229th ENMC international workshop: Limb girdle muscular dystrophies – Nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017

Straub, Volker; Murphy, Alexander Peter; Udd, Bjarne; Angelini, Corrado; Aymé, Ségolène; Bönneman, Carsten; Visser, Marjolein; Hamosh, Ada; Jacobs, Laura; Khizanishvili, Nina; Kroneman, Madelon; Laflorêt, Pascal; Murphy, A. St. J.; Nigro, Vincenzo; Rufibach, Laura; Sárközy, Anna; Swanepoel, Shaun; Torrente, Ivan; Urtizberea, Andoni; Vissing, John; Walter, Maggie C.

doi:10.1016/j.nmd.2018.05.007

Cited by 285 publications

(264 citation statements)

References 30 publications

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“…POPDC3 associated muscular dystrophy seems to fit a typical LGMD as defined by Walton and Nattrass in 1954 and the LGMD consortium of the European Neuromuscular Centre . MRI helped to further characterize the muscle phenotype in our patients.…”

Section: Discussionsupporting

confidence: 54%

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Vissing

Johnson

Töpf

et al. 2019

Annals of Neurology

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Objective The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene. Methods We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK‐1 current. Results We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy‐terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands’ muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice‐site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano‐gated potassium channel, TREK‐1. Interpretation Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832–843

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Section: Discussionsupporting

confidence: 54%

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Vissing

Johnson

Töpf

et al. 2019

Annals of Neurology

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“…Of note, a subtype of autosomal dominant LGMD, LGMD1B, was previously associated with LMNA mutations . However, a recent reclassification of the LGMDs recognizes laminopathy as a separate category of muscle disease …”

Section: Genotype–phenotype Correlationsmentioning

confidence: 99%

“…87 However, a recent reclassification of the LGMDs recognizes laminopathy as a separate category of muscle disease. 88 The two subtypes also differ in that the severity of skeletal muscle symptoms in EDMD2 is less predictable than in EDMD1. In general, most patients with EDMD2 have a slowly progressive course during the first 3 decades of life with more rapid progression thereafter.…”

Section: Edmd1 and Edmd2mentioning

confidence: 99%

Emery‐Dreifuss muscular dystrophy

et al. 2019

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Emery‐Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life‐threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin‐1, nesprin‐2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.

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“…LGMDs are classified according to the inheritance mode into LGMD1/LGMD‐D, with autosomal dominant inheritance, and LGMD2/LGMD‐R, with autosomal recessive inheritance. Among these groups, each specific subtype is designated by a letter or number given in the chronological order of locus mapping, respectively, in the classical and novel nomenclature systems …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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229th ENMC international workshop: Limb girdle muscular dystrophies – Nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017

Abstract: Udd b , c , d , on behalf of the LGMD workshop study group

Cited by 285 publications

References 30 publications

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Emery‐Dreifuss muscular dystrophy

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

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