Email updates

Keep up to date with the latest news and content from Orphanet Journal of Rare Diseases and BioMed Central.

Open Access Review

Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Dorothea Haas and Georg F Hoffmann*

Author Affiliations

Department of General Pediatrics, University Children's Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany

For all author emails, please log on.

Orphanet Journal of Rare Diseases 2006, 1:13  doi:10.1186/1750-1172-1-13


The electronic version of this article is the complete one and can be found online at: http://www.OJRD.com/content/1/1/13


Received:4 April 2006
Accepted:26 April 2006
Published:26 April 2006

© 2006 Haas and Hoffmann; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.

Disease name and synonyms

Mevalonic aciduria (MVA, OMIM 251170).

Hyperimmunoglobulinemia D and periodic fever syndrome; Periodic fever, Dutch type (HIDS, OMIM 260920).

Definition and diagnostic criteria

MVA is an autosomal recessively inherited disorder caused by deficiency of mevalonate kinase (MVK; E.C. 2.7.1.36; ATP:(R)-mevalonate 5-phosphotransferase) and identified as the first defect in cholesterol biosynthesis (Figure 1) by Hoffmann et al. in 1986 [1]. Mutations in the MVK gene and reduced activity of MVK have been identified as underlying cause of both MVA and HIDS syndrome.

thumbnailFigure 1. Pathway of cholesterol biosynthesis, showing the defect in mevalonate kinase (MVK) deficiency.

MVA is caused by homozygosity or compound heterozygosity for disease-causing mutations in the MVK gene, which has been localized to chromosome 12q24 [2]. MVA is biochemically characterized by accumulation of mevalonic acid and mevalonolactone.

The diagnosis of MVA should be suspected in patients with mild dysmorphic features, progressive cerebellar ataxia, psychomotor retardation, failure to thrive, hepatosplenomegaly and recurrent febrile episodes. Uveitis, retinitis pigmentosa and cataracts, as well as myopathy may develop in childhood and adolescence.

HIDS is clinically characterized by recurrent fever episodes starting in infancy and associated with lymphadenopathy, arthralgia, gastrointestinal problems and skin rashes.

A subgroup of HIDS patients may also develop neurological abnormalities of varying degree, such as mental retardation, ataxia, ocular symptoms and epilepsy, a finding that confirms the existence of a continuous spectrum between MVA and HIDS [3].

The diagnosis is established by the detection of elevated excretion of mevalonic acid in urine (MVA) or increased immunoglobulins (Ig) D and A in combination with elevated excretion of mevalonic acid (HIDS). The diagnosis is confirmed by demonstration of deficient MVK enzyme activity or by identification of two disease-causing mutations in the MVK gene.

Differential diagnosis

The constellation of congenital malformations, hepatosplenomegaly, cholestatic liver disease, lymphadenopathy, anemia, severe failure to thrive and developmental retardation, which is found in severely affected MVA patients might suggest chromosomal aberrations or congenital infections. When hematological abnormalities such as anemia, leukocytosis, thrombocytopenia and abnormal blood cell forms predominate, myelodysplastic syndromes may be suspected. Moderately affected MVA patients may be classified among those with psychomotor retardation, myopathy and ataxia.

Recurrent crises from infancy of fever, diarrhea and mucocutaneous manifestations might suggest infectious or autoimmune disease [4]. The development of uveitis in some patients parallels that seen in juvenile rheumatoid arthritis [5]. If developmental delay and neurological symptoms are neither present nor prominent, the differential diagnosis is likely to focus within the group of auto-inflammatory disorders. This group consists of other inherited syndromes: familial Mediterranean fever (FMF); TNF receptor-associated periodic syndrome (TRAPS); familial cold autoinflammatory syndrome/Muckle-Wells syndrome/chronic infantile neurological cutaneous and articular syndrome (FCAS/MWS/CINCA) and periodic fever, aphthous ulcers, pharyngitis, adenitis (PFAPA).

Epidemiology

MVA is a rare disease. So far, approximately 30 patients have been reported. HIDS seems to be more common. In 2001, the number of reported HIDS patients was about 180 [6] and more patients have been identified since.

