I (33,46).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to having severely reduced levels of glycosylated α-dystroglycan protein, these patients have decreased levels of laminin matrix proteins that may explain some of the severe retinal and brain pathologies (15). While the genetic causes of both LGMD2I and WWS/MEB have been identified, the consequential disparate clinical pathologies between the 2 disorders with the same causative gene remain poorly understood (16,17).…”

Section: Introductionmentioning

confidence: 99%

A limb-girdle muscular dystrophy 2I model of muscular dystrophy identifies corrective drug compounds for dystroglycanopathies

Serafini¹,

Feyder²,

Hightower³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

Zebrafish are a powerful tool for studying muscle function owing to their high numbers of offspring, low maintenance costs, evolutionarily conserved muscle functions, and the ability to rapidly take up small molecular compounds during early larval stages. Fukutin-related protein (FKRP) is a putative protein glycosyltransferase that functions in the Golgi apparatus to modify sugar chain molecules of newly translated proteins. Patients with mutations in the FKRP gene can have a wide spectrum of clinical symptoms with varying muscle, eye, and brain pathologies depending on the location of the mutation in the FKRP protein. Patients with a common L276I FKRP mutation have mild adult-onset muscle degeneration known as limb-girdle muscular dystrophy 2I (LGMD2I), whereas patients with more C-terminal pathogenic mutations develop the severe Walker-Warburg syndrome (WWS)/muscle-eye-brain (MEB) disease. We generated fkrp-mutant zebrafish that phenocopy WWS/MEB pathologies including severe muscle breakdowns, head malformations, and early lethality. We have also generated a milder LGMD2I-model zebrafish via overexpression of a heat shock-inducible human FKRP (L276I) transgene that shows milder muscle pathology. Screening of an FDA-approved drug compound library in the LGMD2I zebrafish revealed a strong propensity towards steroids, antibacterials, and calcium regulators in ameliorating FKRP-dependent pathologies. Together, these studies demonstrate the utility of the zebrafish to both study human-specific FKRP mutations and perform compound library screenings for corrective drug compounds to treat muscular dystrophies.

show abstract

“…It has been reported that there is no correlation between the clinical disease severity, histopathology, and glycosylated α -DG levels in patients with LGMD2I [ 10 ]. Muscle magnetic resonance imaging (MRI) is a noninvasive tool that can contribute to the diagnosis and assessment of disease severity and progression in a number of neuromuscular disorders.…”

Section: Introductionmentioning

confidence: 99%

Magnetic Resonance Imaging Findings in the Muscle Tissue of Patients with Limb Girdle Muscular Dystrophy Type 2I Harboring the Founder Mutation c.545A>G in the FKRP Gene

Xie

Xiao

Zheng

et al. 2018

BioMed Research International

View full text Add to dashboard Cite

Limb girdle muscular dystrophy type 2I (LGMD2I) is an autosomal recessive muscular dystrophy that is rare in Asia and is caused by mutations in the fukutin-related protein gene (FKRP). The aim of this study was to determine if there are any characteristic features of muscle on magnetic resonance imaging (MRI) in patients with LGMD2I harboring the founder mutation c.545A>G in FKRP. Using MRI, we delineated changes in the thigh muscles of ten patients with genetically confirmed LGMD2I. The majority of muscle biopsy specimens showed reduced glycosylation of α-dystroglycan, decreased expression of laminin α2, and a dystrophic pattern. In our cohort, the muscles with the most severe fatty infiltration were adductor magnus and vastus intermedius, whereas the rectus femoris, sartorius, and gracilis muscles were relatively spared. In seven patients, we identified a concentric fatty infiltration pattern that was most pronounced in the vastus intermedius and vastus medialis muscles around the distal femoral diaphysis. In this disease, the initial fatty infiltration of the posterior thigh muscles gradually progresses anteriorly regardless of the founder mutation in FKRP. Muscle tissue in patients with LGMD2I who have the founder mutation c.545A>G in FKRP shows a distinctive concentric pattern of fatty infiltration and edema on MRI.

show abstract

Limb girdle muscular dystrophy type 2I: No correlation between clinical severity, histopathology and glycosylated α-dystroglycan levels in patients homozygous for common FKRP mutation

Cited by 31 publications

References 29 publications

Clinicogenetic lessons from 370 patients with autosomal recessive limb‐girdle muscular dystrophy

Clinicogenetic lessons from 370 patients with autosomal recessive limb‐girdle muscular dystrophy

A limb-girdle muscular dystrophy 2I model of muscular dystrophy identifies corrective drug compounds for dystroglycanopathies

Magnetic Resonance Imaging Findings in the Muscle Tissue of Patients with Limb Girdle Muscular Dystrophy Type 2I Harboring the Founder Mutation c.545A>G in the FKRP Gene

Contact Info

Product

Resources

About