alpha-Dystroglycanopathy
The alpha-Dystroglycan Related Disorders represent a large spectrum of neurological and physical impairment.  Affected individuals that present in infancy are classified as having congenital muscular dystrophy (Walker-Warburg Syndrome, Muscle Eye Brain Disease and Fukuyama) and often have brain involvement, including seizures and cognitive disabilities. Affected individuals that present in childhood or adulthood are classified as having limb girdle muscular dystrophy, with muscle involvement and possible cognitive impairment.  Respiratory and cardiac involvement may also present during disease progression. Inheritance in this group of disorders is autosomal recessive.

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alpha-Dystroglycan

The genes involved in the dystroglycanopathies modify a protein called alpha-dystroglycan (α-DG). This modification is called glycosylation and it is necessary for (α)-DG to work. α-DG anchors the structural framework of the cell to the lattice of proteins and other molecules outside the cell (extracellular matrix). In skeletal muscle, this anchoring function stabilizes and protects muscle fibers. In the brain, it directs the migration of nerve cells (neurons) during early development.

Disorder
Genes
Onset
Walker-Warburg Syndrome, Muscle Eye Brain Disease
ALG13, B3GLNT2, B4GAT1, DAG1, FKRP, FKTN, GMPPB, ISPD, LARGE, POMGnT1, POMGnT2, POMT1, POMT2, RXYLT1/TMEM5
Congenital
Fukuyama CMD
FKTN
Congenital
CMD with or without Cognitive Impairment
DOLK, DPM1, DPM2, DPM3, FKRP, FKTN, POMT1,POMT2, POMGnT1
Congenital
Limb Girdle Muscular Dystrophy with or without Cognitive Impairment
DAG1, FKRP, FKTN, GMPPB, ISPD, POMT1, POMT2, POMGnT1, POMGnT2
Childhood or
early adulthood

Diagnosing α-DG Related Disorders

To confirm a diagnosis beyond the clinical characteristics, genetic panel testing can identify which gene is affected.  Genetic panel testing involves looking for genetic mutations in genes known to cause congenital muscular dystrophy.  It is possible that the gene-causing mutations cannot be identified with current testing technology. New genes that can cause dystroglycanopathy continue to be discovered. 

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Walker-Warburg Syndrome

WWS is associated with brain and eye abnormalities. Signs and symptoms present at birth and may include hypotonia, developmental delay, intellectual disability, and seizures. WWS is also associated with lissencephaly, hydrocephalus, cerebellar malformations, and eye abnormalities. Respiratory and cardiac involvement are also common.

 

Muscle Eye Brain Disease 

MEB symptoms present at birth, and may include hypotonia, myopia, glaucoma, and brain abnormalities. Affected individuals have developmental delay and intellectual disability, and may experience hydrocephalus. Respiratory and cardiac involvement are also common.

 

Fukuyama CMD

FCMD presents at birth or in early infancy and involves feeding difculties, hypotonia, ptosis, joint contractures.  Affected individuals experience developmental delay in speech, motor function, and may have moderate to severe intellectual disability.  Seizures, respiratory and cardiac complications are also common.  

 

CMD with Cognitive Impairment

Symptoms can be present at birth or within the first two years of life, and may include muscle weakness, feeding difficulties, hypotonia, joint contractures and scoliosis. Motor skill delays are observed with walking achieved only in some cases.  Cognitive Impairment is present, ranging from moderate to severe intellectual disability. Respiratory and cardiac abnormalities may also be present. 

 

CMD without Cognitive Impairment

Symptoms can present at birth or later in life, and may include hypotonia, feeding difficulties,  joint contractures and scoliosis. Affected individuals may have delayed motor skills, and may never achieve ambulation. Respiratory and cardiac abnormalities may also be present. 

 

Limb Girdle Muscular Dystrophies
LGMDR9 FRRP Related (formerly LGMD2I), LGMDR11 POMT1 Related (formerly LGMD2K), LGMDR13 FKTN Related (formerly LGMD2M), LGMDR14 POMT2 Related (formerly LGMD2N) and LGMDR15 POMGnT1 (formerly LGMD2O), LGMDR16 DAG1 Related (formerly LGMD2P), LGMDR19 GMPPB Related (formerly LGMD2T), LGMDR20 ISPD Related (formerly LGMD2U), and LGMDR24 POMGnT2 Related (formerly known as POMGnT2).

LGMD associated with glycosylation abnormalities primarily involve weakness in distal muscles (arms and legs). Affected individuals should be monitored for respiratory and cardiac complications. Some may experience mild cognitive impairment.

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