MKD is usually caused by changes (variations) in a gene called MVK.

This gene helps the body produce an enzyme called mevalonate kinase. This enzyme is important in making cholesterol and isoprenoids, which are vital for normal growth and development.

In HIDS (milder form of MKD), the enzyme activity is “partially blocked”. Individuals with HIDS may still produce enough cholesterol and isoprenoids for normal development but do not have enough enzyme activity to generate signals that switch off the innate immune system.

In MA, (more severe form) enzyme activity is “severely blocked or nearly absent”, which means that there is not enough cholesterol and isoprenoids being made for vital physiological processes such as neurodevelopment, immune regulation and protection of the skin from sun damage. This means patients with MA may experience developmental delays, eye abnormalities, loss of sensation, balance problems, widespread bodily inflammation and sun-damage associated skin lesions.

Most cases occur when a child inherits two pathogenic MVK variants, typically one from each parent. This is called autosomal recessive inheritance.

However, even though two individuals may share the same genetic variations, the presentation of disease can be different. This is known as variable expressivity.

Some individuals may display all the classical symptoms of HIDS, but no pathogenic MVK gene variants are identified on testing. This may simply be due to limitations of genetic technology and understanding from a research perspective. However, there is active ongoing research and advancements of genomic technologies. Australia is one of the world leaders in this area of research.

To date, there are more than 280 known MVK variants that are associated with disease. The most well-known variants are p.V377I and p.I268T which are notably prevalent among European populations.

MKD is very rare globally.

Many cases have been reported in Western Europe, particularly in people with Dutch or French ancestry. About 60% of known cases are from these populations. This is likely due to pathogenic variants that have remained in the gene pool of these communities across generations (known as “founder variants”).

In the Netherlands, about 1 in 350 people carry a founder variant of the MVK gene (p.V377I). Carriers of this variant (without a second pathogenic variant) will not develop the condition. However, if a child inherits two copies of this variant, then they are very likely to develop HIDS.

It is important to note that disease can develop when an individual inherits two copies of the same pathogenic MVK variant (homozygous) or two different pathogenic MVK variants that contribute to substantial reduction of enzyme activity (compound heterozygous).

MKD can occur in any ethnic group, including people living in Australia and Aotearoa New Zealand. There are no confirmed numbers of MKD patients locally, but we estimate there to be at least 10 cases.

Most people first develop symptoms before age 1.

Symptoms usually happen during flares (attacks).

Flares usually last 3 to 7 days and is accompanied by significant fatigue.

They may occur every 2 to 6 weeks, although this varies between people.

Common symptoms during an inflammatory flare:

Chills followed by a rapid rise in temperature

• High fever
• Headache
• Swollen lymph nodes in the neck
• Abdominal pain
• Joint pain
• Joint swelling (arthritis), often in large joints (knee, hips, shoulders)
• Extreme tiredness
• Skin rash
• Some people develop a rash during flares. The rash usually appears during the fever episode and fades afterwards.
• The rash may appear as:
• Red patches
• Flat or raised spots (maculopapular rash)
• Hive-like rash (urticaria)
• Small red or purple spots on the skin (petechiae)
• Purplish rash (purpura)

Other symptoms may include:

• Vomiting
• Diarrhoea
• Mouth ulcers
• Genital ulcers
• Enlarged liver
• Enlarged spleen
• Children may sometimes develop very high fevers, which can cause febrile seizures.

In Mevalonic Aciduria (MA), the severe form of MKD, patients often present with signs and symptoms that involve more than inflammatory attacks.

This may include:

• Developmental delay
• Seizures
• Abnormalities of the eyes and vision
• Poor growth
• Distinctive facial and physical features
• Organ involvement such as enlarged liver and spleen
• Neurological problems such as balance impairment and sensory changes in hands and feet
• Porokeratosis – sun-damage associated skin lesions

Flares can happen without a clear cause, but common triggers include:

Immunisations, Minor injuries, Emotional stress, Physical stress, Surgery, Infections

Symptoms usually improve after a few days.

Once the flare ends:

• Most symptoms disappear
• Joint pain or rash may take longer to fully settle
• Some people may go many months or even years without symptoms
• In many patients, flares become less frequent in adulthood

Doctors diagnose MKD using a combination of:

• Medical history
• Symptoms
• Blood and urine tests
• Genetic testing
• Specialised Research Tests – Protein Prenylation Assay at Prof. Mike Rogers’ Laboratory in the Garvan’s Research Institute

No single test can confirm the condition in all patients.

Blood test findings

During a flare, blood tests usually show signs of inflammation, including:

• High C-reactive protein (CRP)
• High erythrocyte sedimentation rate (ESR)
• Increased White Blood Cells and Neutrophils
• High Serum Amyloid A (SAA)
• These results show active inflammation in the body.
• UEC, LFTs, CMP – To evaluate kidney and liver function, alongside, bone health

Immunoglobulin testing

• Some patients have high Immunoglobulin D (IgD) levels.
• Doctors may test IgD twice, about one month apart
• Levels above 100 IU per millilitre may support a diagnosis of HIDS.

However, this test has limits:

• It is not reliable in children under 2–3 years
• About 20% of patients never have high IgD
• High IgD can also occur in other inflammatory diseases
• Because of this, doctors do not rely on IgD alone for diagnosis.
• Many patients also have high IgA levels.

Urine Testing

A urine organic acid profile may show high levels of mevalonic acid and/or mevalolactone, especially during flares. This test can help screen patients who are candidates for further genetic testing with 90% specificity.

Genetic Testing & Functional Research Studies

Ultimately, sequencing of the MVK gene to identify pathogenic variants is needed to establish a formal diagnosis of MKD. However, functional studies (often done on a research level) can help determine how severely the enzymatic function is reduced and may therefore provide information for health professionals to determine treatment options, potential prognosis and ongoing monitoring.

There is no cure for MKD, but treatment can help reduce symptoms and prevent flares.

Common treatments include medicines that reduce inflammation.

These may include:

• Corticosteroids during flares
• Anti-inflammatory medicines (NSAIDs)
• Colchicine
• JAK inhibitors e.g. Baricitinib
• Biologic (Targeted) Therapies:
• IL-1 Inhibitors: Canakinumab or Anakinra
• IL-6 inhibitors: Tocilizumab
• TNF-a inhibitors: Adalimumab or Etanercept

In Australia and Aotearoa New Zealand access to biologics can be difficult. It is currently necessary for specialists to prescribe via special consideration/compassionate use.

Serious complications are highly uncommon, but may include:

• Amyloidosis, where inflammatory proteins build up in organs and impact their function.
• Macrophage Activation Syndrome (MAS) which is a potentially life-threatening inflammatory state characterised by persistent high fevers, low blood cell counts, liver dysfunction and widespread inflammatory damage to healthy tissues.
• Psychomotor Regression – when a person loses skill that they have learnt before such as walking talking, social skills and feeding oneself.

Early diagnosis, Regular monitoring and prompt intervention helps doctors reduce this risk.

MKD can not be cured, it is often a lifelong condition. Systemic Autoinflammatory disease can significantly impact on people’s lives.

However:

• Some people have fewer symptoms as they get older
• Others may have long periods without flares
• With the right treatment and specialist care, many people are able to manage the condition well.
• Early diagnosis can help manage symptoms and prevent complications.
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