Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype.

Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM# 260920) is a rare recessively-inherited autoinflammatory condition caused by mutations in the MVK gene, which encodes for mevalonate kinase, an essential enzyme in the isoprenoid pathway. HIDS is clinically characterized by recurrent episodes of fever and inflammation. Here we report on the case of a 2 year-old Portuguese boy with recurrent episodes of fever, malaise, massive cervical lymphadenopathy and hepatosplenomegaly since the age of 12 months. Rash, arthralgia, abdominal pain and diarrhea were also seen occasionally. During attacks a vigorous acute-phase response was detected, including elevated erythrocyte sedimentation rate, C-reactive protein, serum amyloid A and leukocytosis. Clinical and laboratory improvement was seen between attacks. Despite normal serum IgD level, HIDS was clinically suspected. Mutational MVK analysis revealed the homozygous genotype with the novel p.Arg277Gly (p.R277G) mutation, while the healthy non-consanguineous parents were heterozygous. Short nonsteroidal anti-inflammatory drugs and corticosteroid courses were given during attacks with poor benefits, whereas anakinra showed positive responses only at high doses. The p.R277G mutation here described is a novel missense MVK mutation, and it has been detected in this case with a severe HIDS phenotype. Further studies are needed to evaluate a co-relation genotype, enzyme activity and phenotype, and to define the best therapeutic strategies.

Systemic and neuronal inflammatory markers in a mouse model of mevalonate kinase deficiency: a strain-comparative study.

BACKGROUND/AIM: There is a lack of reliable animal models for the study of the rare auto-inflammatory disease mevalonate kinase deficiency (MKD). The one most frequently used is a biochemical model, obtained by treating BALB/c mice in order to block the mevalonate pathway, thus attempting to reproduce the inflammatory pattern presented in patients. This study aims to assess the role played in pathology by the inflammasome and the reliability of this model. MATERIALS AND METHODS: We mimicked MKD using two different mice strains (BALB/c and C57BL/6), evaluating typical inflammatory markers of MKD and inflammasome modulation. RESULTS: Without significant differences, both strains exhibited a general MKD-like inflammation, including the modulation of the molecular platform inflammasome, mimicking the characteristics observed in human patients. CONCLUSION: Although with some limitations, the mouse model appears robust and suitable for studying MKD. Results do not seem to vary with the mouse strain used, and appear to be treatment-dependent. Finally, in vivo inflammasome activation was assessed for the first time here.

Temperature and drug treatments in mevalonate kinase deficiency: an ex vivo study.

Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused by mutations in the mevalonate kinase (MK) gene, leading to MK enzyme decreased activity. The consequent shortage of mevalonate-derived isoprenoid compounds results in an inflammatory phenotype, caused by the activation of the NALP3 inflammasome that determines an increased caspase-1 activation and IL-1 ß release. In MKD, febrile temperature can further decrease the residual MK activity, leading to mevalonate pathway modulation and to possible disease worsening. We previously demonstrated that the administration of exogenous isoprenoids such as geraniol or the modulation of the enzymatic pathway with drugs, such as Tipifarnib, partially rescues the inflammatory phenotype associated with the defective mevalonic pathway. However, it has not been investigated yet how temperature can affect the success of these treatments. Thus, we investigated the effect of temperature on primary human monocytes from MKD patients. Furthermore the ability of geraniol and Tipifarnib to reduce the abnormal inflammatory response, already described at physiological temperature in MKD, was studied in a febrile condition. We evidenced the role of temperature in the modulation of the inflammatory events and suggested strongly considering this variable in future researches aimed at finding a treatment for MKD.

A taste of periodic fever syndromes.

Periodic fevers are acquired or inherited disorders of innate immunity, which were first described in the 1940s. The patients are typically young at onset and have regularly recurring fevers for a few days to a few weeks with systemic inflammatory symptoms that are interrupted by symptom-free periods. There is a variety of clinical manifestations including gastrointestinal complaints, myalgias, arthralgias, and rash. A differential diagnosis in these patients may include recurrent infections, other inflammatory disorders, and neoplastic disease. This clinical review focuses on a sample of autoinflammatory disorders including familial Mediterranean fever, tumor necrosis factor receptor 1-associated periodic syndrome, hyperimmunoglobulinemia D syndrome, the cryopyrin-associated periodic syndrome, and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. We review the basics, pertinent clinical and laboratory features, and management of each entity.

Long chain fatty acid (Lcfa) abnormalities in hyper Igd syndrome (Hids) and Familial Mediterranean Fever (Fmf): new insight into heritable periodic fevers.

