The Congenital Muscular Dystrophies: Recent Advances and Molecular Insights

Abstract

Over the past decade, molecular understanding of the congenital muscular dystrophies (CMDs) has greatly expanded. The diseases can be classified into 3 major groups based on the affected genes and the location of their expressed protein: abnormalities of extracellular matrix proteins (LAMA2, COL6A1, COL6A2, COL6A3), abnormalities of membrane receptors for the extracellular matrix (fukutin, POMGnT1, POMT1, POMT2, FKRP, LARGE, and ITGA7), and abnormal endoplasmic reticulum protein (SEPN1). The diseases begin in the perinatal period or shortly thereafter. A specific diagnosis can be challenging because the muscle pathology is usually not distinctive. Immunostaining of muscle using a battery of antibodies can help define a disorder that will need confirmation by gene testing. In muscle diseases with overlapping pathological features, such as CMD, careful attention to the clinical clues (e.g., family history, central nervous system features) can help guide the battery of immunostains necessary to target an unequivocal diagnosis.

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

“…15e19 Mutations in FKRP and fukutin (FKTN ), the gene with which FKRP shares homology and from which FKRP got its name, 20,21 both can give rise to forms of either congenital MD or LGMD. 22,23 Recently, both FKRP and fukutin have been shown to possess ribitol 5-phosphate transferase activity, and a tandem ribitol 5-phosphate moiety was shown to be present on a dystroglycan on which laminin binding glycans could be synthesized and which are themselves absent in FKRP-, fukutin-, and isoprenoid synthase domain containingedeficient cells. 24 Lu and colleagues 25 have designed a series of mouse knockin models of disease-relevant human FKRP mutations that give rise to varying degrees of muscle disease pathology and dysfunction.…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…The clinical course is broadly variable and can comprise the involvement of the brain and eyes [1][2][3][4][5][6][7] .…”

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

“…This posttranslational modification is potentially important to α-dystroglycan's affinity for its ligands, including Lama2 [86,89]. Such a relationship, if correct, would nicely explain the similar phenotypes of the dy and myd mice.…”

“…Not long after, mutations in the human LAMA2 gene were identified in muscular dystrophy patients [88]. Muscular dystrophy caused by LAMA2 deficiency (MDC1A) is currently the most common form of the disorder [89].…”

“…Such a relationship, if correct, would nicely explain the similar phenotypes of the dy and myd mice. So far, only one human patient with congenital muscular dystrophy (MDC1D) has been reported to carry a mutation in LARGE [89]. Meanwhile, another LARGE mutation was found in a patient diagnosed with the more severe Walker-Warburg Syndrome (WWS), suggesting phenotypic variation due to allele differences or genetic background that has not yet been observed in mouse models [91].…”