Etiology

For MVA, seven mutations have been identified in 10 out of 20 known patients [7]. Most of these mutations cluster in the C-terminal region of the protein.

Most patients with HIDS are compound heterozygotes for missense mutations in the MVK gene. One mutation, V337I, is present in more than 80% of patients [8]. This mutation primarily affects maturation (folding) of the protein resulting in temperature-sensitive expression of MVK in vivo [9]. In HIDS patients, MVK may have a residual activity of 5%–15%. In contrast, no residual activity is present in MVA patients [4].

Clinical description

Mevalonic aciduria

MVA shows considerable clinical heterogeneity. Severely affected patients present from birth with congenital malformations such as microcephaly, dolichocephaly and wide irregular fontanels, as well as low set and posteriorly rotated ears, downslanted palpebral fissures, blue sclerae, and central cataracts (Figure 2). Cholestatic liver disease [10] may be present, and patients may die from recurrent septicemia [11]. Stillbirths with skeletal malformations have been observed in affected families, possibly resulting from the same genetic defect. Cardinal manifestations from late infancy include mild to severe psychomotor retardation, recurrent crises (fever, vomiting and diarrhea), failure to thrive, hypotonia and myopathy. Sometimes hematological abnormalities predominate with normocytic hypoplastic anemia, leukocytosis, thrombocytopenia and abnormal blood cell forms [10], leading to misdiagnoses of congenital infection or myelodysplastic syndromes.

thumbnailFigure 2. A patient with mevalonic aciduria at the age of 21 months displaying the characteristic facial dysmorphism.

After preschool age, short stature, ataxia due to a progressive cerebellar atrophy and ocular involvement with uveitis, cataracts and tapetoretinal degeneration become predominant findings, and can be the major manifestations in milder cases [3-5,12].

Most patients suffer from frequent crises characterized by fever, vomiting and diarrhea. These episodes appear to be noninfectious in origin, and are often accompanied by arthralgia, subcutaneous edema and a morbilliform rash. Two patients developed uveitis, which worsened during crises. In childhood, episodes occur as often as 25 times per year, lasting in average 4 to 5 days. Laboratory investigations reveal elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, leukocytosis) and elevated immunoglobulins, including IgA, IgE and especially IgD. Anemia, elevations of creatine kinase (CK) and transaminases are present in the more severely affected patients, and worsen during crises. Over the years, the severity and the frequency of the attacks decline.

Hyperimmunoglobulinemia D syndrome

In HIDS, the clinical picture is dominated by recurrent febrile attacks that usually start before the end of the first year of life [13]. The fever lasts 4 to 6 days and can be provoked by vaccination, minor trauma, surgery or stress. It is usually associated with abdominal pain, vomiting, diarrhea and cervical lymphadenopathy. Other common symptoms include hepatosplenomegaly, headache, arthralgia and rashes. Occasionally, patients present with oral and vaginal aphthous ulcers. After the attack, the patients are free of symptoms, although skin and joint symptoms disappear slowly [6]. Most patients display neither malformations nor neurological abnormalities. However, a subgroup of adult patients also develop neurological abnormalities of varying degree, such as mental retardation, ataxia, ocular symptoms and epilepsy, reflecting the existence of a continuous spectrum between MVA and HIDS [3].

Diagnostic methods

Generally, the metabolic abnormalities seen in MVA are not those suggestive of an inherited organic aciduria. There is no episodic metabolic decompensation, hypoglycemia, metabolic acidosis, ketosis or hyperammonemia. The key for diagnosis is the elevated level of mevalonic acid in the urine, plasma and cerebrospinal fluid, which can be detected through organic acid analysis [14]. However, in patients with a mild form of MVA and especially in HIDS patients, elevations measured by routine gas chromatography/mass spectrometry may only be found during febrile attacks. The sensitivity of general organic acid analysis is inadequate for recognizing the very low concentrations of mevalonic acid present in control urine. Even moderate, but definitely pathological, elevations can remain below the detection limit [14], and must be verified by isotope dilution mass spectrometry [15]. As the absolute level of mevalonic acid is always elevated in patients with MVK deficiency, samples from patients with a suspected MVA deficiency should undergo a sensitive measurement of mevalonic acid by stable isotope dilution analysis to detect even slight abnormalities. The diagnosis of MVA should be confirmed by mutational analysis or by a radiometric assay of MVK in white blood cells or cultured fibroblasts [16,17]. Urinary excretion of leukotriene E4 is elevated in most patients, with a positive linear correlation with increased mevalonic acid excretion [18].

