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Congenital Muscular Dystrophies  (CMD)

(last modified February 1, 2004)

CMD / LGMD

The Congenital Muscular Dystrophies (CMD) and the Limb-Girdle Muscular Dystrophy (LGMD) are common forms of highly heterogeneous muscular dystrophies which can be distinguished by their age at onset. In CMD, onset of symptoms is at birth or within the first 6 months of life; in LGMD onset of symptoms is in late childhood, adolescence or even adult life. Inheritance in LGMD can be autosomal dominant (LGMD type 1) or autosomal recessive (LGMD type 2), CMD is always recessively inherited. Recent data show that CMD and LGMD can overlap both clinically and genetically, which suggests that the underlying pathology may follow similar pathways.

CMD

• ENMC - diagnostic criteria for CMD
• CMD entry in GeneTests - GeneClinics

Congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessively inherited diseases, presenting at birth or within the first 6 months of life. Initial signs include hypotonia, muscle weakness and the variable appearance of contractures characterized by dystrophic changes on skeletal-muscle biopsy. The heterogeneous nature of CMD is reflected by differing degrees of motor developmental delay, physical disability, muscle pathology, elevation of serum creatine kinase (CK) and a  variable presence of mental retardation and structural brain defects. The incidence of CMD has been estiamted at 4.7 x 10^-5 and its prevalence at 8 x 10^-6 (Mostacciuolo et al. 1996). Thus, CMD is among the most frequent autosomal recessively inherited neuromuscular disoders.

An international consortium was formed to delineate and subdivide the various forms of CMD (Dubowitz 1994, Muntoni 2003). Until now 8 genetically distinct forms have been found;

• MDC1A (congenital muscular dystrophy type 1A, OMIM 607855), the most common form of CMD (40% of cases), maps to chromosome 6q22-q23 and is due to a primary deficiency in the laminin alpha-2 chain of merosin (laminin-2), resulting from mutations in the LAMA2 gene
  **   LAMA2 on these pages  /  LAMA2 mutation database
• MDC1B (congenital muscular dystrophy type 1B, OMIM 604801) is a variant characterized by secondary merosin deficiency and muscle hypertrophy, which maps to chromosome 1q42 (Brockington et al. 2000); the gene involved has not yet been identified
• MDC1C (congenital muscular dystrophy type 1C, OMIM 606612) maps to chromosome 19q13.3 and is caused by mutations in the FKRP gene, encoding the fukutin-releated protein (Brockington et al. 2001). Mutations in FKRP also cause LGMD2I (limb-girdle muscular dystrophy type 2I, OMIM 607155)
  **   FKRP on these pages  /  FKRP mutation database
• congenital myopathy (OMIM 600536) maps to chromosome 12q13 and is caused by mutations in the ITGA7 gene that lead to integrin alpha7 deficiency (Hayashi et al. 1998)
• FCMD ( Fukuyama congenital muscular dystrophy; OMIM 253800) maps to chromosome 9q31 and results from mutations in the FCMD gene (fukutin, Kobayashi et al. 1998)
• MEB (muscle-eye-brain disease, OMIM 253280), maps to chromosome 1p32-34 and is caused by mutations in the POMGnT1 gene ( O-mannose beta-1,2-N-acetylglucosaminyltransferase), which participates in O-mannosyl glycan synthesis (Yoshida et al. 2001)
• WWS (Walker-Warburg syndrome, OMIM 236670) maps to chromosome 9q34 and is caused by mutations in the POMT1 gene (O-mannosyltransferase 1, Beltran-Valero de Bernabe et al. 2002)
• RSMD1, rigid spine muscular mystrophy ( Muscular Dystrophy, Congenital, merosin-positive, with early spine rigidity; OMIM 602771) and severe classic multi minicore myopathy map to chromosome 1p35-36 (Moghadaszadeh et al. 1998) and are caused by mutations in the SEPN1 gene (selenoprotein N 1, Moghadaszadeh et al. 2001, Ferreiro et al. 2002). In contrast to congenital muscular dystrophy patients with merosin deficiency, those with mutations in the SEPN1 gene are ambulant and present a milder muscular dystrophy with no basal membrane alteration and almost normal levels of serum CK (Moghadaszadeh et al. 2001)
• UCMD (Ullrich Congenital Muscular Dystrophy or Ullrich disease; OMIM 254090); types 1, 2 and 3 map to chromosomes 21q22.3, 21q22.3 and 2q37 resp, resulting from mutations in the COL6A1, COL6A2 and COL6A3 genes coding for chains of collagen VI (Camacho Vanegas et al. 2001)

MDC1A - LAMA2

Merosin is an extracellular matrix protein which consists of three laminin chains, alpha2-beta1-gamma1. Laminin-alpha2 (LAMA2) forms a link between the peripheral membrane protein alpha-dystroglycan and the basal lamina. Children with mutations in the LAMA2-gene usually have no detectale protien expression and a severe form of Congenital Muscular Dystrophy (CMD), commonly known as merosin-deficient CMD (MDC1A). Tan et al. (1997) described a large Turkish family with a clear LGMD phenotype which was linked to the LAMA2 locus on 6q22-23 (patients had a reduced laminin-alpha2 expression in a skeletal muscle biopsy). Recently, Allamand (1997), Naom (1998) and Naom (2000) identified mutations in the LAMA2-gene in patients with an LGMD-like phenotype and a partial laminin-alpha2 deficiency.
**   LAMA2 on these pages  /  LAMA2 mutation database

A number of CMD forms have been described which have a reduced laminin-alpha2 expression but which are not due to mutations in the LAMA2-gene, designated "secondary laminin-alpha2 deficiency". One of these is Fukuyama CMD (FCMD, OMIM:253800), a multi-system disease in which skeletal muscle, cardiac muscle and brain are affected. The gene mutated in FCMD encodes fukutin, a protein of unknown function (Kobayashi, 1998). Hayashi et al. (2001) noted a profound depletion of alpha-dystroglycan in skeletal and cardiac muscle of FCMD patients. Brockington et al. (2001) idetified a gene similar to fukutin, designated "fukutin-related protein (FKRP)", which was mutated in a severe form of CMD, MDC1C (OMIM:606596). MDC1C is characterized by early onset, inability to achieve independent ambulation, muscle hypertrophy, marked elevation of serum creatine kinases, no brain involvement, a secondary laminin-alpha2 deficiency as well as a marked decrease in immunostaining of muscle alpha-dystroglycan and a reduction of its molecular weight on Western blot analysis (Brockington). Mutations in the FKRP gene also cause Limb-Girdle muscular dystrophy type 2I (LGMD-2I).
**   FKRP on these pages  /  FKRP mutation database

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