Mevalonate kinase deficiency: therapeutic targets, treatments, and outcomes

ABSTRACT

Introduction: Mevalonate Kinase Deficiency (MKD) is a rare inborn disease caused by the mutation of mevalonate kinase gene.

The clinical phenotype encompasses recurrent fever episodes in combination with gastrointestinal, immunological, rheumatological and neurological complaints. No specific treatment is available, apart from the newly approved biologics (canakinumab), but MKD can be still considered an orphan-drug disease, since the identification of a reliable therapeutic target needs an improved knowledge on the pathogenesis of the disease, which is so far controversial.

Areas covered: On one hand, shortage of isoprenoid compounds downstream of mevalonate led to a defective geranylgeranylation of RhoA/Rac proteins and increased caspase-1-dependent inflammation. On the other hand, recent studies pointed the attention to the pathogenic role of the mitochondrial dysfunction and to defective production of 25-hydroxycholesterol. These mechanisms are not exclusive of each other, as they can contribute to different pathogenic features of MKD.

Expert opinion: Innovative therapeutic approaches to MKD may count upon various medicaments, such as isoprenoid compounds that can enter the metabolic pathway, specific enzyme inhibitors and mitochondria-targeted drugs. Some of these compounds have already passed the clinical phase for other uses and may be repositioned to the treatment of MKD, fostering the development of clinical trials.

KEYWORDS:

• Rare disease
• cholesterol
• immunology
• inflammation

Article highlights

• Mevalonate Kinase Deficiency (MKD) is a neglected disease with onset in infancy.

• MKD clinical picture is characterized by recurrent fever attacks, abdominal pain arthralgia, lymphadenopathy and, in the most severe case, neurological involvement.

• The main MKD pathogenic hypothesis is represented by a shortage of isoprenoid compounds that led to a defective geraylgeranylation of RhoA proteins and increased caspase-1-dependent inflammation.

• Mitochondrial dysfunction and altered production of 25-hydroxycholesterol represent innovative pathogenic assumptions to understand the MKD progression.

• The emerging evidences on MKD pathogenesis could widen the therapeutic approaches focused particularly on Mitochondrial-Target Antioxidants or squalene synthetase inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

A. Tommasini performed experimental research for Takeda in 2014 receiving a total amount 18.000 euros for research expense. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by the Ministry of Health grant RC 36/11.