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Alpha-mannosidosis
This condition occurs due to a deficiency in the alpha-mannosidase enzyme, leading to the accumulation of undigested sugars in cells. It can affect many body systems, including skeletal, neurological, and immune function, with symptoms varying in severity.
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Overview
Alpha-mannosidosis is a very rare genetic disorder belonging to a group known as lysosomal storage disorders. These conditions arise when cellular components called lysosomes, which normally act as the cell's recycling centres, are unable to properly break down certain complex molecules [PMID:33671239]. In alpha-mannosidosis, the body cannot break down specific sugar chains (oligosaccharides) containing mannose, leading to their accumulation in various tissues and organs. This build-up disrupts normal cell function and can cause a wide range of health problems.
The global prevalence of alpha-mannosidosis is estimated to be around 1 in 500,000 live births, making it an extremely rare condition. The features and severity can vary significantly among affected individuals, typically categorised into types that reflect different ages of onset and progression [PMID:33671239].
Symptoms & clinical features
The symptoms of alpha-mannosidosis can be diverse and may affect many parts of the body. Common features often include skeletal abnormalities, such as a prominent forehead, thickened bones, or spinal curvature (kyphoscoliosis). Hearing loss is also frequently observed.
Neurological symptoms may develop, including intellectual disability, which can range from mild to severe, and issues with coordination and balance. Some individuals might experience speech difficulties or behavioural challenges. Recurrent infections, particularly ear and respiratory infections, are also common in those with alpha-mannosidosis, suggesting an impact on the immune system [PMID:32252199].
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Affected organs
Alpha-mannosidosis can affect multiple organ systems due to the widespread accumulation of undigested sugar molecules. The skeletal system is commonly impacted, leading to bony changes and joint problems. The central nervous system, including the brain, can be affected, contributing to developmental delay and intellectual disability.
Other organs that may show effects include the liver and spleen, which can become enlarged (hepatosplenomegaly). The immune system is often compromised, leading to increased susceptibility to infections. Hearing can be impaired, and eye abnormalities such as clouding of the cornea may occur.
Risks & severity
The severity of alpha-mannosidosis varies considerably. Previously, it was classified into three types based on age of onset and progression, but current understanding recognises a spectrum rather than distinct categories. Generally, symptoms may appear anytime from infancy to later childhood, with earlier onset often associated with more severe and rapidly progressive forms [PMID:32252199].
Individuals with an earlier onset form may experience more profound intellectual disability, skeletal changes, and a shorter lifespan. Those with a later onset phenotype might have milder neurological involvement and a slower disease progression. The condition progresses over time, and regular monitoring for potential complications is an important part of care.
Genetic causes
Alpha-mannosidosis is caused by pathogenic variants in the MAN2B1 gene. This gene provides instructions for making the alpha-mannosidase enzyme, which is crucial for breaking down specific sugar chains within the cell's lysosomes [PMID:33671239]. The enzyme acts like a molecular scissor, cutting down complex sugar molecules into smaller, manageable pieces.
When there are disease-causing changes in the MAN2B1 gene, the alpha-mannosidase enzyme is either deficient or completely absent. This prevents the proper breakdown of mannose-containing oligosaccharides, causing them to accumulate inside lysosomes. This build-up impairs the normal function of cells and tissues throughout the body, leading to the diverse symptoms observed in alpha-mannosidosis.
- MAN2B1 mannosidase alpha class 2B member 1The MAN2B1 gene provides instructions for producing the alpha-mannosidase enzyme, crucial for breaking down sugar molecules within cellular lysosomes.
Inheritance pattern
Alpha-mannosidosis is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the MAN2B1 gene - one from each parent - to develop the condition. Individuals who inherit only one altered copy of the gene are called carriers. Carriers typically do not show any symptoms of alpha-mannosidosis but can pass the altered gene copy on to their children.
If both parents are carriers of a pathogenic variant in the MAN2B1 gene, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies and develop alpha-mannosidosis. There is also a 2 in 4 (50%) chance that the child will be a carrier, and a 1 in 4 (25%) chance that the child will inherit two normal copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of alpha-mannosidosis typically begins with clinical suspicion based on the characteristic symptoms. Initial screening tests may involve measuring the activity of the alpha-mannosidase enzyme in a blood sample (leukocytes) or dried blood spots [PMID:32252199]. Elevated levels of undigested oligosaccharides can also be detected in urine samples.
