About lysosomal alpha-d-mannosidase deficiency

What is lysosomal alpha-d-mannosidase deficiency?

Alpha-mannosidosis is a rare genetic disorder characterized by a deficiency of the enzyme alpha-D-mannosidase. Alpha-mannosidosis is best thought of as a continuum of disease that is generally broken down into three forms: a mild, slowly progressive form (type 1); a moderate form (type 2); and a severe, often rapidly progressive and potentially life-threatening form (type 3). The symptoms and severity of the disorder are highly variable. Symptoms may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and dysfunction of the immune system. Alpha-mannosidosis is caused by mutations of the MAN2B1 gene. This genetic mutation is inherited as an autosomal recessive trait.

Alpha-mannosidosis belongs to a group of diseases known as the lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units. Enzymes within the lysosomes break down or digest particular nutrients, such as complex molecules composed of a sugar attached to a protein (glycoproteins). Low levels or inactivity of the alpha-mannosidase enzyme leads to the abnormal accumulation of compounds upstream in the metabolic pathway in the cells of affected individuals with unwanted consequences.



What are the symptoms for lysosomal alpha-d-mannosidase deficiency?

The symptoms, progression and severity of alpha-mannosidosis vary widely from one person to another, including between siblings who share the same mutation. Alpha-mannosidosis represents a spectrum or continuum of disease and is highly individualized. Some individuals develop symptoms shortly after birth and may develop potentially life-threatening complications in infancy or early childhood. Other individuals develop more moderate symptoms usually with onset before the age of 10. In some cases, individuals may not be diagnosed until adulthood.

The disorder is generally broken down into three separate subtypes: mild (type 1), moderate (type 2) and severe (type 3). Most affected individuals fall into the moderate subtype. It is important to note, because of the highly variable nature of the disorder, that affected individuals will not have all of the symptoms discussed below.

The mild form (type 1) may not be evident until the teen years and progresses slowly. Symptoms typically include muscle weakness. Skeletal abnormalities are usually not present. The person with type 1 may have normal cognitive and physical development. However, even this later-onset form may be accompanied by mild to moderate intellectual disability. In some cases, the clinical progression of the disease appears to slow down or stop as the affected individual grows beyond school age.

In the moderate form of the disorder (type 2), signs of Skeletal abnormalities and Muscle Weakness may appear before ten years of age and progress slowly. Ataxia (an impaired ability to coordinate voluntary movements) may develop by the age of 20-30.

The severe form (type 3) begins within the first year of life. In most cases, infants appear normal at birth, but the condition grows progressively worse. Type 3 alpha-mannosidosis is characterized by rapid progression of intellectual disability, hydrocephalus, progressive impairment of the ability to coordinate voluntary movements (ataxia), enlargement of the liver and spleen (hepatosplenomegaly), skeletal abnormalities, and coarse facial features.

Intellectual disabilities associated with alpha-mannosidosis can range from mild Cognitive impairment to profound mental deficiency. The severity can vary dramatically even among siblings. Children often experience delays achieving the ability to speak, and their speech stays blured.

Motor skills may also be affected in alpha-mannosidosis. Affected children may experience delays in learning to walk and may appear clumsy. Diminished muscle tone (hypotonia) is often present.

Many individuals with alpha-mannosidosis develop moderate to severe hearing loss. Hearing loss is caused by a defect of the inner ear or the auditory nerve that prevents sound vibrations from being transmitted to the brain (With normal hearing, a portion of the inner ear serves to convert sound vibrations to nerve impulses, which are then transmitted via the auditory nerve to the brain.). Hearing can worsen even further with otitis with accumulation of fluid in the middle ear.

The Skeletal abnormalities associated with type 2 and type 3 may include facial abnormalities such as a Prominent forehead and jaw, and a flattened nose. Affected children may be especially prone to dental problems such as cavities. In addition, some infants are born with an abnormally twisted ankle (ankle equinus) or hydrocephalus, a condition in which the accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain.

Types 2 and 3 also may be characterized by Distinctive facial features including widely spaced or unevenly developed teeth, a thickened, enlarged tongue (macroglossia), prominent forehead, flattened nasal bridge, and a protruding lower jaw (prognathism). Abnormalities affecting the eyes may include an inability to align the eyes (strabismus or crossed eyes), clouding (opacity) of the transparent outer covering of the eye (cornea), and farsightedness (hyperopia) and, less commonly, Nearsightedness (myopia).

