Alpha-mannosidosis
Disease Details
Family Health Simplified
- Description
- Alpha-mannosidosis is a rare genetic lysosomal storage disorder characterized by a deficiency of the enzyme alpha-mannosidase, leading to the accumulation of complex sugars in various tissues.
- Type
- Alpha-mannosidosis is a lysosomal storage disorder. It is transmitted in an autosomal recessive manner.
- Signs And Symptoms
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Alpha-mannosidosis is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-mannosidase. Signs and symptoms can include:
1. **Intellectual disability:** Developmental delay and learning difficulties.
2. **Skeletal abnormalities:** Coarsening of facial features, scoliosis, and joint abnormalities.
3. **Hearing loss:** Progressive hearing impairment.
4. **Recurrent infections:** Frequent respiratory infections.
5. **Muscle weakness:** Hypotonia and muscle weakness.
6. **Speech difficulties:** Delayed speech development.
7. **Behavioral issues:** Hyperactivity and behavioral problems.
8. **Neurological issues:** Seizures and ataxia.
9. **Organomegaly:** Enlargement of the liver and spleen. - Prognosis
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The long-term forecast for the condition is poor. There is generally a slow progression of neuromuscular and bone changes over decades. Behavioural problems or psychiatric disorders may also be present. 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.
Independent living will be difficult, and patients with alpha-mannosidosis may become socially isolated, and during the late stages of the disease they may become wheelchair-using, as they can no longer walk unaided. This is likely to have a negative impact upon the quality of life of caregivers and family members. - Onset
- Alpha-mannosidosis typically has an onset in early childhood. The condition can manifest within the first few years of life, with symptoms progressively worsening over time.
- Prevalence
- Alpha-mannosidosis is a rare genetic disorder. The prevalence estimates vary, but it is generally considered to affect approximately 1 in 500,000 to 1 in 1,000,000 individuals worldwide.
- Epidemiology
- The worldwide incidence of alpha-mannosidosis is not known exactly. However, a number of reports from different countries estimate that it occurs in approximately one in every million babies born worldwide. Mannosidosis is found in all ethnic groups in Europe, America, Africa, and Asia.
- Intractability
- Alpha-mannosidosis is considered a progressive and potentially intractable condition, meaning it can be difficult to manage and treat effectively over the long term. It is a rare genetic lysosomal storage disorder caused by deficient activity of the enzyme alpha-mannosidase. While there are treatments available, such as enzyme replacement therapy and hematopoietic stem cell transplantation, these do not cure the disease but may help manage symptoms and slow disease progression. The efficacy of treatments can vary, and ongoing medical management is typically required.
- Disease Severity
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**Disease Severity:**
Alpha-mannosidosis is a progressive and variable disorder. Its severity can range from mild to severe, depending on the level of enzyme deficiency. Symptoms often worsen over time and can include intellectual disability, hearing loss, skeletal abnormalities, immune deficiency, and motor problems. Early diagnosis and supportive care are important in managing the disease. - Healthcare Professionals
- Disease Ontology ID - DOID:3413
- Pathophysiology
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A defective alpha-mannosidase enzyme, which normally helps to break down complex sugars derived from glycoproteins in the lysosome, causes progressive lysosomal accumulation of mannose-rich oligosaccharides in all tissues, resulting in impaired cellular function and apoptosis (Figure 2). Complete absence of functionality in this enzyme leads to death during early childhood due to deterioration of the central nervous system. Enzymes with low residual activity lead to a milder form of the disease, with symptoms such as impaired hearing, cognitive impairment, susceptibility to bacterial infections, and skeletal deformities. The course of the disease is progressive.Depending on the severity of the disease, alpha-mannosidosis has been classified into three proposed subtypes, based on severity and age of onset.