A definitive diagnosis is confirmed through genetic testing, which looks for pathogenic variants in the MAN2B1 gene. In the UK, genetic testing for suspected cases of alpha-mannosidosis (R-code R115, R116, R117, R118, R119, R120) is typically arranged by a clinical genetics service, often following a referral from a specialist paediatrician or other relevant consultant. Genetic counselling is an important part of the diagnostic process.
Management & lifestyle
While there is currently no cure for alpha-mannosidosis, management focuses on alleviating symptoms and improving quality of life. Treatment approaches are supportive and multidisciplinary, involving various specialists such as paediatricians, neurologists, orthopaedic surgeons, audiologists, and physiotherapists.
Regular monitoring for hearing loss, developmental progress, and skeletal issues is key. Interventions may include hearing aids, educational support, speech therapy, and physical therapy. Some individuals may benefit from surgical procedures for skeletal problems. Enzyme replacement therapy with velmanase alfa has been approved in some regions and helps to reduce the accumulation of storage material, particularly in milder forms of disease, and is assessed on an individual basis [PMID:32252199].
UK care pathway
In the UK, individuals suspected of having genetic conditions like alpha-mannosidosis are typically referred through their GP or specialist to a regional NHS Clinical Genetics service. These services provide comprehensive assessment, diagnosis, and genetic counselling. Genetic testing for alpha-mannosidosis falls under specific NHS Genomic Medicine Service (GMS) R-codes (e.g., R115 for childhood onset neurological disorders, R116 for skeletal dysplasias) and is performed in accredited laboratories. Genetic counsellors play a crucial role in explaining the condition, its inheritance, and implications for the family.
Frequently asked questions
What is the difference between alpha-mannosidosis and other lysosomal storage disorders?
Alpha-mannosidosis specifically involves the deficiency of the alpha-mannosidase enzyme, leading to the build-up of mannose-rich sugar molecules. While other lysosomal storage disorders share similar symptoms, they are caused by deficiencies in different enzymes and involve the accumulation of other specific substances.
Can alpha-mannosidosis be detected before birth?
Prenatal diagnosis for alpha-mannosidosis is possible if a pathogenic variant has been identified in the family. This typically involves testing cells obtained through chorionic villus sampling or amniocentesis during pregnancy.
Is there a newborn screening programme for alpha-mannosidosis in the UK?
Alpha-mannosidosis is not currently included in the routine NHS newborn screening programme in the UK. Diagnosis usually occurs after symptoms begin to appear and clinical suspicion is raised.
What support is available for families affected by alpha-mannosidosis?
Families can access support through their local NHS clinical genetics service, which can provide information and connect them with relevant specialist services. Patient support groups and charities specific to lysosomal storage disorders can also offer valuable resources and community connections.
What is the life expectancy for someone with alpha-mannosidosis?
Life expectancy can vary significantly depending on the severity and type of alpha-mannosidosis. More severe, earlier-onset forms may lead to a reduced lifespan, while milder forms can allow individuals to live into adulthood. Regular medical care and managing symptoms are important for overall well-being.
References
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- Adam MP, Bick S, Mirzaa GM. Alpha-Mannosidosis. 1993. PMID: 20301570
- Ceccarini MR, Codini M, Conte C. Alpha-Mannosidosis: Therapeutic Strategies. International journal of molecular sciences. 2018. PMID: 29772816
- Malm D, Nilssen Ø. Alpha-mannosidosis. Orphanet journal of rare diseases. 2008. PMID: 18651971
- Paciotti S, Codini M, Tasegian A. Lysosomal alpha-mannosidase and alpha-mannosidosis. Frontiers in bioscience (Landmark edition). 2017. PMID: 27814608
- Matlach J, Zindel T, Amraoui Y. Retinal and optic nerve degeneration in α-mannosidosis. Orphanet journal of rare diseases. 2018. PMID: 29859105
- Beccari T, Stinchi S, Orlacchio A. Lysosomal alpha-D-mannosidase. Bioscience reports. 1999. PMID: 10513892
- Hennermann JB, Raebel EM, Donà F. Mortality in patients with alpha-mannosidosis: a review of patients' data and the literature. Orphanet journal of rare diseases. 2022. PMID: 35871018