Study On The Clinical Phenotype And Immune Metabolism Characteristics Of Mevalonate Kinase Deficiency

Objective To initially establish the normal reference ranges for plasma mevalonate kinase(MVK)activity and IgD levels in healthy children,and further use it to validate the immune and metabolic characteristics in a case of genetically diagnosed child with mevalonate kinase deficiency(MKD).Meanwhile,we propose to elaborate the pathogenesis,epidemiology,clinical manifestations,diagnostic criteria and treatment principles of MKD by retrospectively analyzing the multi-center large sample data from abroad,aiming to improve the clinicians' understanding of the disease.Methods(1)Peripheral blood samples were collected from 40 healthy children,and the normal ranges for plasma MVK activity and IgD levels were established by sandwich ELISA.Relevance between blood MVK activity and IgD levels,measure difference between sexes and ages were analyzed by SPSS 17.0.(2)A pedigree of MKD at the Rheumatology Department of Shenzhen Children's Hospital in May 2017 was studied and the clinical data,physical examination and laboratory results were summarized.Difference between plasma MVK activity,IgD levels of MKD patient and healthy children and its corresponding normal values were compared with single-sample t-test.(3)Literature search in both abroad and domestic database like PubMed,EMBASE,Ovid,WanFang Database,CNKI and China Biology Medicine disc was conducted using the key words"Mevalonate Kinase Deficiency(MKD),Hyperimmunoglobulinemia D with periodic fever syndrome(HIDS),mevalonic aciduria(MA),mevalonate kinase deficiency,high IgD syndrome,mevalonic aciduria".More than 10 cases of multi-center,large-sample data were reviewed and the pathogenesis,epidemiology,clinical manifestations,diagnostic criteria,treatment principles and prognosis of MKD were retrospectively summarized.Results(1)ELISA results from 40 healthy children showed that the normal range of blood MVK activity was 96.17±19.24?g/L,and the normal range of blood IgD levels was 44.11±28.51mg/L.No statistical difference was observed between sexes and ages.(2)The research subject was a male patient aged 5 years and 10 months,with an onset occurred 10 days after birth.The primary manifestation was repetitive fever,persisting for 3-7 days each time,with an interval time being 2-4 weeks.And there may be associated fatigue,hyperhidrosis,abdominal pain,joint swelling and pain,headache.Body examination showed anaemic appearance,cervical adenopathy and hepatosplenomegaly.Ancillary testing:blood tests suggested that blood IgA 5.31-11.26 g/L(with a normal range of 0.41-2.97 g/L),blood cholesterol 2.07-2.97 mmol/L(with a normal range of 3.1-5.8 mmol/L),Hb 65-102 g/L(with a normal range of 110-160 g/L);Direct Coomb's test positive;Joint MRI indicated effusion in bitaleral ankle joints,with apparent thickened synovial membrane;Next generation sequancing showed complicated heterozygous genetic variants of MVK genes c.827A>G,p.E276G and c.827A>G,p.E276G,originated from father and mother respectively.The MVK activity at acute exacerbation was 10.987ug/L while it at the intervals between attacks was 25.078ug/L,both significantly lower than the normal ranges of 96.17±19.24?g/L.The IgD level at acute exacerbation was 4894.97mg/L while it at the intervals between attacks was 4968.75mg/L,both significantly higher than the normal ranges of 44.11±28.51 mg/L.The patient responded poorly to non-steroidal anti-inflammatory drugs(NSAIDs)but oral glucocorticoids was effective and patient could go to school normally.(3)MKD is an autosomal recessive type of monogenic autoinflammatory disease,with causative genes located at chromosome 12q24.Mutation of this loci could decrease MVK activity,causing mevalonate pathway disorders,isoprenoids deficiency,overproduction of inflammatory cytokines like IL-1? and subsequent systemic inflammation.MKD is divided into two phenotypes based on the severity of clinical manifestations and decreased enzyme activity,namely hyperimmunoglobulinemia D with periodic fever syndrome(HIDS)and mevalonic aciduria(MA).Characterized by repetitive and periodic fevers,HIDS usually accompanied by lymphadenopathy,splenomegaly,arthralgia/arthritis,abdominal pain and rash,but amyloidosis is rarely seen.MA patients may be accompanied by severe neurological impairment,developmental malformations and ocular lesions,with the majority of them ended up with early death.The diagnosis of MKD is mainly based on the clinical diagnostic criteria put forward by PRINTO and Eurofever Project in 2015 and genetic test.Attack frequency may decrease with age.Also,the disease could be under control after treatment in some patients.However,MA patients usually have poor prognosis,with approximately 40%of them die as an infant.So far there is no radical treatments of MKD.Complying with the principle of individualized treatment,symptomatic treatments are main objectives.NSAIDs is our first choice of drug and secondary treatments include glucocorticoid and biologics.Besides,it is reported that hematopoietic stem cell therapy was successful in some cases.And plant isopentyl glycol may be a new therapeutic targets of MKD.Conclusion In this paper,we have initially established the normal reference ranges for plasma mevalonate kinase(MVK)activity and IgD levels in healthy children,and further use it to validate the immune and metabolic characteristics in a case of genetically diagnosed child with mevalonate kinase deficiency(MKD).The onset of the cases in the neonatal period to periodically repetitive fever with severe abdominal pain,vomiting,joint pain,headache,as the main performance,auxiliary examination prompt nonspecific inflammation index increases,genetic testing prompt MVK gene compound heterozygous mutations,and eliminate the infectious disease and tumor,so HIDS can diagnosis,laboratory results prompt the decrease of MVK activity and increase of IgD concentration MVK reduced activity,IgD levels,conform to the MKD immune metabolic features.