Explore chapters and articles related to this topic
Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
The autosomal recessive forms of LGMD are in fact more common than the autosomal dominant forms, and present between two and 40 years of age. The most common form of adult onset LGMD in Northern Europe is LGMD2I, which is caused by mutations in the gene fukutin-related protein (FKRP). LGMD2I presents with axial, neck flexor and proximal girdle weakness, associated with hypertrophy of muscles such as the tongue, and calves. Respiratory muscle weakness leading to nocturnal hypoventilation is common, and a cardiomyopathy occurs in a third of cases. LGMD2B is caused by mutations in the dysferlin gene. This may present either as a proximal LGMD subtype or a distal lower limb posterior calf compartment weakness (also known as Miyoshi myopathy). LGMD2A is caused by mutations in the calpain gene. It presents with a typical LGMD phenotype but is associated with atrophy of muscles rather than hypertrophy. Cardiac involvement is rare in LGMD2A and 2B.
Structural and ultrastructural changes in the skeletal muscles of dysferlin-deficient mice during postnatal ontogenesis
Published in Ultrastructural Pathology, 2022
O. N. Chernova, I. A. Chekmareva, M. O. Mavlikeev, I. A. Yakovlev, A. P. Kiyasov, R.V. Deev
Dysferlin is a protein located in sarcolemma and a t-tubule system encoded by the DYSF gene. Dysferlin is responsible for many functions in muscle fibers, such as the repair of damaged sarcolemma, vesicle fusion, cell adhesion, intercellular signaling,1–5 myoblast fusion6 and t-tubule reorganization during myogenesis.3,7,8 Normally, in sarcolemmal rupture, calcium ions trigger synaptic vesicle fusion with membrane “patch” formation. Without dysferlin, vesicular trafficking to the site of rupture is impaired. Progressive sarcolemma disruption results in necrosis of skeletal muscles with fibrosis and lipoidosis.9 Moreover, the lack of dysferlin expression decreases lysosomal exocytosis.10 Mutations in the DYSF gene cause inherited autosomal-recessive muscle dystrophies called dysferlinopathies. This group of disorders includes three clinical phenotypes: limb-girdle muscular dystrophy (LGMD) R2 (OMIM 254130), Myoshi muscular dystrophy (OMIM 253601) and distal myopathy with anterior tibial onset (OMIM 606678). These patients usually manifest limb-girdle muscle weakness in the second decade of life.11 Approximately 5% of previously described patients develop asymptomatic hyperCPKemia.12,13 This finding indicates a probable prolonged subclinical course of dysferlinopathies. As dysferlinopathy is an orphan disease (prevalence of 7.4:1000000),14 the absence of clinical manifestations prevents patients from being within the health care system. Moreover, studying dysferlinopathy pathogenesis at early stages is almost impossible due to the traumatic nature of muscle biopsy in asymptomatic pediatric patients.
An update on diagnostic options and considerations in limb-girdle dystrophies
Published in Expert Review of Neurotherapeutics, 2018
Corrado Angelini, Laura Giaretta, Roberta Marozzo
In dysferlinopathy, a severe reduction or loss of dysferlin (<20% of controls) is a rather specific marker of the disease [32]. Western blotting analysis has been proven to be more efficient than IHC to detect partial dysferlin defects, including the identification of heterozygous carriers (reduction of about 50%), also in blood monocytes [37].