Mannosidase is an enzyme that functions like a pair of biological scissors inside cellular recycling centers called lysosomes. Its job is to break down complex sugar molecules by snipping specific sugars from larger molecules, allowing the cell to reuse the basic components. This process is a part of normal cellular maintenance, ensuring materials are properly disassembled and recycled.
The Biological Role of Mannosidase
Inside lysosomes, mannosidase enzymes participate in the glycoprotein degradation pathway, which breaks down proteins linked to sugar chains. This task is handled by two principal forms of the enzyme: alpha-mannosidase and beta-mannosidase. Alpha-mannosidases hydrolyze alpha-1,2, alpha-1,3, and alpha-1,6-mannoside linkages. In contrast, beta-mannosidase is responsible for hydrolyzing terminal, non-reducing beta-D-mannose residues in larger sugar molecules.
The distinct actions of these two enzymes are complementary and necessary for the orderly disassembly of glycoproteins. By removing mannose units, they allow other enzymes to access and break down the rest of the molecule. This systematic degradation ensures that building blocks are available for new synthesis and that waste products do not accumulate.
Mannosidase Deficiency Disorders
When mannosidase enzymes are deficient, their failure to break down mannose-containing oligosaccharides leads to conditions known as mannosidosis. These are classified as lysosomal storage disorders because the undigested molecules accumulate within the lysosomes. This buildup disrupts normal cellular function and causes progressive damage to tissues and organs.
A deficiency in the alpha-mannosidase enzyme, caused by mutations in the MAN2B1 gene, results in alpha-mannosidosis. This disorder is characterized by a broad spectrum of symptoms, including immune deficiency leading to recurrent infections, skeletal abnormalities, hearing loss, and intellectual disability. The progression of the disease can be slow or rapid.
Mutations in the MANBA gene lead to a deficiency of beta-mannosidase and cause the much rarer disorder, beta-mannosidosis. The clinical presentation of beta-mannosidosis can also be variable but often involves neurological complications. Both alpha- and beta-mannosidosis are inherited in an autosomal recessive pattern, meaning an individual must inherit a mutated gene from both parents to be affected.
Diagnosis and Medical Evaluation
Diagnosis of a mannosidase deficiency begins when an individual presents with suggestive clinical features, such as recurrent infections or developmental delays. The primary diagnostic tool is an enzyme activity assay, which measures mannosidase function in a patient’s cells. This test is performed on a blood sample using white blood cells or on cultured skin cells called fibroblasts.
These assays use an artificial substrate that releases a fluorescent signal when cleaved by the mannosidase enzyme. A reduced or absent level of enzyme activity points toward a diagnosis of mannosidosis. In affected individuals, the measured activity is between 5% and 15% of that found in healthy individuals.
A urine test can also screen for abnormal levels of mannose-rich oligosaccharides. While the presence of these undigested sugar chains in the urine is a strong indicator, it is not definitive on its own. To confirm the diagnosis, molecular genetic testing is performed. This analysis identifies the disease-causing mutations in either the MAN2B1 or MANBA gene, which provides a definitive diagnosis.
Therapeutic Approaches
Management of mannosidosis focuses on addressing the enzyme deficiency and managing the resulting symptoms. A primary treatment for alpha-mannosidosis is Enzyme Replacement Therapy (ERT). This approach involves regular intravenous infusions of a recombinant human alpha-mannosidase called velmanase alfa. This therapy helps break down the accumulated oligosaccharides in various tissues, although it does not treat the neurological aspects of the disease as the enzyme does not cross the blood-brain barrier.
For some younger patients with severe forms of alpha-mannosidosis, Hematopoietic Stem Cell Transplantation (HSCT) may be an option. HSCT replaces the patient’s stem cells with those from a healthy donor, enabling the body to produce its own functional enzyme. This procedure carries significant risks and is most effective when performed early in life before irreversible organ damage has occurred.
Comprehensive supportive care is also used to manage mannosidosis. This multidisciplinary approach addresses specific symptoms to improve a patient’s quality of life and can include:
- Physical therapy to address muscle weakness and joint issues
- Hearing aids for hearing loss
- Specialized educational support for developmental delays
- Regular monitoring and prompt treatment of infections due to associated immune deficiencies