HIDS is diagnosed on the basis of characteristic clinical findings and continuously high IgD values (more than 100 IU/ml). However, IgD may be normal in patients under three years of age [19]. Consistently normal IgD levels were found in two patients with typical clinical findings and genotype for the syndrome [3,20]. More than 80% of patients have, in addition, high IgA levels [19,21]. During febrile episodes, urinary mevalonate concentrations were found to be significantly elevated in patients with at least one mutation in the MVK gene, but slight elevations were also detected between the fever attacks [22]. Therefore, specific sensitive determination of mevalonic acid, mutational analysis and determination of enzyme activity should be performed in all cases with suggestive clinical symptoms and normal IgD levels.

Genetic counseling and prenatal diagnosis

Genetic counseling should be offered to families at risk of MVA. As MVA is an autosomal recessive disorder, the risk for future pregnancies is 25% for families who already have a child with MVA.

Prenatal diagnosis of an affected fetus is possible by stable isotope-dilution gas chromatography/mass spectrometry, by determination of MVK activity in cultured amniocytes and biopsied chorionic villus [1,12,14,17], and by mutational analysis in informative families. In affected pregnancies, elevated levels of mevalonic acid have been detected in maternal urine [1,12,14]. Significant elevations of mevalonic acid have been detected in autopsied tissues (including lymph nodes, adrenals, ovaries, spleen, liver and brain) from an affected fetus, [14].

Prenatal diagnosis is usually not considered to be appropriate for HIDS.

Management including treatment

There is no established therapeutic regime for patients with MVA. Dietary supplementation of cholesterol may reduce the frequency and severity of febrile attacks in some mildly affected patients, but may further compromise more severely affected patients [4]. An experimental trial with lovastatin in two patients with MVA resulted in clinical decompensation manifested by fever, acute myopathic changes, highly elevated creatine kinase activity, and worsened ataxia, diarrhea and vomiting. Intervention with corticosteroids (prednisone 2 mg/kg per day) was highly beneficial during clinical crises, with resolution of the crises within 24 hours. Additional long-term administration of ubiquinone-50, together with vitamin C and vitamin E, appeared to stabilize the clinical course and improve somatic and psychomotor development. The rationale is to correct the ubiquinone-50 deficiency and to increase the level of free radical scavengers [23].

Treatment of HIDS is difficult and largely supportive. Various standard anti-inflammatory drugs (including colchicine, non steroidal anti-inflammatory drugs (NSAIDs), steroids and thalidomide) have failed to suppress the attacks. Despite the severe side effects of 3'-hydroxy-3'-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors in patients with classic MVA, a recently completed study showed a reduced excretion of mevalonic acid in all patients, a decreased number of febrile days in most of the patients with HIDS, and no side effects during simvastatin treatment [24]. Similarly, a beneficial effect of anakinra (a recombinant interleukin-1 receptor antagonist) was described in one patient [25].

Prognosis

In early-onset multisystemic MVA, the prognosis is poor, with about half of patients succumbing in infancy or early childhood [4]. Mildly affected patients will develop short stature, progressive myopathy and, possibly, visual impairment due to uveitis, cataracts and tapetoretinal degeneration. The severity and frequency of the febrile attacks decline with age. In general, HIDS is considered to be a relatively benign condition. However, life expectancy may be reduced in some patients due to severe infections or the development of renal amyloidosis [26].

Unresolved questions

It is still not known how the deficiency of MVK is related to the inflammatory periodic fever syndrome. Elevations of IgD, IgA and urinary leukotriene E4 excretion are probably secondary to stimulation of the immune system [27].

