Alpha-mannosidosis is a rare genetic disorder that falls under the category of lysosomal storage diseases. It is caused by mutations in the MAN2B1 gene, leading to a deficiency of the enzyme alpha-mannosidase. This enzyme is essential for breaking down complex sugar molecules within the lysosomes of cells.
Alpha-mannosidosis 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).
Key features and aspects of alpha-mannosidosis include:
- Enzyme Deficiency: Alpha-mannosidosis results from a deficiency of the alpha-mannosidase enzyme, which is involved in the breakdown of glycoproteins.
- Accumulation of Mannose-Containing Oligosaccharides: Due to enzyme deficiency, mannose-containing oligosaccharides accumulate within the lysosomes of cells, leading to cellular dysfunction and damage.
- Cognitive Impairment: Individuals with alpha-mannosidosis may experience intellectual disability, delayed development, and progressive cognitive decline.
- Physical Abnormalities: Facial features may be distinctive, with coarse facial features, a prominent jaw, and a large tongue. Skeletal abnormalities, hearing loss, and muscle weakness may also be present.
- Immune System Compromises: Individuals with alpha-mannosidosis may have an increased susceptibility to infections due to the impact on the immune system.
- Disease Severity: The severity of alpha-mannosidosis can vary widely. Some individuals may have a milder form with later onset and slower progression, while others may experience more severe symptoms from an early age.
- Genetic Inheritance: Alpha-mannosidosis is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the mutated gene (one from each parent) to manifest the disorder.
- Management and Treatment: There is currently no cure for alpha-mannosidosis. Management focuses on alleviating symptoms and providing supportive care. This may include physical therapy, speech therapy, and interventions to address specific complications. Due to the rarity and complexity of alpha-mannosidosis, a multidisciplinary approach involving medical professionals from various specialties is often necessary to provide comprehensive care and support to affected individuals and their families.
- Genetic Counseling: Genetic counseling is essential for families affected by alpha-mannosidosis to understand the inheritance pattern and assess the risk for future generations.
Diagnosis involves enzyme activity assays and genetic testing to confirm alpha-mannosidase deficiency and identify mutations in the MAN2B1 gene.
The study by Riise Stensland et al. showed that the most common pathogenic variants of alpha-mannosidosis are c.2248C>T (p.Arg750Trp), c.1830+1G>C and c.2426T>C (p.Leu809Pro) representing approximately 27%, 5% and 3% of the disease alleles, respectively. These mutations suppress the activity of the MAN2B1 gene, which codes for lysosomal alpha-mannosidase because they lead to the formation of truncated and non-functional proteins.
The ClinVar database lists about 120 pathogenic variants in MAN2B1. Other alterations that can produce the disease have also been described, such as large deletions in the MAN2B1 sequence that cannot be detected with the technique used here.
The Genetic Test of Alpha-Mannosidosis analyzes the six most frequent pathogenic mutations of the MAN2B1 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).