Type 1: A mild form, recognized after age ten years, with absence of skeletal abnormalities, muscle problems (myopathy), and slow progression
Type 2: A moderate form, recognized before age ten years, with presence of skeletal abnormalities, myopathy, and slow progression. This is the most common form
Type 3: A severe form, leading to early death from progressive central nervous system involvementHowever, given the variety of mutations that have been documented, and the broad range and severity of symptoms, the disease is considered clinically as a continuum. - Carrier Status
- Carrier status for alpha-mannosidosis relates to individuals who carry one copy of the mutated gene responsible for the condition but do not exhibit symptoms themselves. Alpha-mannosidosis is inherited in an autosomal recessive pattern, meaning two copies of the mutated gene (one from each parent) are required to manifest the disorder. Carriers usually do not show symptoms but can pass the mutated gene to their offspring.
- Mechanism
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Alpha-mannosidosis is a rare genetic lysosomal storage disorder caused by mutations in the MAN2B1 gene, which encodes the enzyme alpha-mannosidase. This enzyme is responsible for breaking down mannose-rich oligosaccharides within lysosomes.
Mechanism:
Defective or deficient alpha-mannosidase activity leads to the accumulation of mannose-rich oligosaccharides in various tissues, disrupting normal cellular and tissue functions. This accumulation causes progressive damage to cells, particularly affecting the central nervous system, liver, and other organs.
Molecular Mechanisms:
- Mutations in the MAN2B1 gene result in either unstable or non-functional alpha-mannosidase enzymes.
- With deficient enzymatic activity, oligosaccharides that are normally degraded by alpha-mannosidase accumulate within lysosomes.
- This leads to the formation of intracellular vacuoles containing undegraded oligosaccharides, causing lysosomal swelling and cellular dysfunction.
- Accumulation of these oligosaccharides disrupts cellular homeostasis and affects signaling pathways, leading to broad-spectrum tissue damage and contributing to the clinical features of the disease, such as intellectual disability, skeletal abnormalities, and immune deficiencies. - Treatment
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There is no cure for congenital alpha-mannosidosis, and in general, the approach to management is proactive, with the aim of preventing emerging complications. After a full physical examination, physicians should focus on the known complications of alpha-mannosidosis, such as hydrocephalus, otitis media, hearing loss, dental caries, joint symptoms, kyphoscoliosis, and mental state. Treatment is often limited to reducing or controlling the symptoms of the condition by, for example, medications to control seizures, hearing aids to ameliorate hearing loss, and routine physical therapy to assist with muscular pain and weakness. In some cases, a wheelchair may be appropriate if muscle or spinal impairments immobilize the individual affected.
Hematopoietic stem cell transplantation (HSCT) can be a treatment option for some patients, however the risk-benefit profile is more favourable in younger patients, therefore ensuring an early diagnosis is critical for this to be a viable option. The rationale is that enzyme-producing donor cells repopulate the host tissue and transfer enzyme to nearby enzyme-deficient host cells. Despite early reports to the contrary, The possible benefits of HSCT must be weighed against the overall risk of procedure related morbidity and mortality. The benefits are greater in younger patients before complications have developed, and also transplant related complications are more frequent and severe in older patients.
Enzyme replacement therapy (ERT) is a therapeutic alternative in a number of lysosomal storage diseases. The overall principle of ERT is that a recombinantly produced version of the deficient enzyme is introduced into the blood stream, from where it is internalised by the cells and reaches the lysosomes by mannose-6-phosphate receptor mediated uptake, thus replacing the missing endogenous enzyme. An ERT with velmanase alfa is approved for use in the European Union and the US. - Compassionate Use Treatment
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Alpha-mannosidosis is a rare lysosomal storage disorder caused by deficient activity of the enzyme alpha-mannosidase. For compassionate use, off-label, or experimental treatments:
1. **Bone Marrow Transplant (BMT)**: While not universally accepted, BMT has been used to provide a source of functional enzyme and has shown positive outcomes in some cases by potentially halting disease progression.
2. **Enzyme Replacement Therapy (ERT)**: Lamzede (velmanase alfa) is the first approved ERT for alpha-mannosidosis in some regions. It's designed to supplement the deficient enzyme in patients. Although still relatively new, it represents a significant advancement in treatment options.
