1. Mevalonate Kinase Deficiency A metabolic and inflammatory disorder

2. Deficiency of Mevalonate Kinase enzyme = MKD Transmission autosomal recessive Undetectable MK activity = mevalonic aciduaria (MA) - neonatal onset - severe multisystemic inflammation - failure to thrive - epatopahty - cerebellar ataxia, psychomotor impairment - cataracts, blindness, dysmorphic features MK between 1 and 10-15% = hyper-IgD syndrome

3. SEPSISKAWASAKI DISEASE PFAPASoJIA HSP Behcet IBD Acute abdomen AppendicitisRecurrent infections

4. Laboratory evaluations: - Increased acute phase reactants and leukocytosis during attacks - in severe cases, lowered cholesterol during attacks - increased mevalonic acid in blood and urine during attacks (HyperIgD) or always (MA) - chronic anemia - increased IgD and or IgA - No definite immune defect but in some cases an increased rate or severity of infections has been reported. - Not clear whether infections are worsened due to uncontrolled inflammation or if the disease is associated with deficiency of ntiviral mevalonate derived sterols

5. Bone Marrow Transplantation cures inflammatory recurrence, but questionable risk/benefits ratio in most patients. Unknown effect on neurologic signs. Glucocorticoids, effective in single flares, but dependency/resistance. Anakinra, can control flares, but high daily doses may be needed, leading to discomfort for the patient. In severe cases can’t lead to complete relief from symptoms. Canakinumab seems more effective, but it has very high costs. Unknown long term risks. Manipulation of the mevalonate pathway promising in vitro, but still not clear which is the best target. Possible relevance to other inflammatory and/or periodic disorders. Biphosphonates and statins proposed but dangerous.

7. J Am Coll Cardiol. 2008;51(4):415-426. doi:10.1016/j.jacc.2007.10.009 eNOS = endothelial nitric oxide synthase; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LPS = lipopolysaccharide; NAD(P)H = nicotinamide adenine dinucleotide phosphate; NFκB = nuclear factor kappa B; PI3 = phosphatidylinositol-3; PP = pyrophosphate; tRNA = transfer ribonucleic acid. MKD

8. What causes inflammation? Mevalonate Kinase Deficiency INFLAMMATION ???

9. PROPOSED PATHOGENESIS OF MKD Accumulation of mevalonate FPP HMG-CoA mevalonate phosphomevalonate mevalonate diphosphate IPP squalene Farnesylation GGPP GeranylgeranylationCholesterol mevalonate kinase Shortage of isoprenoids intermediates Hypothesis is not confirmied (Mandey, 2006; 1 st hyphotesis 2 st hyphotesis

10. Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency. Henneman et al. 2010 J Inherit Metab Dis

12. Targeting farnesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches. De Leo L, Marcuzzi A, Decorti G, Tommasini A, Crovella S, Pontillo A.Pharmacol Res. 2010

14. Lovastatin induces apoptosis through the mitochondrial pathway in an undifferentiated SH- SY5Y neuroblastoma cell line. Marcuzzi A, Tricarico PM, Piscianz E, Kleiner G, Vecchi Brumatti L, Crovella S.Cell Death Dis. 2013

15. HMG-CoA Mevalonate Mevalonate PP Isopentenyl PPDimetylallyl PP Geranyl PP Farnesyl PP Geranylgeranyl PP Protein geranylation localization to membrane Squalene Cholesterol Heme, dolichol ubiquinon Statins HMGCR MK farnesylation FTI GGTI LAPAQUISTAT ZAA