URL path: Index page // Alpha-Dystroglycanopathies, Genetic Testing

Alpha-Dystroglycanopathies, Genetic Testing

Congenital muscular alpha-dystroglycanopathy (alpha-dystroglycanopathies or dystroglycanopathies) and Walker-Warburg syndrome are related genetic disorders that fall within a spectrum of congenital muscular dystrophies. Both conditions are characterized by abnormalities in the glycosylation of alpha-dystroglycan, a protein essential for maintaining the integrity of muscle and brain tissues. The dystroglycanopathies are a group of clinically heterogeneous disorders associated with central nervous system disorders and, less frequently, with ocular pathology. They are caused by eight genes encoding for glycosyltransferase enzymes or other accessory proteins.

Alpha-dystroglycanopathies genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Congenital Muscular Alpha-Dystroglycanopathy (Dystroglycanopathies)

This group of disorders includes a range of conditions caused by mutations in various genes involved in the glycosylation of alpha-dystroglycan. Glycosylation is a process where sugar molecules are attached to proteins, and in dystroglycanopathies, abnormalities in this process affect muscle and brain development.

Clinical features of congenital muscular alpha-dystroglycanopathy may include muscle weakness, hypotonia (low muscle tone), developmental delay, intellectual disability, and structural brain abnormalities.

The severity of symptoms can vary widely, and affected individuals may experience a broad spectrum of clinical manifestations.

Walker-Warburg Syndrome

Walker-Warburg syndrome is a severe form of congenital muscular alpha-dystroglycanopathy with additional features affecting the eyes and brain. A triad of congenital muscular dystrophy, structural brain abnormalities, and eye malformations characterize it.

Brain abnormalities in Walker-Warburg syndrome often include cobblestone lissencephaly, a condition where the brain's surface is bumpy due to abnormal neuronal migration.

Eye malformations may include retinal abnormalities, congenital glaucoma, and other ocular anomalies.

Both congenital muscular alpha-dystroglycanopathy and Walker-Warburg syndrome are genetically heterogeneous, caused by mutations in various genes involved in the glycosylation pathway.

Key aspects and considerations

  • Genetic Inheritance: Both conditions are typically inherited in an autosomal recessive manner, meaning that affected individuals inherit a mutated gene from both parents.
  • Diagnosis: Genetic testing is crucial for diagnosing these conditions and identifying the specific gene mutations. Additionally, imaging studies, such as brain MRI, may reveal structural abnormalities.
  • Management: There is currently no cure for these conditions, and management is focused on supportive care, including physical therapy, occupational therapy, and other interventions to address specific symptoms.
  • Prognosis: The prognosis can vary, with Walker-Warburg syndrome generally having a more severe clinical course. Individuals affected by these conditions often require multidisciplinary care involving neurologists, geneticists, ophthalmologists, and other specialists.

Both research and clinical efforts are ongoing to understand these disorders better and explore potential therapeutic interventions. Early diagnosis and comprehensive care can improve outcomes for affected individuals and their families.

Genetically, dystroglycanopathies are heterogeneous; the genes involved include POMT1, POMT2, POMGNT1, FKTN, FKRP, and LARGE. These myopathies generally follow an autosomal recessive mode of inheritance, and pathogenic variants can occur in both homozygosity and compound heterozygosity.

The POMT1 and POMT2 genes are involved in the first steps of the alpha-dystroglycan glycosylation process, and the POMGNT1 gene is involved in the next step. The FKTN gene (formerly known as FCMD) codes a protein particularly abundant in muscle and brain involved in the glycosylation of alpha-dystroglycan in the Golgi apparatus.

About 76 mutations in POMT1 have been identified that may cause various phenotypes of dystroglycanopathies, including WWS and more than 15 genes that may be altered in WWS. Mutations in POMT1 account for between 6.7% and 45.8% of WWS cases, depending on the population.

This test analyzes some of the pathogenic variants related to WWS that are more frequent in people with congenital muscular dystrophies. However, it should be noted that there are many more, so if there are symptoms, it is recommended to perform a complete study by sequencing or other molecular techniques that allow in-depth analysis of the related genes.

The genetic test of alpha-Dystroglycanopathies analyzes the 3 most frequent pathogenic mutations of the FKRP gene plus the 3 most frequent pathogenic mutations of the FKTN gene plus the 1 most frequent pathogenic mutation of POMGNT1 gene plus the 8 most frequent pathogenic mutations of POMT1 gene plus the 2 most frequent pathogenic mutations of POMT2 gene.

With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
Share it