Mevalonic aciduria (MVA, OMIM 251170).

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

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.

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.

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).

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.

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.

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 1617. 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 320. More than 80% of patients have, in addition, high IgA levels 1921. 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 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 1121417, and by mutational analysis in informative families. In affected pregnancies, elevated levels of mevalonic acid have been detected in maternal urine 11214. 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.

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.

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.

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.

http://www.hids.net: 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.

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