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Mevalonic Aciduria

Disease Details

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Description: Mevalonic aciduria is a rare genetic metabolic disorder characterized by an inability to properly metabolize mevalonic acid, leading to developmental delays, severe dysmorphic features, and recurrent febrile episodes.
Type: Mevalonic aciduria is a metabolic disorder. It is inherited in an autosomal recessive pattern.
Signs And Symptoms: HIDS is one of a number of periodic fever syndromes. It is characterised by attacks of fever, arthralgia, skin lesions including cyclical mouth ulcers, and diarrhea. Laboratory features include an acute phase response (elevated CRP and ESR) and markedly elevated IgD (and often IgA), although cases with normal IgD have been described.It has mainly been described in the Netherlands and France, although the international registry includes a number of cases from other countries.The differential diagnosis includes fever of unknown origin, familial Mediterranean fever (FMF) and familial Hibernian fever (or TNFα reception associated periodic syndrome/TRAPS).
Prognosis: Mevalonic aciduria is a rare genetic disorder that affects the body's ability to produce cholesterol and other essential compounds. The prognosis for individuals with mevalonic aciduria can vary. Some individuals may experience severe developmental delays, growth failure, and recurrent fevers, while others may have milder symptoms. Lifespan can be significantly shortened in severe cases, but early diagnosis and supportive care can improve outcomes. Regular monitoring and treatment of symptoms are essential for managing the condition.
Onset: Mevalonic aciduria typically presents in infancy or early childhood. It often manifests with symptoms such as developmental delay, hypotonia, failure to thrive, recurrent fevers, and dysmorphic features.
Prevalence: The prevalence of mevalonic aciduria is extremely rare, with only a few dozen cases reported worldwide. Exact prevalence rates are not well-defined due to the rarity of the condition.
Epidemiology: Globally, less than 1 in 100,000 people have HIDS, and of these, ~200 individuals have MKD. This categorises the condition as a rare genetic disease.
Intractability: Yes, mevalonic aciduria is considered an intractable disease. It is a rare genetic metabolic disorder caused by mutations in the MVK gene, leading to a deficiency of the enzyme mevalonate kinase. This enzyme deficiency results in the accumulation of mevalonic acid in the body. The disease is characterized by a range of severe symptoms, including developmental delays, recurrent fevers, progressive cerebellar ataxia, and failure to thrive. Currently, there is no cure for mevalonic aciduria, and treatment primarily focuses on managing symptoms and complications.
Disease Severity: Mevalonic aciduria is a rare metabolic disorder caused by a deficiency of the enzyme mevalonate kinase. The severity of the disease can vary, but it often leads to significant health issues. Patients may experience developmental delays, recurrent fever episodes, failure to thrive, and other serious complications such as liver and spleen enlargement, anemia, and progressive neurological involvement. It is generally considered a severe condition requiring careful medical management.
Healthcare Professionals: Disease Ontology ID - DOID:0050452
Pathophysiology: It is not known how mevalonate kinase mutations cause the febrile episodes, although it is presumed that other products of the cholesterol biosynthesis pathway, the prenylation chains (geranylgeraniol and farnesol) might play a role.
Carrier Status: For mevalonic aciduria:

Carrier Status: Mevalonic aciduria is inherited in an autosomal recessive manner. Carriers of the condition have one normal copy and one mutated copy of the MVK gene but typically do not show symptoms. Both parents must be carriers for a child to be affected.
Mechanism: Mevalonic aciduria is a rare autosomal recessive metabolic disorder caused by mutations in the MVK gene, which encodes the enzyme mevalonate kinase. This enzyme is essential for the mevalonate pathway, which is crucial for cholesterol and non-sterol isoprenoid biosynthesis.

**Mechanism:**
The primary defect in mevalonic aciduria is the deficiency of mevalonate kinase. This deficiency leads to an accumulation of mevalonic acid, as the conversion of mevalonate to 5-phosphomevalonate is impaired. This buildup of mevalonic acid and a subsequent lack of downstream products result in several metabolic disturbances and clinical symptoms.

**Molecular Mechanisms:**
1. **Enzyme Deficiency:** The mutation in the MVK gene results in a deficient or non-functional mevalonate kinase enzyme, disrupting the mevalonate pathway.

2. **Metabolite Accumulation:** Without adequate mevalonate kinase activity, mevalonic acid accumulates, which can be detected in elevated levels in the urine of affected individuals.

3. **Deficient Isoprenoids Production:** The lack of downstream isoprenoids, crucial for various cellular functions including cholesterol synthesis, protein prenylation, and cell membrane integrity, leads to multiple systemic issues.

4. **Inflammation and Immune Dysregulation:** The shortage of isoprenoids also affects the regulation of inflammatory processes, contributing to recurrent fever, arthritis, and other inflammatory symptoms seen in mevalonic aciduria patients.

The combination of these molecular disturbances leads to the diverse clinical spectrum associated with mevalonic aciduria, including developmental delay, hypotonia, dysmorphic features, and significant immunological abnormalities.
Treatment: There is no treatment for MKD. But, the inflammation and the other effects can be reduced to a certain extent.