OBJECTIVE: To examine essential fatty acids (EFAs) in hyper-IgD syndrome (HIDS) and Familial Mediterranean Fever (FMF). METHODS: EFAs were determined in sera derived from an archival, cross-sectional group of HIDS/FMF patients, stratified for presence and absence of fever. Control populations included healthy afebrile adults, and individuals with non-periodic fever (septic shock). EFAs were quantified using isotope dilution gas chromatography-mass spectrometry and data analyzed employing a Kruskal-Wallis non-parametric ANOVA with Dunn's post-hoc test. RESULTS: Sera samples derived from HIDS patients showed significantly decreased C20, C26, phytanic and pristanic acids during febrile crises that normalized in the afebrile state, and a significantly increased afebrile C22_4ω6 level that normalized with fever. Samples derived from FMF patients revealed increased ω-oxidized LCFAs as compared to controls, and the trend was for these same species to be increased in comparison to febrile, but not afebrile, HIDS patients. Individuals with non-periodic fever demonstrated global decreases in C10-C24 fatty acids, both saturated and unsaturated, accompanied by an elevated triene/tetraene ratio. CONCLUSIONS: Our results suggest that different mechanisms are active in hereditary periodic fever syndromes that appear unrelated to fever, including depletion of very long chain fatty acids (VLCFAs) in febrile HIDS patients and increased ω-oxidized LCFAs in patients with FMF. These findings underscore new roles for EFAs in the potential production of inflammatory species in patients with hereditary periodic fever.

On-demand anakinra treatment is effective in mevalonate kinase deficiency.

BACKGROUND: Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory syndrome marked by recurrent attacks of fever and inflammation. Severe enzyme deficiency results in mevalonic aciduria (MA) and milder deficiency in hyperimmunoglobulin D syndrome (HIDS). Treatment remains a challenge. OBJECTIVE: To observe the effect of the recombinant interleukin-1 receptor antagonist anakinra in patients with MKD. METHODS: A prospective observational study was undertaken. Two patients with MA started continuous treatment with anakinra (1-2 mg/kg/day) and nine patients with HIDS chose between continuous treatment and on-demand treatment (starting at first symptoms of attack, 100 mg/day or 1 mg/kg/day for 5-7 days). RESULTS: Anakinra induced partial remission in one patient with MA but there was no response in the other patient with MA. In one patient with HIDS continuous treatment induced complete remission for 7 months but was stopped because of side effects. Eight patients with HIDS preferred on-demand treatment from the start. This induced a clinical response (≥50% reduction in duration) in 8 of 12 treated attacks without a change in attack frequency. Anakinra prevented fever attacks due to vaccination without inhibiting antibody induction. No major side effects were seen. CONCLUSIONS: On-demand treatment with anakinra in HIDS decreases the duration and severity of fever attacks. Because of the burden of daily injections and relatively long asymptomatic intervals of HIDS, all patients with HIDS preferred on-demand treatment.

Measurement of human serum IgD levels.

This unit describes an ELISA for the quantitative measurement of IgD levels in human serum. The ELISA is highly specific and sensitive, with a minimum detectable concentration of 30 pg/ml and more than 10,000-fold specificity for IgD over all other human immunoglobulins. Linear dilution characteristics enable measurement of IgD concentrations ranging over 5 orders of magnitude. These factors are vital for the IgD assay, since IgD makes up only a small proportion of the total immunoglobulins present in normal sera, and IgD serum concentrations are known to vary widely between individuals.

B cell cytopenia in two brothers with hyper-IgD and periodic fever syndrome.

UNLABELLED: We report on two brothers with hyperimmunoglobulinemia D (patient 1: serum immunoglobulin D [IgD] concentration initially 61 IU/ml, later on 340 IU/ml; patient 2: serum IgD concentration 144 IU/ml; normal <100 IU/ml, 97th centile) and periodic fever syndrome (HIDS). Both are compound heterozygous for the mevalonate kinase (MVK) mutations V377I and I268T. They developed significant B cell cytopenia (7%, 129/microl and 11%, 132/microl, respectively; normal ranges 12-22%, 300-500/microl) with hypogammaglobulinemia (IgG 5.48 g/l and IgG 5.22 g/l, respectively; normal range IgG 6-13 g/l). Furthermore, the clinical spectrum shows an interesting atypical autoinflammatory symptomatology. The therapy consisted of prednisone, azathioprine, and intravenous immunoglobulins (IVIG), which results in reduced incidence and severity of febrile attacks. CONCLUSION: The pathogenesis and clinical presentation of HIDS is still not fully understood and show a great variability. To our knowledge, severe B cell cytopenia in children with HIDS has not been reported before. Furthermore, the therapy of febrile episodes is still performed on an individual basis in affected patients.