Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is a rare, apparently monogenic, autosomal recessive disorder characterized by recurrent episodes of fever accompanied with lymphadenopathy, abdominal distress, joint involvement and skin lesions. All patients have high serum IgD values (>100 U/ml) and HIDS 'attacks' are associated with an intense acute phase reaction whose exact pathophysiology remains obscure. Two other hereditary febrile disorders have been described. Familial Mediterranean fever (MIM 249100) is an autosomal recessive disorder affecting mostly populations from the Mediterranean basin and is caused by mutations in the gene MEFV (refs 5,6). Familial Hibernian fever (MIM 142680), also known as autosomal dominant familial recurrent fever, is caused by missense mutations in the gene encoding type I tumour necrosis factor receptor. Here we perform a genome-wide search to map the HIDS gene. Haplotype analysis placed the gene at 12q24 between D12S330 and D12S79. We identified the gene MVK, encoding mevalonate kinase (MK, ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36), as a candidate gene. We characterized 3 missense mutations, a 92-bp loss stemming from a deletion or from exon skipping, and the absence of expression of one allele. Functional analysis demonstrated diminished MK activity in fibroblasts from HIDS patients. Our data establish MVK as the gene responsible for HIDS.

Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.

Characterization of mevalonate kinase V377I, a mutant implicated in defective isoprenoid biosynthesis and HIDS/periodic fever syndrome.

The list of diseases linked to defects in lipid metabolism has recently been augmented by the addition of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS: MIM 260920), which are correlated with depressed levels of mevalonate kinase activity [1,2] and protein [1]. More specifically, a V377I substitution has been proposed to account for this disease. We observed that V377 appears to be far from invariant in eukaryotic mevalonate kinases. Prokaryotic mevalonate kinases are lower in molecular weight and several terminate prior to residue 377 of the eukaryotic proteins. These observations prompted our direct test of the impact of V377 on activity and protein stability by engineering a V377I mutation in a recombinant human mevalonate kinase. The mutant protein has been isolated and kinetically characterized. In comparison with wild-type enzyme, V377I exhibits only modest differences (notably > or = 6-fold inflation of K(m(MVA))) that do not account for the diminished mevalonate kinase activity assayed in HIDS cell extracts. Moreover, thermal inactivation (50 degrees C) of isolated wild-type and V377I enzymes demonstrates little difference in stability between these proteins. We conclude that a single V377I substitution is unlikely to explain the observation of depressed mevalonate kinase stability and catalytic activity in HIDS.

Type two hyper-IgM syndrome caused by mutation in activation-induced cytidine deaminase.

Thirteen Japanese patients with hyper-IgM syndrome but normal CD40 ligand were characterized. All patients had mutations in AID (activation-induced cytidine deaminase) gene. Five of them had a missense mutation of Arg112His. In all patients, serum IgG, IgA and IgE levels were undetectable, B cells failed to produce detectable amounts of IgE even if cultured them with anti-CD40 and IL-4. Somatic hypermutation (SHM) was also impaired in their peripheral blood B cells. These results suggest that Arg112 is the hot spot of AID mutation and demonstrate that AID plays indispensable roles in class switch recombination (CSR) and somatic hypermutation (SHM) in human B cells. In addition, serum IgM levels in the patients have been continuously high even after proper intravenous immunogloburin infusion (IVIG) and without infection, indicate that AID has the function to induce spontaneous IgM production in B cells.

[Identification of the gene for hyper-IgD syndrome: a model of modern genetics]. / Identificatie van het gen voor het hyper-IgD-syndroom: een schoolvoorbeeld van moderne genetica.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a rare autosomal recessive disorder. Patients suffer from recurrent attacks (3-6 days) with fever, abdominal distress, lymphadenopathy, skin lesions and arthralgias. Patients display a constantly elevated serum IgD which serves as a biological marker of the disease. Recently, the gene for HIDS was discovered by two independent groups using positional and functional cloning methods. One group used linkage analysis (positional cloning) and was able to locate the gene for HIDS on the long arm of chromosome 12 (12q24). Mevalonate kinase was an interesting candidate gene because patients with a near complete absence of this enzyme (mevalonic aciduria) do exhibit attacks of fever. Indeed subsequent data showed that there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene. The other group detected slightly elevated urinary excretion of mevalonic acid during attacks in a HIDS patient (functional cloning). The enzyme activity of mevalonate kinase was lower in cultured cells and sequence analysis identified several missense mutations in cDNA encoding for mevalonate kinase. Mevalonate kinase is a key enzyme in the cholesterol synthesis pathway and it is rather surprising that a defect in the cholesterol metabolism can cause a periodic inflammatory disease such as HIDS.

