alpha-mannosidosis

What Is Alpha-Mannosidosis?

Alpha-mannosidosis is an inherited disease that can cause intellectual disability, skeletal abnormalities, hearing loss, muscle weakness, coarse facial features, increased susceptibility to infection, and problems with controlling body movement. This disease, caused by mutations in the MAN2B1 gene, blocks an enzyme that breaks down the sugar mannose, leading to abnormal accumulation of specific compounds called glycoproteins. The accumulation of sugar-binding glycoproteins results in organ and tissue damage, and the symptoms associated with alpha-mannosidosis.

The severity of symptoms can vary widely among individuals with the disease. However, there are three main types:

Type 1

The mildest form, type 1, appears after the age of ten. Individuals with type 1 typically do not have skeletal abnormalities but do show muscle weakness. Their symptoms may be so mild as to be barely detectable. Symptoms tend to progress slowly.

Type 2

In the moderate form, type 2, symptoms appear before the age of ten. This form of the disease causes skeletal abnormalities and muscle weakness, but symptoms often progress slowly.

Type 3

In the severe form, type 3, the disease is usually fatal in childhood; some affected fetuses even die before birth. The symptoms appear early in infancy and progress rapidly.

While most individuals who are affected with alpha-mannosidosis fall into the moderate category, it may not be possible to predict which form of the disease a person will have based on their specific genetic mutations. Even siblings with the same genetic mutations may have symptoms that vary in severity.

All forms of alpha-mannosidosis involve some degree of intellectual disability, ranging from mild or moderate in type 1 to severe in type 3. Individuals may also demonstrate hearing loss and speech delay. People with alpha-mannosidosis often experience a lack of muscle coordination (ataxia) and general muscle weakness (myopathy) which can translate into individuals learning to walk later than other children and the appearance of clumsiness.

Many individuals with alpha-mannosidosis have a reduced immune response that leads to frequent infection, particularly of the lungs, ears, and digestive system. These infections are most frequent in childhood. Those with type 2 and 3 alpha-mannosidosis experience skeletal abnormalities that may include a reduction in bone density, a deformed spine, bowed legs, and a deterioration of the bones and joints.

Some individuals with the disease experience a buildup of fluid around the brain (hydrocephaly). Some also have an enlargement of the liver and spleen, although this is not thought to cause health problems. Individuals with alpha-mannosidosis may also experience vision problems.

Individuals with this condition share certain facial characteristics, regardless of race. They have prominent foreheads, flattened nasal bridges, broad mouths, and protruding jaws. About 25% of individuals with the disease experience psychiatric problems, often beginning in late puberty or early adolescence. These psychiatric issues have included depression, confusion, anxiety, and hallucinations.

How Common Is Alpha-Mannosidosis?

Alpha-mannosidosis can affect individuals from any race or ethnic group. The prevalence of alpha-mannosidosis is estimated at 1 in 500,000 people worldwide. However, there is currently insufficient information on the prevalence of alpha-mannosidosis in distinct populations.

How Is Alpha-Mannosidosis Treated?

There is no treatment for the underlying cause of alpha-mannosidosis, but physicians can treat symptoms that arise to prevent complications or to enhance an individual's quality of life. Treatments may include the following: antibiotics to reduce bacterial infections; hearing aids and/or tubes to drain fluid from the middle ear; physical therapy to aid in movement; speech therapy and special-education classes to facilitate learning and speech; the use of wheelchairs and other orthopedic aids to improve mobility; and the placement of an implanted shunt near the brain to help drain fluid buildup.

Additional treatments may include treatment for bone disorders such as osteoporosis and vision correction for vision problems. Bone-marrow and stem-cell transplants may improve some symptoms but can carry their own risk for complications.

What Is the Prognosis for an Individual with Alpha-Mannosidosis?

Individuals with milder forms of alpha-mannosidosis typically live until adulthood, with many living into their fifties. Those with the most severe forms, however, usually die before birth or in childhood. Infections are common during childhood but become less frequent when an individual reaches their 20s and 30s, when bone and muscle problems are more of a concern.

Insufficient information on life expectancy, the primary causes of death, and the factors determining disease severity limit the accuracy of prognoses for individuals with alpha-mannosidosis.