The Congenital and Limb-Girdle Muscular Dystrophies

Abstract

During the past decade, outstanding progress in the areas of congenital and limb-girdle muscular dystrophies has led to staggering clinical and genetic complexity. With the identification of an increasing number of genetic defects, individual entities have come into sharper focus and new pathogenic mechanisms for muscular dystrophies, like defects of posttranslational O-linked glycosylation, have been discovered. At the same time, this progress blurs the traditional boundaries between the categories of congenital and limb-girdle muscular dystrophies, as well as between limb-girdle muscular dystrophies and other clinical entities, as mutations in genes such as fukutin-related protein, dysferlin, caveolin-3 and lamin A/C can cause a striking variety of phenotypes. We reviewed the different groups of proteins currently recognized as being involved in congenital and limb-girdle muscular dystrophies, associated them with the clinical phenotypes, and determined some clinical and molecular clues that are helpful in the diagnostic approach to these patients.

Classification, diagnosis and potential mechanisms in Pontocerebellar Hypoplasia

“…Dystroglycanopathies cause neocortical dysplasia and variable pontocerebellar hypoplasia and microcephaly or hydrocephalus (Table 3) [64,65]. An X-linked brain malformation phenotype with a moderately simplified gyral pattern and mild cortical dysplasia, only visible on autopsy is due to mutations in the calcium/calmodulin dependent serine protein kinase gene ( CASK ).…”

Classification, diagnosis and potential mechanisms in Pontocerebellar Hypoplasia

“…Dystroglycanopathies cause neocortical dysplasia and variable pontocerebellar hypoplasia and microcephaly or hydrocephalus (Table 3) [64,65]. An X-linked brain malformation phenotype with a moderately simplified gyral pattern and mild cortical dysplasia, only visible on autopsy is due to mutations in the calcium/calmodulin dependent serine protein kinase gene ( CASK ).…”

Myomesin is part of an integrity pathway that responds to sarcomere damage and disease

“…The M-line anchors parts of the contractile sarcomere (myosin and titn) and contains proteins such as myomesin and obscurin. Titin is the most extensively studied of the M-line proteins and mutations in titin’s C-terminus lead to limb girdle muscular dystrophies, tibial and Salih congenital muscular dystrophies [9,24,25]. Although a mutation in the dimerization domain of myomesin 1 leads to hypertrophic cardiomyopathy in humans, no other mutations have been described in M-line proteins, including myomesin 2 and 3 [26].…”

Dysferlin Homozygous Mutation G1418D Causes Limb-Girdle Type 2B in a Mexican Family

“…M UTATIONS ON THE GENES that encode sarcolemmal proteins (sarcoglycans, dysferlin, and caveolin-3) may cause diverse muscular disorders (Cohn and Campbell, 2000;Kirschner and Bonnemann, 2004). Mutations on dysferlin (DYSF) are related to at least three known different pathologic phenotypes of muscular dystrophy called dysferlinopathies (Liu et al, 1998;Nguyen et al, 2005) that includes pathologic phenotypes as the autosomal type B recessive limb-girdle muscular dystrophy (LGMD2B), which affects proximal limbs; Miyoshi myopathy (MM), which is characterized by affections on distal lower limb muscles (Liu et al, 1998;Bushby, 1999;Illa et al, 2001), and the distal anterior compartment myopathy (DMAT).…”

Classification, diagnosis and potential mechanisms in Pontocerebellar Hypoplasia

“…Dystroglycanopathies cause neocortical dysplasia and variable pontocerebellar hypoplasia and microcephaly or hydrocephalus (Table 3) [64,65]. An X-linked brain malformation phenotype with a moderately simplified gyral pattern and mild cortical dysplasia, only visible on autopsy is due to mutations in the calcium/calmodulin dependent serine protein kinase gene ( CASK ).…”

Myomesin is part of an integrity pathway that responds to sarcomere damage and disease

“…The M-line anchors parts of the contractile sarcomere (myosin and titn) and contains proteins such as myomesin and obscurin. Titin is the most extensively studied of the M-line proteins and mutations in titin’s C-terminus lead to limb girdle muscular dystrophies, tibial and Salih congenital muscular dystrophies [9,24,25]. Although a mutation in the dimerization domain of myomesin 1 leads to hypertrophic cardiomyopathy in humans, no other mutations have been described in M-line proteins, including myomesin 2 and 3 [26].…”

Dysferlin Homozygous Mutation G1418D Causes Limb-Girdle Type 2B in a Mexican Family

“…M UTATIONS ON THE GENES that encode sarcolemmal proteins (sarcoglycans, dysferlin, and caveolin-3) may cause diverse muscular disorders (Cohn and Campbell, 2000;Kirschner and Bonnemann, 2004). Mutations on dysferlin (DYSF) are related to at least three known different pathologic phenotypes of muscular dystrophy called dysferlinopathies (Liu et al, 1998;Nguyen et al, 2005) that includes pathologic phenotypes as the autosomal type B recessive limb-girdle muscular dystrophy (LGMD2B), which affects proximal limbs; Miyoshi myopathy (MM), which is characterized by affections on distal lower limb muscles (Liu et al, 1998;Bushby, 1999;Illa et al, 2001), and the distal anterior compartment myopathy (DMAT).…”

Classification, diagnosis and potential mechanisms in Pontocerebellar Hypoplasia

“…Dystroglycanopathies cause neocortical dysplasia and variable pontocerebellar hypoplasia and microcephaly or hydrocephalus (Table 3) [64,65]. An X-linked brain malformation phenotype with a moderately simplified gyral pattern and mild cortical dysplasia, only visible on autopsy is due to mutations in the calcium/calmodulin dependent serine protein kinase gene ( CASK ).…”

Myomesin is part of an integrity pathway that responds to sarcomere damage and disease

“…The M-line anchors parts of the contractile sarcomere (myosin and titn) and contains proteins such as myomesin and obscurin. Titin is the most extensively studied of the M-line proteins and mutations in titin’s C-terminus lead to limb girdle muscular dystrophies, tibial and Salih congenital muscular dystrophies [9,24,25]. Although a mutation in the dimerization domain of myomesin 1 leads to hypertrophic cardiomyopathy in humans, no other mutations have been described in M-line proteins, including myomesin 2 and 3 [26].…”

Dysferlin Homozygous Mutation G1418D Causes Limb-Girdle Type 2B in a Mexican Family

“…M UTATIONS ON THE GENES that encode sarcolemmal proteins (sarcoglycans, dysferlin, and caveolin-3) may cause diverse muscular disorders (Cohn and Campbell, 2000;Kirschner and Bonnemann, 2004). Mutations on dysferlin (DYSF) are related to at least three known different pathologic phenotypes of muscular dystrophy called dysferlinopathies (Liu et al, 1998;Nguyen et al, 2005) that includes pathologic phenotypes as the autosomal type B recessive limb-girdle muscular dystrophy (LGMD2B), which affects proximal limbs; Miyoshi myopathy (MM), which is characterized by affections on distal lower limb muscles (Liu et al, 1998;Bushby, 1999;Illa et al, 2001), and the distal anterior compartment myopathy (DMAT).…”