Pseudodominant inheritance of the hyperimmunoglobulinemia D with periodic fever syndrome in a mother and her two monozygotic twins.

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is a recessively inherited recurrent fever syndrome. We describe a family of 2 monozygotic twins and their mother with characteristic symptoms of HIDS, but normal levels of IgD and IgA, and with a dominant inheritance pattern. Mevalonate kinase (MK) activity was deficient in both children, and analysis of the MVK gene revealed compound heterozygosity for 2 new mutations, G25G and R277H. Being positioned adjacent to a donor splice site, the G25G mutation was shown by reverse transcription-polymerase chain reaction analyses to cause aberrant splicing of the MVK messenger RNA, thus being disease-relevant. The mother, who was also symptomatic during her childhood and adolescence, was a compound heterozygote for I268T and R277H. Our findings expand the genetic and ethnic spectrum of HIDS and show that the possible presence of this disease cannot be excluded based solely on inheritance patterns. In each case in which HIDS is clinically suspected, analysis of MK activity and/or the MVK gene (especially exons 9 and 11) should be performed.

[A spectrophotometric method of determining the myeloperoxidase activity in phagocytic cells]. / Spektrofotometricheskii sposob opredeleniia aktivnosti mieloperoksidazy v fagotsitiruiushchikh kletkakh.

A spectrophotometric method has been developed for measurements of myeloperoxidase activity in phagocytes, and conditions of measurements specified. Contribution of mononuclear cells to myeloperoxidase activity was found negligible, the major role here was played by neutrophils and eosinophils. Myeloperoxidase activity was found reduced in the patients with chronic granulomatous disease, agammaglobulinemia, and elevated in hyper-IgE-syndrome; this parameter was unchanged in ataxia telangiectasia and chronic dermatomucosal candidiasis.

[Cytological study of acid phosphatase activity of plasma cells in monoclonal gammopathies]. / Zytologische Untersuchung der sauren Phosphataseaktivität in den Plasmazellen bei monoklonalen Gammopathien.

The activity of acid phosphatase in bone marrow plasma cells was investigated by a cytochemical method in 12 patients with multiple myeloma, in 12 patients with benign monoclonal gammopathy and in 5 normal controls. The activity of acid phosphatase was significantly higher in the multiple myeloma patients compared with the activity observed in controls and in benign monoclonal gammopathy patients (p less than 0.001). It is therefore suggested that this method may be a valuable adjunct in the differential diagnosis of monoclonal immunoglobulinemias .

A novel activation-induced cytidine deaminase gene mutation in a Tunisian family with hyper IgM syndrome.

UNLABELLED: Mutations in activation-induced cytidine deaminase can cause an autosomal recessive form of hyper-IgM syndrome. We have examined a Tunisian family composed of six members: two healthy parents, their two healthy daughters and two affected sons. We found a homozygous transversion G to T in the two sons while heterozygosity for the mutation was found in all other family members. This alteration is localised in intron 2 at the +1 position resulting in defective splicing. Use of various intronic cryptic splice-sites led to expression of various aberrant mRNA species. CONCLUSION: This is a novel mutation found in the gene encoding for activation-induced cytidine deaminase in a Tunisian family with hyper-IgM type 2 syndrome. This alteration leads to the use of two cryptic splicing sites causing the formation of two different mRNA species.

Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome.

Recent studies have shown that mutations in a newly described RNA editing enzyme, activation-induced cytidine deaminase (AID), can cause an autosomal recessive form of hyper IgM syndrome. To determine the relative frequency of mutations in AID, we evaluated a group of 27 patients with hyper IgM syndrome who did not have defects in CD40 ligand and 23 patients with common variable immunodeficiency. Three different mutations in AID were identified in 18 patients with hyper IgM syndrome, including 14 French Canadians, 2 Lumbee Indians, and a brother and sister from Okinawa. No mutations were found in the remaining 32 patients. In the group of patients with hyper IgM syndrome, the patients with mutations in AID were older at the age of diagnosis, were more likely to have positive isohemagglutinins, and were less likely to have anemia, neutropenia, or thrombocytopenia. Lymphoid hyperplasia was seen in patients with hyper IgM syndrome and normal AID as well as the patients with hyper IgM syndrome and defects in AID.

