Diagnosis: Alpha-mannosidosis

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

Alpha-mannosidosis is a rare genetic disorder characterized by a deficiency of the enzyme alpha‑D‑mannosidase. Alpha‑mannosidosis is best understood as a disease continuum that is generally divided 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 signs and severity of the disorder are highly variable. Symptoms may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and immune system dysfunction. Alpha‑mannosidosis is caused by mutations in the MAN2B1 gene. This genetic mutation is inherited in an autosomal recessive manner.

Symptoms

The symptoms, course, and severity of alpha‑mannosidosis vary greatly among affected individuals, even among siblings who share the same mutation. Alpha‑mannosidosis represents a spectrum or continuum of disease and is highly individualized. In some individuals, symptoms appear shortly after birth, and potentially life‑threatening complications may develop during childhood or early childhood. In others, manifestations are milder, typically with onset before 10 years of age. In certain cases, individuals may not be diagnosed until adulthood.

The disorder is generally divided into three distinct subtypes: mild (type 1), moderate (type 2), and severe (type 3). Most affected individuals fall within the mild subtype. It is important to note that due to the highly variable nature of the disorder, affected individuals will not exhibit all of the symptoms listed below.

The mild form (type 1) may not become apparent until adolescence and progresses slowly. Symptoms typically include muscle weakness. Skeletal abnormalities are usually absent. A 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, clinical progression appears to slow or stabilize as the affected individual grows beyond school age.

In the moderate form of the disorder (type 2), symptoms of skeletal abnormalities and muscle weakness may appear before the age of ten and progress slowly. Ataxia (impaired ability to coordinate voluntary movements) may develop between 20 and 30 years of age.

The severe form (type 3) begins during the first year of life. In most cases, infants appear normal at birth, but the condition progressively worsens. Type 3 alpha‑mannosidosis is characterized by rapid progression of intellectual disability, hydrocephalus, progressive impairment of voluntary movement coordination (ataxia), enlargement of the liver and spleen (hepatosplenomegaly), skeletal abnormalities, and coarse facial features.

Intellectual disability associated with alpha‑mannosidosis may range from mild cognitive impairment to severe intellectual deficit. Severity may differ dramatically even among siblings. Children often experience delays in the development of speech, and their speech may remain slurred.

Motor skills may also be affected in alpha‑mannosidosis. Affected children may exhibit delayed psychomotor development—walking may occur later than expected, and overall they may appear clumsy. Reduced muscle tone (hypotonia) is commonly present.

Many individuals with alpha‑mannosidosis have moderate to severe hearing loss. Hearing loss is caused by dysfunction of the inner ear or the auditory nerve, which prevents the transmission of sound vibrations to the brain (under normal conditions, part of the inner ear converts sound vibrations into nerve impulses that are then transmitted to the brain through the auditory nerve). Hearing may deteriorate further due to middle‑ear infections or the accumulation of fluid in the middle ear.

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 also be particularly prone to dental issues, such as increased susceptibility to cavities. Additionally, some children are born with an abnormally twisted ankle (equinus ankle) or hydrocephalus, a condition in which excess cerebrospinal fluid (CSF) accumulates in the skull, causing pressure on brain tissue.

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

Growth rate may fluctuate, with accelerated early growth followed by slowed growth, ultimately resulting in short stature. Thin arms and/or legs with stiff joints may develop. Spinal abnormalities may in some cases lead to severe curvature. Degenerative disease affecting multiple joints (destructive polyarthropathy) may develop over time.

In type 3 disease, reduced or abnormal immune response may make affected individuals more vulnerable to bacterial infections, especially of the respiratory system. Middle‑ear and gastrointestinal infections are also common. Recurrent infections occur more frequently 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 several days or weeks, followed by excessive sleepiness (hypersomnia).

Diagnosis

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

Alpha‑mannosidosis is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one healthy gene and one abnormal gene for the disorder, that person will be a carrier but will typically not show symptoms. The risk that two carrier parents will pass on the abnormal gene and have an affected child is 25% with each pregnancy. The risk that the child will be a carrier, like the parents, is 50%. The chance that the child will inherit two normal genes is 25%. The risks are the same for males and females.

The prevalence of alpha‑mannosidosis is estimated to be 1 in 500,000 people in the general population. Alpha‑mannosidosis affects males and females equally and may potentially occur in individuals of any ethnic background worldwide.

The diagnosis of alpha‑mannosidosis can be confirmed by molecular‑genetic testing, which can detect the characteristic mutation of the MAN2B1 gene responsible for the disorder. Molecular‑genetic testing is available on a clinical basis.

Elevated levels of certain mannose‑rich oligosaccharides (a complex carbohydrate) can be detected through urine analysis. Although this finding is considered suggestive of alpha‑mannosidosis, it is not diagnostic.

Therapy

Treatment of alpha‑mannosidosis is symptomatic and supportive. Therapy focuses on preventing and managing complications of the disorder. Therefore, a proactive approach is essential. Antibiotics are used to control bacterial infections. Hearing aids and pressure‑equalizing tubes are used to correct hearing impairment. Physiotherapy exercises are frequently prescribed to improve muscle tone due to the presence of hypotonia.

Orthopedic interventions, including surgical procedures or prescribing orthopedic aids (e.g., special footwear or orthotic devices), may be necessary to address skeletal abnormalities. Some individuals may require the use of a wheelchair.

Hydrocephalus may be treated by placing a shunt to divert excess cerebrospinal fluid (CSF) from the brain to another part of the body (such as the abdominal cavity), where the CSF can be readily absorbed into the surrounding tissues.

Early intervention is important for improving cognitive abilities and supporting intellectual and social functioning. Social services that may be beneficial or necessary include special and therapeutic education, speech therapy, specialized services for children with hearing impairments (audiologic or surdopedic services), and additional medical, social, and/or vocational or specialized support services. Genetic counseling may be helpful for patients and their families.

Alpha-mannosidosis

General

Symptoms

Diagnosis

Therapy

Do you want to see more?