Alpha-mannosidosis is a rare inherited disorder that causes problems in many organs and tissues of the body. Affected individuals may have intellectual disability, distinctive facial features, and skeletal abnormalities. Characteristic facial features can include a large head, prominent forehead, low hairline, rounded eyebrows, large ears, flattened bridge of the nose, protruding jaw, widely spaced teeth, overgrown gums, and large tongue. The skeletal abnormalities that can occur in this disorder include reduced bone density (osteopenia), thickening of the bones at the top of the skull (calvaria), deformations of the bones in the spine (vertebrae), knock knees, and deterioration of the bones and joints.

Affected individuals may also experience difficulty in coordinating movements (ataxia); muscle weakness (myopathy); delay in developing motor skills such as sitting and walking; speech impairments; increased risk of infections; enlargement of the liver and spleen (hepatosplenomegaly); a buildup of fluid in the brain (hydrocephalus); hearing loss; and a clouding of the lens of the eye (cataract). Some people with alpha-mannosidosis experience psychiatric symptoms such as depression, anxiety, or hallucinations; episodes of psychiatric disturbance may be triggered by stressors such as having undergone surgery, emotional upset, or changes in routine.

The signs and symptoms of alpha-mannosidosis can range from mild to severe. The disorder may appear in infancy with rapid progression and severe neurological deterioration. Individuals with this early-onset form of alpha-mannosidosis often do not survive past childhood. In the most severe cases, an affected fetus may die before birth. Other individuals with alpha-mannosidosis experience milder signs and symptoms that appear later and progress more slowly. People with later-onset alpha-mannosidosis may survive into their fifties. The mildest cases may be detected only through laboratory testing and result in few if any symptoms.

Mutations in the MAN2B1 gene cause alpha-mannosidosis. This gene provides instructions for making the enzyme alpha-mannosidase. This enzyme works in the lysosomes, which are compartments that digest and recycle materials in the cell. Within lysosomes, the enzyme helps break down complexes of sugar molecules (oligosaccharides) attached to certain proteins (glycoproteins). In particular, alpha-mannosidase helps break down oligosaccharides containing a sugar molecule called mannose.

Mutations in the MAN2B1 gene interfere with the ability of the alpha-mannosidase enzyme to perform its role in breaking down mannose-containing oligosaccharides. These oligosaccharides accumulate in the lysosomes and cause cells to malfunction and eventually die. Tissues and organs are damaged by the abnormal accumulation of oligosaccharides and the resulting cell death, leading to the characteristic features of alpha-mannosidosis.

Normal Function

The MAN2B1 gene provides instructions for making the enzyme alpha-mannosidase. This enzyme works in the lysosomes, which are compartments that digest and recycle materials in the cell. Within lysosomes, the enzyme helps break down complexes of sugar molecules (oligosaccharides) attached to certain proteins (glycoproteins). In particular, alpha-mannosidase helps break down oligosaccharides containing a sugar molecule called mannose.

Health Conditions Related to Genetic Changes

Alpha-mannosidosis

More than 120 mutations in the MAN2B1 gene have been identified in people with alpha-mannosidosis, a rare inherited disorder that causes problems in many organs and tissues of the body. Affected individuals may have intellectual disability, distinctive facial features, and skeletal abnormalities. Some of the MAN2B1 gene mutations that cause alpha-mannosidosis change one protein building block (amino acid) in the alpha-mannosidase enzyme. Other mutations result in an abnormally shortened enzyme, or cause the enzyme to be pieced together incorrectly.

These mutations interfere with the ability of the alpha-mannosidase enzyme to perform its role in breaking down mannose-containing oligosaccharides. These oligosaccharides accumulate in the lysosomes and cause the cells to malfunction and eventually die. Tissues and organs are damaged by the abnormal accumulation of oligosaccharides and the resulting cell death, leading to the characteristic features of alpha-mannosidosis.

Other Names for This Gene

• LAMAN
• lysosomal acid alpha-mannosidase
• MA2B1_HUMAN
• MANB
• mannosidase, alpha B, lysosomal
• mannosidase, alpha, class 2B, member 1

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms varies among the affected people. In general, affected individuals may have intellectual disability, distinctive facial features, and skeletal abnormalities. At least three clinical types (mild, moderate, and severe) have been suggested according to the severity of the symptoms:

• Type 1.Mild form with onset after age ten years, with muscle weakness (myopathy), slow progression, and absence of skeletal abnormalities
• Type 2. Moderate form with onset before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities such as reduced bone density (osteopenia), thickening of the bones at the top of the skull (calvaria), deformations of the bones in the spine (vertebrae), bowed legs or knock knees, and deterioration of the bones and joints. Most cases are classified into this type.
• Type 3. Severe form with progressive symptoms, leading to early death from primary central nervous system (brain and spinal cord) involvement or infection

Characteristic facial features can include a large head, prominent forehead, low hairline, rounded eyebrows, large ears, flattened bridge of the nose, protruding jaw, widely spaced teeth, overgrown gums, and large tongue.

Other symptoms may include:

• Difficulty in coordinating movements (ataxia)
• Delay in developing motor skills such as sitting and walking
• Speech impairments
• Increased risk of infections due to immunodeficiency (with decreased ability to produce specific substances to fight infections (antibodies)
• Enlargement of the liver and spleen (hepatosplenomegaly)
• Buildup of fluid in the brain (hydrocephalus)
• Hearing loss
• Eye problems, such as clouding of the lens of the eye (cataract), and near-sightednes (myopia)
• Pain and inflamed joints

Some people with alpha-mannosidosis have mental problems such as depression, anxiety, or hallucinations. Heart and kidney problems may also occur.

Alpha-mannosidosis is estimated to occur in approximately 1 in 500,000 people worldwide.