Further information

http://www.hids.net webcite: A comprehensive website for clinicians, scientists, patients and their carers. The site is maintained by the HIDS research group at the Department of General Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Note

Figure 2 is reproduced with permission from Haas et al. 2001, © Georg Thieme Verlag KG

References

  1. Hoffmann G, Gibson KM, Brandt IK, Bader PI, Wappner RS, Sweetman L: Mevalonic aciduria – an inborn error of cholesterol and nonsterol isoprene biosynthesis.

    N Engl J Med 1986, 314:1610-1614. PubMed Abstract OpenURL

  2. Gibson KM, Hoffmann GF, Tanaka RD, Bishop RW, Chambliss KL: Mevalonate kinase map position 12q24.

    Chromosome research 1997, 5:150. PubMed Abstract | Publisher Full Text OpenURL

  3. Simon A, Kremer HP, Wevers RA, Scheffer H, De Jong JG, Van Der Meer JW, Drenth JP: Mevalonate kinase deficiency – Evidence for a phenotypic continuum.

    Neurology 2004, 62:994-997. PubMed Abstract | Publisher Full Text OpenURL

  4. Hoffmann GF, Charpentier C, Mayatepek E, Mancini J, Leichsenring M, Gibson KM, Divry P, Hrebicek M, Lehnert W, Sartor K, et al.: Clinical and biochemical phenotype in 11 patients with mevalonic aciduria.

    Pediatrics 1993, 91:915-921. PubMed Abstract OpenURL

  5. Prietsch V, Mayatepek E, Krastel H, Haas D, Zundel D, Waterham HR, Wanders RJ, Gibson KM, Hoffmann GF: Mevalonate kinase deficiency -enlarging the clinical and biochemical spectrum.

    Pediatrics 2003, 111:258-261. PubMed Abstract | Publisher Full Text OpenURL

  6. Drenth JP, van den Meer JW: Hereditary periodic fever.

    N Engl J Med 2001, 345:1748-1757. PubMed Abstract | Publisher Full Text OpenURL

  7. Houten SM, Koster J, Romeijn GJ, Frenkel J, Di Rocco M, Caruso U, Landrieu P, Kelley RI, Kuis W, Poll-The BT, Gibson KM, Wanders RJA, Waterham HR: Organisation of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome.

    Eur J Hum Genet 2001, 9:253-259. PubMed Abstract | Publisher Full Text OpenURL

  8. Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde Visser S, van der Meer JW, Grateau G, Delpech M: Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome.

    Eur J Hum Genet 2001, 9:260-266. PubMed Abstract | Publisher Full Text OpenURL

  9. Houten SM, Frenkel J, Rijkers GT, Wanders RJ, Kuis W, Waterham HR: Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome.

    Hum Mol Genet 2002, 11:3115-3124. PubMed Abstract | Publisher Full Text OpenURL

  10. Hinson DD, Rogers ZR, Hoffmann GF, Schächtele M, Fingerhut R, Kohlschütter A, Kelley RI, Gibson KM: Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency.

    Am J Med Genet 1998, 78:408-412. PubMed Abstract | Publisher Full Text OpenURL

  11. Raupp P, Varady E, Duran M, Wanders RJA, Waterham HR, Houten SM: Novel genotype of mevalonic aciduria with fatalities in premature siblings.

    Arch Dis Child Fetal Neonatal Ed 2004, 89:F90-F91. PubMed Abstract | Publisher Full Text OpenURL

  12. Mancini J, Philip N, Chabrol B, Divry P, Rolland MO, Pinsard N: Mevalonic aciduria in 3 siblings: a new recognizable metabolic encephalopathy.

    Pediatr Neurol 1993, 9:243-246. PubMed Abstract | Publisher Full Text OpenURL

  13. Frenkel J, Houten SM, Waterham HR, Wanders RJ, Rijkers GT, Duran M, Kuijpers TW, van Luijk W, Poll-The BT, Kuis W: Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D.

    Rheumatology (Oxford) 2001, 40:579-584. PubMed Abstract | Publisher Full Text OpenURL

  14. Hoffmann GF, Sweetman L, Bremer HJ, Hunneman DH, Hyanek J, Kozich V, Lehnert W, Nyhan WL, Speidel I, Trefz FK, et al.: Facts and artefacts in mevalonic aciduria: development of a stable isotope dilution GCMS assay for mevalonic acid and its application to physiological fluids, tissue samples, prenatal diagnosis and carrier detection.