[Plasma cell acid phosphatase in the differential diagnosis of monoclonal gammopathies]. / La fosfatasi acida plasmacellulare nella diagnostica differenziale delle gammopatie monoclonali.

Acid phosphatase activity was studied cytochemically in bone marrow plasma cells of 32 multiple myelomas, 45 non-myelomatous monoclonal gammopathies and 20 normal subjects. We have found significant differences among these three groups (P less than 0.001). The usefulness of this cytochemical reaction for the study of monoclonal gammopathies is discussed.

Enzymecytochemistry and immunohistochemistry in monoclonal gammopathy and reactive plasmacytosis.

Peripheral blood smears and bone-marrow smears from 29 patients with malignant M-components (25 with multiple myeloma and 4 with malignant lymphoma), 13 patients with benign monoclonal gammopathy (BMG), and 20 patients with polyclonal reactive plasmacytosis were examined by leucocyte alkaline phosphatase score (LAP-score) and by acid phosphatase score in plasma cells from bone-marrow smears. Furthermore, tissue sections from marrow biopsies from all patients were examined by the three-layer unlabelled immunoperoxidase technique to detect cytoplasmic immunoglobulin. The LAP-score was significantly higher in patients with malignant M-components than in patients with BMG and also higher in IgA and IgG myeloma than in IgA and IgG BMG, but the latter difference was not significant. Furthermore, a significant positive correlation between paraprotein concentration and LAP-score was found in multiple myeloma. Acid phosphatase score in plasma cells showed no clear distinction between multiple myeloma and BMG. Immunohistochemical examination showed a distinct monoclonal pattern in both multiple myeloma and BMG, allowing identification of the M-component which in all cases corresponded to the M-component detected by serum examination. Cells producing immunoglobulin classes not matching the M-component were more rare in multiple myeloma than in BMG, but the difference between the two conditions was quantitative and allowed no clear distinction.

Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool.

BACKGROUND: The hyper-IgD and periodic fever syndrome (HIDS) is characterized by recurrent attacks of fever, abdominal distress, and arthralgia and is caused by mevalonate kinase mutations. OBJECTIVE: To ascertain the role of mevalonate kinase and the usefulness of molecular diagnosis in HIDS. DESIGN: Cross-sectional study. SETTING: The international Nijmegen HIDS registry. PATIENTS: 54 patients from 41 families who met the clinical criteria for HIDS. MEASUREMENTS: Clinical symptoms and signs, immunoglobulin concentration, leukocyte count, erythrocyte sedimentation rate, mutation analysis, and mevalonate kinase enzyme activity assay. RESULTS: There were two groups of patients: 41 patients with mevalonate kinase mutations (classic-type HIDS) and 13 patients without mutations (variant-type HIDS). Patients with classic-type HIDS had a lower mevalonate kinase enzyme activity, a higher IgD level, and more additional symptoms with attacks. The IgD level did not correlate with disease severity, mevalonate kinase enzyme activity, or genotype. CONCLUSION: Genetic heterogeneity exists among patients with a clinical diagnosis of HIDS.

Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum.

OBJECTIVE: Mevalonic aciduria as a result of mevalonate kinase deficiency is an inborn error of cholesterol biosynthesis characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Pathogenic mutations in the mevalonate kinase gene in both disorders have demonstrated a common genetic basis. Our aim was to describe the clinical picture of adolescent patients with mevalonate kinase deficiency and to expand the clinical and biochemical spectrum of mevalonate kinase deficiency, particularly with regard to HIDS. METHODS: We report the clinical history and biochemical findings of 3 patients with mevalonic aciduria. RESULTS: In 2 siblings with mevalonic aciduria, a 15-year-old girl and a 14-year-old boy, the phenotype shifted with age. Ataxia has become the predominant clinical manifestation, whereas the febrile attacks occur less frequently but as yet have not disappeared. Both of them show marked elevations of immunoglobulin D (IgD). Psychomotor development is retarded but not regressive. Short stature developed in both patients. Additional findings include the development of retinal dystrophy and cataracts in both of them. The third patient is a 6-year-old boy who presented at the age of 5 years with cerebellar ataxia and retinal dystrophy. He is different from all known patients with mevalonic aciduria because of the mild neurologic involvement and because he has never developed febrile crises. In addition, levels of IgD were repeatedly normal. CONCLUSION: The clinical and biochemical spectrum of patients with mevalonic aciduria is heterogeneous. Manifestations of the disease seem to be age dependent, as evident from this first report of adolescent patients. In patients who survive infancy, short stature, ataxia caused by cerebellar atrophy, and ocular involvement with retinal dystrophy become predominant findings. Recurrent febrile crises seem to diminish with increasing age and may not even be an obligatory finding. Elevation of IgD is most likely a secondary phenomenon that seems to be linked to recurrent febrile crises.

