Mannosidosis - Causes, Symptoms, and Treatment

Introduction

Mannosidosis is an inherited disease that belongs to a group of diseases called lysosomal storage disorders. Lysosomes are organelles enclosed in a membrane within cells that function as the primary digestive units. Within the lysosomes, the enzymes break down or digest particular nutrients, such as complex molecules composed of sugar attached to a protein (glycoproteins). Inactivity or low levels of the alpha-mannosidase enzyme results in the abnormal accumulation of compounds upstream in the metabolic pathway in the cells of affected individuals with unwanted consequences. Mannosidosis is broadly divided into two types: alpha-mannosidosis and beta-mannosidosis.

What Are the Types, Signs, and Symptoms of Alpha- Mannosidosis?

Alpha-mannosidosis is a genetic condition characterized by the deficiency of an enzyme known as alpha-D-mannosidase, and it usually causes a slowly progressive disease. The deficiency of this enzyme causes an accumulation of mannose-containing oligosaccharides in tissues of the body, including the nervous system. Based on clinical characteristics, alpha-mannosidosis is divided into three major types:

1. Type 1 - It is the mild form that is evident until the teen years and progresses slowly. It does present with skeletal abnormalities and myopathy (diseases that affect the muscles).

2. Type 2 - It is the moderate form that appears before ten years of age and is present with signs of skeletal abnormalities and muscle weakness. This type also progresses slowly. The majority of the affected individuals fall in this category.

3. Type 3 - It is the severe form that begins within the first year after birth. Babies appear normal at birth, but the condition gets progressively worse. It is manifested as early death or prenatal loss from progressive central nervous system involvement or infection.

The cause of this condition is the mutations in the MAN2B1 (mannosidase alpha class 2B member 1) gene. This gene, located in the lysosome, instructs the production of the enzyme lysosomal alpha-mannosidase (LAMAN). This enzyme is essential for the breakdown and recycling of specific complex sugars, which has a sugar molecule called mannose. Mutation in the MAN2B1 gene leads to the inability of alpha-mannosidase to perform its function properly, causing an accumulation of complex sugar molecules in the cell that eventually leads to the malfunctioning of the cells.

Alpha-mannosidosis is an autosomal recessive disease, which means the child gets one copy of the mutated gene from each of his parents.

Some people develop signs and symptoms shortly after birth and may have life-threatening complications in infancy or early childhood. In some cases, people develop moderate symptoms with onset before the age of ten. At times, people may not get diagnosed with the condition until later in life. The signs and symptoms of alpha-mannosidosis:

• Muscle weakness.

• Intellectual disability.

• Skeletal abnormalities.

• Impaired ability to coordinate voluntary movements (ataxia).

• Enlarged liver and spleen (hepatosplenomegaly).

• Coarse facial features (low hairline, large head, prominent forehead).

• Delayed motor skill development.

• Frequent infections.

• Immune deficiency.

• Macroglossia (enlarged tongue).

• Excessive growth of the gums.

What Is the Cause, Signs, and Symptoms of Beta-Mannosidosis?

Beta-mannosidosis is an inherited disease that affects the way certain sugar molecules are processed in the body. It is a rare condition and is one of the fifty diseases that are classified as lysosomal storage disease, where a genetic change interferes with the normal activity of lysosomes in human cells. Beta-mannosidosis is also an autosomal recessive condition, which means the parents of the affected child carry one copy of the mutated gene each.

The cause of beta-mannosidosis is the mutation in the gene called MANBA (mannosidase beta). This gene provides instructions for making beta-mannosidase enzymes. Beta-mannosidase is involved in breaking down complexes of two sugar molecules (disaccharides) containing a sugar molecule called mannose. Mutations in this gene affect the ability of the beta-mannosidase enzyme to perform its function of breaking down mannose-containing disaccharides. These disaccharides eventually accumulate in the lysosomes and result in the malfunctioning of the cells, leading to signs and symptoms of beta-mannosidosis.

The signs and symptoms of beta-mannosidosis are:

• Seizures.

• Frequent ear infections or respiratory infections.

• Hypotonia (poor muscle tone).

• Behavioral and psychiatric disturbances.

• Loss of hearing.

• Intellectual disability.

• Motor development is delayed.

• Angiokeratomas (clusters of dark, red spots on the skin).

• Distinctive facial features and facial dysmorphism.

How to Diagnose Mannosidosis?

The diagnosis of mannosidosis is based on characteristic findings, a thorough clinical evaluation, and detailed case history. The diagnosis is established by the identification of deficient acid alpha-mannosidase and beta-mannosidase enzyme activity in peripheral blood leukocytes and other nucleated cells like fibroblasts. By molecular genetic testing, the identification of pathogenic variants in MAN2B1 and MANBA genes can be made to confirm the diagnosis and allow for family studies. Finding elevated levels of certain mannose-rich oligosaccharides in urine analysis is not a confirmed diagnostic test, though it is considered suggestive of mannosidosis.

What Are the Treatment Options for Mannosidosis?

1. Enzyme Replacement Therapy (ERT) - It is approved in some European countries as a treatment option for mannosidosis. It is a medical treatment that involves intravenous infusions to correct the underlying deficiency of the particular enzyme that causes the symptoms of mannosidosis. This therapy is commonly used for the treatment of lysosomal storage disease.

2. Treatment Options for Preventing Complications and Optimizing the Quality of Life-

• The use of hearing aids for hearing loss.

• Early use of antibiotics for bacterial infections.

• Inserting pressure equalizing tubes when fluid accumulates in the middle ear.

• Use of glasses to correct refractive error.

• Shunting in the case of hydrocephalus involves the insertion of a tube to drain the excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where it can be absorbed.

• Physiotherapy for muscle weakness.

Also, educational considerations include early educational intervention for social skills, the use of sign language for people with hearing loss, speech therapy, and special education to maximize learning.

Conclusion

The prevalence of alpha-mannosidosis is estimated to be one in 50,000, based on a study from Australia. That is why it is considered a rare disease. This disease is not specific to any ethnic group worldwide, and it affects men and women equally. Since it is a genetic condition, genetic counseling is recommended, as it may prove beneficial for patients and their families.