NORD gratefully acknowledges Dag Malm, MD, PhD, Researcher, Tromso Centre of Internal Medicine (TIS as), Tromso, Norway, for assistance in the preparation of this report; and Line Borgwardt, MD, Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University, Copenhagen, Denmark, for critical review of the therapy section.
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.
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.
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.
The prevalence of alpha-mannosidosis is estimated to be 1 in every 500,000 people in the general population. Alpha-mannosidosis affects men and women in equal numbers and can potentially affect individuals of any ethnic group worldwide.
A diagnosis of alpha-mannosidosis is suspected based upon identification of characteristic findings, a thorough clinical evaluation, a detailed a patient history, and specialized tests that can detect deficient levels or activity of the enzyme alpha-mannosidase in white blood cells (leukocytes) or cultured tissue cells (fibroblasts).
A diagnosis of alpha-mannosidosis can be confirmed through molecular genetic testing, which can reveal the characteristic mutation of the MAN2B1 gene that causes the disorder. Molecular genetic testing is available on a clinical basis.
Elevated levels of certain mannose-rich oligosaccharides (a complex carbohydrate) may be found through urinary analysis. Although this finding is considered suggestive of alpha-mannosidosis, it is not diagnostic.
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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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Bone marrow transplantation (BMT) is under investigation for the treatment of lysosomal storage disorders, such as alpha-mannosidosis. In alpha-mannosidosis all cells are devoid of LAMAN. The rationale of BMT is to substitute the blood system of the patient with BMT from a donor with blood cells competent of producing LAMAN. Researchers acknowledge that early diagnosis and prompt treatment with a bone marrow transplant increases the chances of preventing cognitive decline and improving symptoms. This has proven effective both in kittens and man.
However, more research is necessary to determine the long-term safety and effectiveness of this potential therapy for alpha-mannosidosis. A BMT is not without drawbacks. The procedure carries the risk of serious complications including graft-versus-host disease and other long-term and late effects as described by Myranek in 2011 where 2 of 17 patients died of procedure-related causes, two developed severe and six developed chronic graft-versus-host-disease (GvHD). After BMT, patients made developmental progress, although normal development was not achieved. The potential benefits of a BMT must be weighed against such drawbacks. The perfect donor is familial HLA-identical, but in many cases this donor cannot be found, in which case enzyme replacement therapy (ERT) will be the best option.
Substantial time and effort have gone into studies of enzyme replacement therapy as a means of treating alpha-mannosidosis. Enzyme replacement therapy involves replacing the missing enzyme with a weekly infusion. Human alpha-mannosidosis is produced in an industrial scale in CHO cells and used to treat individuals with alpha-mannosidosis.
Velmanase, an enzyme replacement therapy, has been developed as a potential treatment for individuals with alpha-mannosidosis in the EU studies EURAMAN, HUEMAN and ALPHAMAN. Clinical trials in animals began in 2006 with very promising results. The effects of ERT in Knock-out mice could be seen in both TLC and histology. At lower doses, the clearing of oligosaccharides in spleen and kidney was obvious, but not in brain. However, by increasing dose there was even an effect both in PMS and CNS. And the reduced pathology in hippocampus had a clinical parallel by reversed ataxia in mice tested in treadmill. So, although basically only a stabilization of the condition was to be expected, a significant improvement both on biochemical and clinical parameter was observed.
Clinical trials in humans began in Dec. 2011. Over 4 years observation, the patients experienced improvement in both biochemical and functional parameters. After completion of a phase III placebo controlled study, ERT with Velmanase was approved by the European Medical Agency (EMA) in July 2018. Velmanase was further very well tolerated.
However, both in BMT as well as in ERT, early treatment during childhood is important to avoid permanent irreversible damage. Therefore, the next priority must be to increase awareness to achieve early diagnosis of alpha-mannosidosis.
Gene therapy is also being studied as another possible approach to therapy for some lysosomal storage disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure.” However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.
Contact for additional information about alpha-mannosidosis:
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