Alpha-mannosidosis
Encyclopedia
Alpha-mannosidosis is a lysosomal storage disorder caused by deficient activity of the enzyme
alpha-D-mannosidase (see Alpha-Mannosidase
). In humans it is known to be caused by an autosomal recessive
genetic mutation. In livestock
it is caused by chronic poisoning with swainsonine
(see Locoweed
).
A defective α-mannosidase
enzyme
, which normally helps to break down complex sugar
s derived from glycoprotein
s in the lysosome
, causes sugar build up and impairs cell
function. Complete absence of functional enzyme leads to death during early childhood due to deterioration of the central nervous system
. Enzyme with low residual activity leads to a milder type of the disease, with symptoms like reduced hearing, mental retardation, susceptibility to bacterial infections and skeletal deformities. The course of the disease is progressive.
Alpha-Mannosidosis is classified into types I through III based on severity and age of onset. In contrast to the usual classifications scheme of these disorders, type III is the most severe.
Symptoms range widely in their onset and severity. The onset of the most severe form, type III, begins within the first months of life and includes a quick progression of mental retardation
, liver and spleen enlargement (splenomegaly
), hearing loss, respiratory infections and skeletal abnormalities. Often the appearance of an affected individual includes the following facial features: protruding forehead, leveled nasal bridge, small nose and wide mouth. Muscular weakness or spinal abnormalities can occur due to the build up of storage materials in the muscle. A milder form of Alpha-mannosidosis involves mild to moderate mental retardation which develops during childhood or adolescence.
The worldwide incidence of alpha-mannosidosis is in the range of 1 per 500,000 to 1 per 1,000,000. Mannosidosis is found in all ethnic groups in Europe, America, Africa and also Asia.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
alpha-D-mannosidase (see Alpha-Mannosidase
Alpha-Mannosidase
alpha-Mannosidase is an enzyme involved in the cleavage of the alpha form of mannose.- Isozymes :Humans express the following three alpha-mannosidase isozymes:- Applications :...
). In humans it is known to be caused by an autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
genetic mutation. In livestock
Livestock
Livestock refers to one or more domesticated animals raised in an agricultural setting to produce commodities such as food, fiber and labor. The term "livestock" as used in this article does not include poultry or farmed fish; however the inclusion of these, especially poultry, within the meaning...
it is caused by chronic poisoning with swainsonine
Swainsonine
Swainsonine is an indolizine alkaloid. It is a potent inhibitor of Golgi alpha-mannosidase II, an immunomodulator, and a potential chemotherapy drug...
(see Locoweed
Locoweed
Locoweed is a common name in North America for any plant that produces swainsonine, a phytotoxin harmful to livestock. Worldwide, swainsonine is produced by a small number of species, most in three genera of the flowering plant family Fabaceae: Oxytropis and Astragalus in North America, and...
).
Pathophysiology
Alpha-Mannosidase
alpha-Mannosidase is an enzyme involved in the cleavage of the alpha form of mannose.- Isozymes :Humans express the following three alpha-mannosidase isozymes:- Applications :...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, which normally helps to break down complex sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
s derived from glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s in the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
, causes sugar build up and impairs cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
function. Complete absence of functional enzyme leads to death during early childhood due to deterioration of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Enzyme with low residual activity leads to a milder type of the disease, with symptoms like reduced hearing, mental retardation, susceptibility to bacterial infections and skeletal deformities. The course of the disease is progressive.
Alpha-Mannosidosis is classified into types I through III based on severity and age of onset. In contrast to the usual classifications scheme of these disorders, type III is the most severe.
Symptoms
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, liver and spleen enlargement (splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
), hearing loss, respiratory infections and skeletal abnormalities. Often the appearance of an affected individual includes the following facial features: protruding forehead, leveled nasal bridge, small nose and wide mouth. Muscular weakness or spinal abnormalities can occur due to the build up of storage materials in the muscle. A milder form of Alpha-mannosidosis involves mild to moderate mental retardation which develops during childhood or adolescence.
Diagnosis and Testing
A diagnosis is made by measuring the enzymatic activity of alpha-D-mannosidase in white blood cells. If there is a decreased level of the enzyme in comparison to standard levels, a diagnosis can be made. It is thought that this disorder might be under-diagnosed for a few different reasons — the diagnosis is often made late in the disease's progression, symptoms are often mild, or the biochemical diagnosis does not yield conclusive results.Life Expectancy
The life expectancy in Alpha-mannosidosis is highly variable. Individuals with early onset severe disease often do not survive beyond childhood, whereas those with milder disorders may survive well into adult life.Treatment
There is no cure for congenital Alpha-Mannosidosis. Treatment is limited to reducing or controlling the symptoms of this disorder by, for example, taking medication to control seizures, using a hearing aid to assist with hearing loss, and by having routine physical therapy to assist with muscular pain and weakness. In some cases, a wheelchair is recommended if muscle or spinal impairments immobilize the individual affected. Despite early reports to the contrary, bone marrow transplants performed at an early age have shown promise in halting the progression of this disorder.Genetic prevalence