Mannosidosis

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Mannosidosis

Definition

Mannosidosis is a rare inherited disorder, an inborn error of metabolism, that occurs when the body is unable to break down chains of a certain sugar (mannose) properly. As a result, large amounts of sugar-rich compounds build up in the body cells, tissues, and urine, interfering with normal body functions and development of the skeleton.

Description

Mannosidosis develops in patients whose genes are unable to make an enzyme required by lysosomes (structures within the cell where proteins, sugars, and fats are broken down and then released back into the cell to make other molecules). Lysosomes need the enzyme to break down, or degrade, long chains of sugars. When the enzyme is missing and the sugar chains are not broken down, the sugars build up in the lysosomes. The lysosomes swell and increase in number, damaging the cell. The result is mannosidosis.

The enzyme has two forms: alpha and beta. Similarly, the disorder mannosidosis has two forms: alpha-mannosidosis (which occurs when the alpha form of the enzyme is missing) and beta-mannosidosis (which occurs when the beta form of the enzyme is missing). Production of each form of the enzyme is controlled by a different gene .

First described in 1967, alpha-mannosidosis is classified further into two types. Infantile (or Type I) alpha-mannosidosis is a severe disorder that results in mental retardation, physical deformities, and death in childhood. Adult (or Type II) alpha-mannosidosis is a milder disorder in which mental retardation and physical deformities develop much more slowly throughout the childhood and teenage years.

Beta-mannosidosis was identified nearly 20 years later in 1986. Patients with this form of the disorder are also mentally retarded but over a wide range of severity, from mild to extreme. Beta-mannosidosis is not well understood, in part because it is such a rare disease. It was discovered only because researchers searched for it: a deficiency of the beta form of the enzyme was known to cause disease in animals.

Genetic profile

The two forms of mannosidosis, alpha and beta, are caused by changes on two different genes. Mutations in the gene MANB, on chromosome 19, result in alpha-mannosidosis. This gene is also known as MAN2B1 or LAMAN. Defects in MANB cause alpha-mannosidosis in both infants and adults.

Beta-mannosidosis is caused by mutations in the gene MANB1 (also called MANBA). This gene is on chromosome 4.

Both genes, MANB and MANB1, are inherited as autosomal recessive traits. This means that if a man and woman each carry one defective gene, then 25% of their children are expected to be born with the disorder. Each gene is inherited separately from the other.

Demographics

Mannosidosis is a rare disorder, occurring in both men and women. The disorder does not affect any particular ethnic group but rather appears in a broad range of people. Alpha-mannosidosis has been studied in Scandinavian, Western and Eastern European, North American, Arabian, African, and Japanese populations. Researchers have identified beta-mannosidosis in European, Hindu, Turkish, Czechoslovakian, Jamaican-Irish, and African families.

Signs and symptoms

The various forms and types of mannosidosis all have one symptom in common: mental retardation. Other signs and symptoms vary.

Infants with alpha-mannosidosis appear normal at birth, but by the end of their first year, they show signs of mental retardation, which rapidly gets worse. They develop a group of symptoms that includes dwarfism, shortened fingers, and facial changes. In these children, the bridge of the nose is flat, they have a prominent forehead, their ears are large and low set, they have protruding eyebrows, and the jaw juts out. Other symptoms include lack of muscle coordination, enlarged spleen and liver, recurring infections, and cloudiness in the back of the eyeball, which is normally clear. These patients often have empty bubbles in their white blood cells, a sign that sugars are being stored improperly.

The adult form occurs in 10–15% of the cases of alpha-mannosidosis. The symptoms in adults are the same as in infants, but they are milder and develop more slowly. Patients with adult alpha-mannosidosis are often normal as babies and young children, when they develop mentally and physically as expected. In their childhood or teenage years, however, mental retardation and physical symptoms become evident. These patients may also lose their hearing and have pain in their joints.

Beta-mannosidosis is characterized by symptoms that range from mild to severe. In all patients, however, the most frequent signs are mental retardation, lung infections, and hearing loss with speech difficulties. In mild cases, patients have red, wart-like spots on their skin. In severe cases, patients may have multiple seizures, and their arms and legs may be paralyzed. Because the symptoms of beta-mannosidosis vary so greatly, researchers suggest that the disorder may frequently be misdiagnosed.

Diagnosis

All types of mannosidosis are tested in the same way. In an infant, child, or adult, doctors can check the patient's urine for abnormal types of sugar. They may also test the patient's blood cells to learn if the enzyme is present.

If doctors suspect that a pregnant woman may be carrying a child with mannosidosis, they can test cells in the fluid surrounding the baby for enzyme activity.

Treatment and management

There is no known treatment for mannosidosis. The symptoms—mental retardation and skeletal abnormalities—are managed by supportive care, depending on the severity. Patients with adult alpha-mannosidosis and beta-mannosidosis may show mild mental retardation or behavior problems (such as depression or aggression) and may be mainstreamed into society. Others may require institutionalization. Skeletal abnormalities may require surgery to correct them, and recurring infections are treated with antibiotics.

Research with animals suggests that mannosidosis can be treated by placing healthy cells without defective genes into the animals' bones (bone marrow transplant). Other researchers have successfully treated mannosidosis in animals by inserting healthy genes into the unborn offspring of a pregnant animal. These treatments have not been proven on humans, however.

Prognosis

The future for patients with mannosidosis varies with the form of their disorder. For infants with alpha-mannosidosis, death is expected between ages three and 12 years. For infants with beta-mannosidosis, death will come earlier, by the time they are 15 months old.

Patients with mild forms of alpha- and beta-mannosidosis often survive into adulthood, but their lives are complicated by mental retardation and physical deterioration. They will generally die in their early or middle years, depending on the severity of their disorder.

Resources

BOOKS

Thomas, George. "Disorders of Glycoprotein Degradation: Alpha-Mannosidosis, Beta-Mannosidosis, Fucosidosis, and Sialidosis." The Metabolic and Molecular Bases of Inherited Disease. Scriver, Charles R., et al., ed. Vol. II, 8th ed. New York: McGraw-Hill, 2001.

PERIODICALS

Alkhayat, Aisha H., et al. "Human Beta-Mannosidase cDNA Characterization and First Identification of a Mutation Associated with Human Beta-Mannosidosis." Human Molecular Genetics 7, no. 1 (1998): 75–83.

Berg, Thomas, et al. "Spectrum of Mutations in Alpha-Mannosidosis." American Journal of Human Genetics 64 (1999): 77–88.

Michalski, Jean-Claude, and Andre Klein. "Glycoprotein Lysosomal Storage Disorders: Alpha- and Beta-Mannosidosis, Glucosidosis, and Alpha-NAcetylgalactosaminidase Deficiency." Biochimica et Biophysica Acta: Molecular Basis of Disease 1455, no. 2–3 (October 8, 1999): 69–84.

ORGANIZATIONS

Arc (a National Organization on Mental Retardation). 1010 Wayne Ave., Suite 650, Silver Spring, MD 20910. (800) 433-5255. <http://www.thearclink.org>.

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

International Society for Mannosidosis and Related Diseases. 3210 Batavia Ave., Baltimore, MD 21214. (410) 254-4903. <http://www.mannosidosis.org>.

National MPS Society. 102 Aspen Dr., Downingtown, PA 19335. (610) 942-0100. Fax: (610) 942-7188. [email protected]. <http://www.mpssociety.org>.