3. **Gene Therapy**: Experimental gene therapy approaches are under investigation. These aim to introduce a functional copy of the gene responsible for alpha-mannosidase production into the patient’s cells, offering a potential long-term treatment solution.
4. **Substrate Reduction Therapy (SRT)**: There is ongoing research into SRT, which aims to reduce the accumulation of harmful substrates that build up due to enzyme deficiency. This approach is still experimental.
5. **Supportive Treatments**: Off-label use of various supportive therapies such as physical therapy, occupational therapy, and medications to manage symptoms (e.g., antibiotics for infections, anti-seizure medications) is common.
The availability and approval status of these treatments can vary by region, and their use might depend on specific patient circumstances and the discretion of the treating physician. - Lifestyle Recommendations
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For individuals with alpha-mannosidosis, lifestyle recommendations are crucial for managing the symptoms and improving quality of life. Here are some suggestions:
1. **Healthcare Monitoring**: Regular check-ups with specialists such as neurologists, orthopedists, and audiologists are essential to monitor and manage the progression of the disease.
2. **Physical Therapy**: Engaging in physical therapy can help maintain muscle strength and mobility. Tailored exercise plans can improve motor skills and reduce joint stiffness.
3. **Occupational Therapy**: This can aid in improving daily living skills and adapting activities to the individual's abilities, enhancing independence.
4. **Speech Therapy**: For those with speech and communication difficulties, working with a speech therapist can improve communication skills.
5. **Nutritional Support**: A balanced diet rich in vitamins and minerals supports overall health. In cases of difficulty swallowing, a nutritionist may recommend specific dietary modifications.
6. **Hearing Aids**: Since hearing loss is common, using hearing aids can alleviate this symptom and improve quality of life.
7. **Mental Health Support**: Psychological support or counseling can help cope with the emotional and mental challenges of living with a chronic condition.
8. **Social Engagement**: Encouraging participation in social and recreational activities can improve mental and emotional well-being.
9. **Education and Support Groups**: Joining patient support groups and educational programs can provide valuable information and emotional support.
By adhering to these lifestyle recommendations, individuals with alpha-mannosidosis can better manage their condition and maintain a higher quality of life. - Medication
- For alpha-mannosidosis, the medication commonly used is velmanase alfa (brand name Lamzede). This enzyme replacement therapy helps to reduce the accumulation of mannose-rich oligosaccharides in the body.
- Repurposable Drugs
- Alpha-mannosidosis is a rare lysosomal storage disorder, and currently, there are no well-established repurposable drugs specifically recommended for its treatment. The primary treatment options include enzyme replacement therapy (ERT) with velmanase alfa and hematopoietic stem cell transplantation (HSCT). ERT aims to provide the deficient enzyme, while HSCT can offer long-term benefits by potentially correcting the underlying enzyme deficiency. Research and clinical trials are ongoing to explore additional therapeutic strategies.
- Metabolites
- Alpha-mannosidosis is characterized by the accumulation of mannose-rich oligosaccharides due to deficient activity of the enzyme alpha-mannosidase. Elevated levels of these unmetabolized oligosaccharides can be detected in various tissues and bodily fluids.
- Nutraceuticals
- Nutraceuticals have not been established as an effective treatment for alpha-mannosidosis. This rare genetic disorder typically requires more targeted interventions such as enzyme replacement therapy or hematopoietic stem cell transplantation. Nutritional supplements may support general health but are not a substitute for these specific treatments. Always consult healthcare providers for personalized medical advice.
- Peptides
- Alpha-mannosidosis is a rare lysosomal storage disorder caused by deficient activity of the enzyme alpha-mannosidase, leading to the accumulation of mannose-rich oligosaccharides in cells. Research on treatment includes enzyme replacement therapy, where peptides and nanoparticles (nanomedicine) are being explored to enhance delivery and efficacy of therapeutic agents. However, standard treatments typically involve bone marrow transplantation and supportive care.