Serum thymidine kinase in monoclonal gammopathies. A prospective study. The Cooperative Group for Study and Treatment of Multiple Myeloma.

Between January 1986 and March 1990, the serum levels of thymidine kinase (TK) were evaluated at diagnosis in 97 patients with monoclonal gammopathy of undetermined significance (MGUS) and 149 patients with multiple myeloma (MM) enrolled in a prospective protocol for treatment of MM. At presentation, patients with MGUS had lower TK levels than those with Stage I MM (P less than 0.05) and the overall population of those with MM (P less than 0.0005). TK levels were increased in advanced stages in comparison with earlier ones (P less than 0.01). The TK level was related to survival. With a median follow-up of 29 months, patients with TK levels greater than 7.0 U/microliters had shorter survival times than those with lower levels (medians, 23 and 42 months; P less than 0.0001). In a multivariate analysis, TK explained most of the variability of survival (P less than 0.0001), the remaining being accounted for by serum creatinine and beta-2 microglobulin. No changes in TK levels occurred during follow-up of patients with stable MGUS, whereas TK levels increased in two patients at time of progression to overt MM. In patients with MM, TK levels decreased (P less than 0.01) in those who responded to treatment but increased in those having relapses (P less than 0.03) and those with progressive disease (P less than 0.03). These results indicate that TK has clinical and prognostic relevance in monoclonal gammopathies, and additional investigations are warranted to determine whether it is a useful tool for the clinical evaluation, staging, and follow-up of patients with MM.

Inherited disorders of cholesterol biosynthesis.

Defects of cholesterol biosynthesis comprise a heterogeneous group of disorders, most of which have only been recently described and more are likely to follow in the near future. Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to allelic defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol and nonsterol isoprene biosynthesis. Clinically, patients affected with these disorders present with recurrent febrile attacks. This is the only manifestation in most patients with HIDS, and, in the case of classical mevalonic aciduria, is part of a severe multisystemic disease, including malformations, severe failure to thrive and neurological abnormalities. The other recognized defects of cholesterol biosynthesis are due to enzyme defects located distally in the pathway beyond the branching points of nonsterol isoprene biosynthesis and solely affecting cholesterol biosynthesis. Patients with these disorders all present with complex malformation syndromes involving different organ systems. The main characteristics of CHILD syndrome and Conradi-Huenermann syndrome are skeletal defects and ichthyosiform skin involvement. Smith-Lemli-Opitz syndrome and desmosterolosis are generalized malformation syndromes involving many different organs including the central nervous system.The diagnosis of MVA and HIDS is based on determination of mevalonic acid in urine followed by determination of enzyme activity, whereas the search for the distally located defects of cholesterol biosynthesis requires sterol analysis in blood or tissues by GCMS. Rational therapeutic approaches have been described for HIDS, MVA and Smith-Lemli-Opitz syndrome.

Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D.

OBJECTIVES: The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was found recently to be caused by a deficiency of mevalonate kinase (MK). The aim of this study was to examine whether a relationship exists between the clinical expression of HIDS and the extent of MK deficiency. METHODS: The medical records of children diagnosed with HIDS were reviewed for clinical features and serum immunoglobulin values. The mevalonic acid excretion in urine and MK enzyme activity in patients' cells were measured and the cDNA of the MVK gene was sequenced. RESULTS: Fifteen patients with recurrent fever and raised serum immunoglobulin (Ig) D were included. Their clinical features varied. Eleven patients had a deficiency of MK, caused by mutations in the MVK gene. One mutation (V377I) was common to all 11 patients. Nine patients were compound heterozygotes for V377I and various other MVK mutations. There was no apparent relationship between the observed mutations and the clinical features. Surprisingly, four boys had normal MK activity and no MVK mutations. CONCLUSIONS: Most HIDS patients have mutations in the MVK gene. The clinical variability observed cannot be explained by genotypic differences. Periodic fever and elevated IgD can result from other, still unknown, causes. Hence, testing for MK deficiency is necessary in patients with unexplained periodic fever.