    Clin Chim Acta 1991, 198:209-227. PubMed Abstract | Publisher Full Text OpenURL

  15. Kelley RI: Inborn errors of cholesterol biosynthesis.

    Adv Pediatr 2000, 47:1-53. PubMed Abstract OpenURL

  16. Gibson KM, Lohr JL, Broock RL, Hoffmann G, Nyhan WL, Sweetman L, Brandt IK, Wappner RS, Bader PI: Mevalonate kinase in lysates of cultured human fibroblasts and lymphoblasts: kinetic properties, assay conditions, carrier detection and measurement of residual activity in a patient with mevalonic aciduria.

    Enzyme 1989, 41:47-55. PubMed Abstract OpenURL

  17. Hoffmann GF, Brendel SU, Scharfschwerdt SR, Shin YS, Speidel IM, Gibson KM: Mevalonate kinase assay using DEAE-cellulose column chromatography and complementation analysis in mevalonic aciduria.

    J Inherit Metab Dis 1992, 15:738-746. PubMed Abstract | Publisher Full Text OpenURL

  18. Mayatepek E, Hoffmann GF, Bremer HJ: Enhanced urinary excretion of leukotriene E4 in patients with mevalonate kinase deficiency.

    J Pediatr 1993, 123:96-98. PubMed Abstract | Publisher Full Text OpenURL

  19. Haraldsson A, Weemaes CM, De Boer AW, Bakkeren JA, Stoelinga GB: Immunological studies in the hyper-immunoglubulin D syndrome.

    J Clin Immunol 1992, 12:424-428. PubMed Abstract | Publisher Full Text OpenURL

  20. Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, Frenkel J, Dorland L, de Barse MM, Huijbers WA, Rijkers GT, Waterham HR, Wanders RJ, Poll-The BT: Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome.

    Nature Genet 1999, 22:175-177. PubMed Abstract | Publisher Full Text OpenURL

  21. Klasen IS, Goertz JH, van de Weil GA, Weemaes CM, Van der Meer JW, Drenth JP: Hyper-immunoglubulin A in the hyperimmunoglobulinemia D syndrome.

    Clin Diagn Lab Immunol 2001, 8:58-61. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  22. Stojanov S, Lohse P, Lohse P, Hoffmann F, Renner ED, Zellerer S, Kery A, Shin YS, Haas D, Hoffmann GF, Belohradsky BH: 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 heterzygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa.

    Arthritis Rheum 2004, 50:1951-1958. PubMed Abstract | Publisher Full Text OpenURL

  23. Haas D, Kelley RI, Hoffmann GF: Inherited disorders of cholesterol biosynthesis.

    Neuropediatrics 2001, 32:113-122. PubMed Abstract | Publisher Full Text OpenURL

  24. Simon A, Drewe E, van der Meer JWM, Powell RJ, Kelley RI, Stalenhoef AF, Drenth JPH: Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome.

    Clin Pharmacol Ther 2004, 75:476-483. PubMed Abstract | Publisher Full Text OpenURL

  25. Bodar EJ, van der Hilst JCH, Drenth , van der Meer JWMJPH, Simon A: Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model.

    Neth J Med 2005, 63:260-264. PubMed Abstract | Publisher Full Text OpenURL

  26. D'Osualdo A, Picco P, Caroli F, Gattorno M, Giacchino R, Fortini P, Corona F, Tommasini A, Salvi G, Specchia F, Obici L, Meini A, Ricci A, Seri M, Ravazzolo R, Martini A, Ceccherini I: MVK mutations and associated clinical features in Italian patients affected with autoinflammatroy disorders and recurrent fever.

    Eur J Hum Genet 2004, 12:1-7. Publisher Full Text OpenURL

  27. Frenkel J, Willemsen MA, Weemaes CM, Dorland L, Mayatepek E: Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome.

    Arch Dis Child 2001, 85:158-159. PubMed Abstract | Publisher Full Text OpenURL