IL-1 targeting drugs can be used to reduce the effects of the disorder. Anakinra is antagonist to IL-1 receptors. Anakinra binds the IL-1 receptor, preventing the actions of both IL-1α and IL-1β, and it has been proved to reduce the clinical and biochemical inflammation in MKD. It can effectively decreases the frequency as well as the severity of inflammatory attacks when used on a daily basis. Disadvantages with the usage of this drug are occurrence of painful injection site reaction and as the drug is discontinued in the near future the febrile attacks start. (Examined in a 12-year-old patient).
Canakinumab is a long acting monoclonal antibody which is directed against IL-1β has shown to be effective in reducing both frequency and severity in patients with mild and severe MKD in case reports and observational case series. It reduces the physiological effects but the biochemical parameter still remain elevated (Galeotti et al. demonstrated that it is more effective than anakinra –considered 6 patients with MKD).
Anti-TNF therapy might be effective in MKD, but the effect is mostly partial and therapy failure and clinical deterioration have been described frequently in patients on infliximab or etanercept. A beneficial effect of human monoclonal anti-TNFα antibody adalimumab was seen in a small number of MKD patients.
Most MKD patients are benefited by anti-IL-1 therapy. However, anti-IL-1-resistant disease may also occur. Example. tocilizumab (a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor). This drug is used when the patients are unresponsive towards Anakinra. (Shendi et al. treated a young woman in whom anakinra was ineffective with tocilizumab). It was found that it was effective in reducing the biochemical and clinical inflammation [30].Stoffels et al. observed reduction of frequency and severity of the inflammatory attacks, although after several months of treatment one of these two patients persistently showed mild inflammatory symptoms in the absence of biochemical inflammatory markers.
A beneficial effect of hematopoietic stem cell transplantation can be used in severe mevalonate kinase deficiency conditions (Improvement of cerebral myelinisation on MRI after allogenic stem cell transplantation was observed in one girl). But, liver transplantation did not influence febrile attacks in this patient.
Compassionate Use Treatment: Mevalonic aciduria is a rare metabolic disorder caused by a deficiency of the enzyme mevalonate kinase. Traditional management primarily involves supportive care to relieve symptoms, but there are a few avenues being explored for treatment:

1. **Compassionate Use Treatment:**
- **Anakinra:** This is an IL-1 receptor antagonist that has been used on a compassionate basis to reduce the inflammatory symptoms associated with mevalonic aciduria.

2. **Off-label or Experimental Treatments:**
- **Statins (e.g., Simvastatin):** These are typically used to lower cholesterol but have been explored off-label to reduce the buildup of mevalonic acid.
- **Bisphosphonates (e.g., Alendronate):** Commonly used to treat osteoporosis, they have been tested off-label to manage bone abnormalities and other symptoms in mevalonic aciduria.
- **Allogeneic Stem Cell Transplant:** Experimental in nature, this treatment aims to correct the underlying enzyme deficiency by introducing healthy donor stem cells.

Research is ongoing, and the effectiveness and safety of these treatments continue to be evaluated. Always consult with a specialist for the most current and personalized medical advice.
Lifestyle Recommendations: Mevalonic aciduria is a rare metabolic disorder resulting from a deficiency in the enzyme mevalonate kinase. While no specific cure exists, managing the condition focuses on supporting overall health and mitigating symptoms. Here are general lifestyle recommendations:

1. **Diet:**
- Maintain a balanced diet rich in nutrients but low in cholesterol and saturated fats.
- Ensure adequate intake of essential vitamins and minerals to support overall health.

2. **Hydration:**
- Ensure proper hydration to support metabolic functions and reduce the risk of acute episodes.

3. **Monitoring:**
- Regular medical check-ups to monitor the condition and adjust treatments as necessary.
- Keep track of any symptoms or changes and report them promptly to healthcare providers.

4. **Medications:**
- Adhere to prescribed medications, which may include anti-inflammatory drugs or immune-modulating treatments, as directed by a healthcare provider.

5. **Physical Activity:**
- Engage in regular, moderate physical activity to promote general well-being but avoid vigorous exercise that may exacerbate symptoms.

6. **Avoid Triggers:**
- Learn and avoid potential triggers for inflammatory episodes, such as infections or certain medications.

7. **Support Network:**
- Build a strong support network, including healthcare providers, family, and support groups, for emotional and practical assistance.

Always consult with healthcare professionals to tailor these recommendations to individual needs and circumstances.
Medication: For Mevalonic Aciduria, the primary treatment approach often involves the use of medications like statins to reduce the production of mevalonate, although responses can vary. Additionally, anti-inflammatory medications and other supportive treatments are sometimes used to manage symptoms. Consultation with a healthcare professional specialized in metabolic disorders is essential for personalized treatment plans.
Repurposable Drugs: Mevalonic aciduria, a rare metabolic disorder, primarily lacks widely recognized repurposable drugs due to its rarity and the complexity of the disease. Standard treatment focuses on managing symptoms and may include Coenzyme Q10, statins, or corticosteroids to reduce inflammation. For potential repurposable drugs, ongoing research is essential to explore more targeted therapies.
Metabolites: In mevalonic aciduria, an autosomal recessive metabolic disorder, the primary metabolite that accumulates is mevalonic acid. Elevated levels of other metabolites associated with this disorder include mevalonolactone and various isoprene derivatives. These accumulations result from the deficiency of the enzyme mevalonate kinase.
Nutraceuticals: Mevalonic aciduria is a rare genetic disorder involving a deficiency of the enzyme mevalonate kinase. There is currently no established treatment with nutraceuticals specifically for mevalonic aciduria. The management typically focuses on anti-inflammatory drugs, statins, and supportive therapies. Consulting with a healthcare professional is crucial for personalized medical advice.
Peptides: Mevalonic aciduria is a rare metabolic disorder characterized by a deficiency in the enzyme mevalonate kinase, leading to the accumulation of mevalonic acid in the body. This condition is associated with recurrent episodes of fever, developmental delay, and failure to thrive. Peptides and nanoparticles (nan.) are not specifically related to the diagnosis or primary treatment of mevalonic aciduria. The management of this disorder typically focuses on minimizing symptoms and may involve the use of anti-inflammatory drugs or other supportive therapies.