Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D

Frenkel, Joost; Houten, Sander M.; Waterham, Hans R.; Wanders, Ronald J. A.; Rijkers, Ger T.; Durán, Marinus; Kuijpers, TW; Luijk, W. van; Poll-Thé, Bwee Tien; Kuis, Wietse

doi:10.1093/rheumatology/40.5.579

Cited by 86 publications

(57 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Combining the results obtained in our laboratory with the data in the international HIDS registry 8 (A Simon, personal communication), we observed that of the 34 Dutch HIDS patients analysed thus far, only four did not carry the V377I allele. 11,12,20,21 Three patients were found to be homozygotes for V377I, 11,12,20,21 , two of whom have been confirmed by analysis of parental DNA. Twenty-seven patients were compound heterozygotes for the V377I allele.…”

Section: Resultsmentioning

confidence: 84%

“…The second allele in the majority of these patients was one that has been identified also in MA, including the allele H20P (59A4C, seven patients) and the allele I268T (803T4C, nine patients). 11,12,20,21 In addition to these HIDS patients, five Dutch MA patients have been analysed. Four of these were heterozygotes for the A334T (1000G4A) allele, and one patient was homozygous for I268T.…”

Section: Resultsmentioning

confidence: 99%

“…These differences do not appear to be associated with a specific genotype. 11,20 The distribution of the V377I allele is not according to the Hardy -Weinberg equilibrium principle It may be expected that HIDS patients who are homozygous for the V377I allele have more residual MK activity than HIDS patients who are compound heterozygotes for this mutation and a mutation that has been identified in MA (eg H20P or I268T). Therefore, these patients may have a milder phenotype.…”

Section: Resultsmentioning

confidence: 99%

“…12 In addition, two other patients homozygous for V377I have been reported. 11,20 The evaluation of all Dutch MVK mutations yields a value for 'R', the proportion of V377I, of 42%. According to the Hardy -Weinberg equilibrium principle, this gives an 1 : 2.7 : 1.9 expected ratio among MK deficient individuals for patients with two V377I alleles, one V377I allele and no V377I alleles, respectively.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

et al. 2003

View full text Add to dashboard Cite

Hyper-IgD and periodic fever syndrome (HIDS) and mevalonic aciduria (MA) are two autosomal recessive disorders that both are caused by a deficient activity of the enzyme mevalonate kinase (MK) due to mutations in the encoding gene (MVK). The most frequently occurring MVK mutation, V377I (1129G4A), has been identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MA. To estimate the incidence of MK deficiency in the Netherlands, we determined the carrier frequency of the V377I mutation in genomic DNA extracted from anonymised newborn screening cards by PCR-RFLP. We found 14 carriers among 2138 analysed samples (1 : 153). Based on the V377I allele frequency of 42% in patients diagnosed with MK deficiency, the carrier frequency of any MVK mutation in the Dutch population can be calculated as 1 : 65. This predicts a disease incidence between 1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis of patients with MK deficiency remains possible, this discrepancy probably is due to a reduced penetrance of V377I homozygosity. Analysis of the distribution of the V377I allele within patients carrying MVK mutations revealed that this was not according to the Hardy -Weinberg equilibrium principle, most probably due to an under-representation of V377I homozygotes in HIDS. Homozygotes for V377I might exhibit a much milder phenotype of MK deficiency or no disease-phenotype at all.

show abstract

Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

et al. 2003

View full text Add to dashboard Cite

show abstract

“…This HIDS subgroup, termed variant-type HIDS, is characterized by normal or only slightly decreased MK activities (9,10). Given the phenotypic similarities, variant-type HIDS raises two important questions: 1) are there HIDS-related mutations in genes other than MVK?…”

Section: Objective To Describe Biochemical Findings and The Spectrummentioning

confidence: 99%

Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: A low‐penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa

Stojanov¹,

Lohse²,

Lohse³

et al. 2004

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A lowpenetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).Methods. The MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured.Results. Mutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Her IgD values varied between normal and slightly increased, and the MK activity was in the low-normal range, while urinary mevalonate concentrations were always normal.Conclusion. The genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS.The hyperimmunoglobulinemia D with periodic fever syndrome (HIDS; MIM no. 260920) is an autosomal recessively inherited autoinflammatory disease. It is characterized by febrile episodes of 3-7 days' duration recurring every 4-8 weeks and by a persistently high serum level of IgD (Ͼ100 IU/ml). Symptoms accompanying a typical attack comprise cervical lymphadeno-

show abstract

Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

Frenkel

Rijkers

Mandey

et al. 2002

Arthritis & Rheumatism

159

109

View full text Add to dashboard Cite

Objective. To investigate whether the increased interleukin-1␤ (IL-1␤) secretion in hyperimmunoglobulinemia D and periodic fever syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds.Methods. The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 ؉ CD28.Results. Lovastatin induced a 15-fold rise in IL-1␤ secretion by normal anti-CD2 ؉ CD28-stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL-1␤ secretion. Stimulated MKdeficient cells secreted 9-fold more IL-1␤ than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1␤ secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL-1␤ secretion by these cells.Conclusion. In this model, shortage of isoprenoid end products contributes to increased IL-1␤ secretion by MK-deficient PBMCs, whereas excess mevalonate does not.

show abstract

Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D

Cited by 86 publications

References 13 publications

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

Contact Info

Product

Resources

About