Growth rates can fluctuate with accelerated early growth but subsequent impaired growth, causing short stature. Thin arms and/or legs with stiff joints may develop. Spinal abnormalities may lead to extreme curvature in some cases. Over time, affected individuals may eventually develop degenerative disease affecting multiple joints (destructive polyarthropathy).

In type 3 disease, a diminished or abnormal immune system response can make affected individuals more susceptible to bacterial infections, particularly of the respiratory system. Infections affecting the middle ear and gastrointestinal tract are also common. Recurrent infections are more common during the first decade of life.

Some individuals with alpha-mannosidosis develop psychiatric abnormalities such as confusion, anxiety, Depression or hallucinations. These symptoms may persist for days or weeks, followed by a need for excessive amounts of sleep (hypersomnia). Psychiatric symptoms or behavioral problems occur in almost half of those affected and usually develop during adolescence or early adulthood.



What are the causes for lysosomal alpha-d-mannosidase deficiency?

Alpha-mannosidosis is caused by changes (mutations) in the MAN2B1 gene. The MAN2B1 gene contains instructions for producing the enzyme lysosomal alpha-mannosidase (LAMAN). This enzyme is essential for breaking down (metabolizing) certain glycoproteins. Without proper levels of functional version of this enzyme, these glycoproteins abnormally accumulate in and damage various tissues and organs of the body. Mutations of the MAN2B1 gene result in the lack of production of the alpha-D-mannosidase enzyme or the production of a defective, inactive form of the enzyme.

Alpha-mannosidosis is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.



What are the treatments for lysosomal alpha-d-mannosidase deficiency?

Treatment of alpha-mannosidosis is symptomatic and supportive. Therapy is directed at preventing and treating the complications of the disorder. Thus, it is important to be pro-active. Antibiotics are used to suppress bacterial infections. Hearing aids and pressure equalizing tubes are used to improve hearing. Physiotherapy for muscle weakness is often prescribed.

Orthopedic interventions including surgery or the use of assistive devices (e.g., special shoes or orthosis) may be necessary to treat associated skeletal abnormalities. Some individuals may require the use of a wheelchair.

Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.

Early intervention is important in ensuring that children with alpha-mannosidosis reach their highest potential. Services that may be beneficial may include special education, speech therapy, special services for children with hearing loss, and other medical, social, and/or vocational services. Genetic counseling may be of benefit for patients and their families.



What are the risk factors for lysosomal alpha-d-mannosidase deficiency?

Lysosomal alpha-d-mannosidase deficiency (also known as GM1 gangliosidosis) is a rare genetic disorder that can cause developmental delays, learning disabilities, and seizures. It's caused by a lack of an enzyme called alpha-d-mannosidase, which helps break down certain proteins in the body.

The enzyme lysosomal alpha-d-mannosidase is responsible for breaking down glycoproteins, which are molecules made up of both proteins and sugars. These sugars are called oligosaccharides, and they include dolichols, mannose oligomers, and mannose monomers.

These sugars can be found on the surface of cells as well as in the extracellular matrix. The extracellular matrix is a meshwork of proteins that surrounds cells in their normal state. When these sugars aren't broken down properly by lysosomal alpha-d-mannosidase, they build up in cells and tissues throughout the body. At first, this buildup occurs in tissues such as bone marrow, lymph nodes, liver and spleen; later on it can also affect muscles (especially cardiac muscle) and nerve tissue.

The symptoms of this condition vary widely from person to person and range from mild to severe. In most cases, children are diagnosed before age 2 and show signs of poor motor skills and delayed speech development.

The four main risk factors of Lysosomal alpha-d-mannosidase deficiency include:

1. Genetic: It is an autosomal recessive disorder caused by mutations in the MAN2B1 gene.

2. Lysosomal: It affects lysosomes, which are organelles that break down cell waste products.

3. Mannosidosis: The condition results from a deficiency of lysosomal α-d-mannosidase.

4. Deficiency: This is when there is not enough of the enzyme to break down mannose-containing molecules.

Symptoms
Impaired growth and development,Seizures and behavioral problems,Atypical facial features,Hearing loss,Bone marrow suppression
Condition
Mutations in the MAN2B1 gene,Carriers of Tay-Sachs Disease (TSD) who have not yet developed the disease,The presence of a defective MNS blood factor,A family history of TSD
Drugs
Amigal,Aldurazyme,Fabryzme,Lumizyme



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