Published online January 29, 2007
PEDIATRICS Vol. 119 No. 2 February 2007, pp. e523-e527 (doi:10.1542/peds.2006-2015)

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EXPERIENCE & REASON

Diagnostics and Therapeutic Insights in a Severe Case of Mevalonate Kinase Deficiency

Marco Nevyjel, CSc^a, Alessandra Pontillo, PhD^a,b, Lorenzo Calligaris, MD^b, Alberto Tommasini, MD^a,b, Andrea D'Osualdo, MD^c, Hans R. Waterham, PhD^d, Marilena Granzotto, PhD^a, Sergio Crovella, BSc^a,b, Egidio Barbi, MD^a and Alessandro Ventura, MD^a,b

^a Institute of Child Health IRCCS Burlo Garofolo, Trieste, Italy
^b Department of Reproduction and Development Science, University of Trieste, Trieste, Italy
^c Department of Molecular Genetics, IRCCS G. Gaslini, Genoa, Italy
^d Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, Amsterdam, Netherlands

ABSTRACT

Mevalonate kinase deficiency is a rare inborn disorder of isoprenoid and sterol biosynthesis characterized by a recurrent autoinflammatory syndrome and, in most severe cases, psychomotor delay. Clinical manifestations can be very complex and, in some cases, mimic a chronic inflammatory disease. Diagnosis is also complex and often requires immunologic, genetic, and biochemical investigations. There is no standardized therapy, but biological agents could help to control inflammatory complaints in some cases. A severe case of mevalonate kinase deficiency that was associated with nephritis and successfully treated with anakinra (interleukin 1 receptor antagonist) is reported here, and new insights into diagnosis and therapy of this complex disorder are discussed.

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Key Words: Anakinra • MVK • nephritis • mevalonic aciduria

Abbreviations: MK, mevalonate kinase • MKD, mevalonate kinase deficiency • MVK, mevalonate kinase gene • Ig, immunoglobulin • HIDS, hyper–immunoglobulin D syndrome • MA, mevalonic aciduria • IL-1, interleukin-1 • IL-1ra, interleukin 1 receptor antagonist • CRP, C-reactice protein

Mevalonate kinase (MK) deficiency (MKD) is a rare autonomic recessive inborn error of cholesterol biosynthesis caused by mutations in the MK gene (MVK) leading to a defect in the production of isoprenoids and sterols.^1–3

A wide and continuous spectrum of clinical presentation is described depending on the residual MK activity and ranging from a recurrent inflammatory syndrome (hyper-immunoglobulin D [IgD] syndrome [HIDS], Online Mendelian Inheritance in Man [OMIM] No. 260920) to a severe metabolic defect with psychomotor retardation, cerebellar ataxia, and recurrent fever attacks (mevalonic aciduria [MA], OMIM No. 251170).^4–6

HIDS is characterized by fever episodes that recur every 2 to 8 weeks and is variably accompanied by malaise, headache, diarrhea, abdominal pain, vomiting, skin rash, arthralgia, arthritis, tender lymphadenopathy, hepatosplenomegaly, and oral and genital ulcers. Urinary mevalonic acid is increased mainly during inflammatory episodes. Laboratory evaluations show granulocytosis and elevated acute-phase reactants, often associated with persistently elevated serum IgD and IgA.^7,8

MA is characterized by the above-mentioned inflammatory symptoms associated with dysmorphic features, cataracts, neurologic impairment (hypotonia, developmental delay, ataxia associated with cerebellar atrophy) and failure to thrive. The urinary excretion of mevalonic acid is high also between attacks, and MK activity in fibroblasts is completely or almost absent. Several mutations in MVK are described both for HIDS and for MA, but a genotype/phenotype correlation has not been established,^9,10 and biochemical and clinical data may be needed to define the diagnostic profile, particularly in patients carrying new mutations.

The wide clinical spectrum of the disease accounts for possible difficulties in differential diagnosis with chronic inflammatory disorders.¹¹ For this reason, it would be important to develop protocols for MKD suspects and diagnosis to avoid useless investigations and treatments. Once a diagnosis has been made, the therapeutic issues are not simple.

Different treatments, including steroids, statins, anti–tumor necrosis factor , and anti–interleukin 1 (IL-1) therapy, have been used (with variable success) to prevent and to cure inflammatory symptoms in HIDS,^12–18 whereas only supportive therapies are available for MA, the prognosis of which is still very poor.

Here we describe a case of severe MKD with a rare atypical symptom (nephritis) resulting from a new homozygous mutation in MVK. We discuss the complex diagnostic evaluations and the successful treatment with IL-1 receptor antagonist (IL-1ra [anakinra]).

CASE REPORTS

An 18-month-old boy was referred to us because of a history of recurrent episodes of fever, irritability, lymphadenopathy, abdominal pain, diarrhea, and skin rash without response to prescribed antibiotic therapy. The attacks recurred monthly since the age of 2 months and were associated with marked elevation of erythrocyte sedimentation rate, C-reactive protein (CRP), and leukocytes. Laboratory data performed in a period of well-being (Table 1) showed increased values of markers of inflammation, severe anemia, and high serum IgA values. Serum autoantibodies were undetectable. Physical examination was unremarkable except for a miserable-looking child with an evident pallor; psychomotor development was normal for his age. Imaging examinations did not reveal a specific localization of the inflammatory process; no abnormality was seen in a skeletal radiograph, abdominal ultrasound scan, or colonoscopy. Results of a bone marrow puncture were normal.

View this table: [in this window] [in a new window]   TABLE 1 Laboratory Data Performed in a Period of Well-being

 
A genetic analysis revealed a new homozygous mutation (c.1006GA leading to G336S) in exon 10 of MVK, which confirmed the diagnosis of MKD. This mutation has not been described before, so it was impossible to predict the severity of the disorder and the prognosis for this child. His urinary mevalonic acid level was very high during febrile attacks (on the order of 3 mmol/mol creatinine) but also between crises, which suggested a severe enzymatic deficiency. This was confirmed by means of MK activity measurements in the patient's fibroblasts (<1% as compared with controls). A magnetic resonance scan of the brain did not show features typical of MA.

Steroid treatment (prednisone 2 mg/kg per day) for 3 consecutive days at every attack (2–3 per month) was associated with a good response of the clinical symptoms, but the anemia and increased acute-phase reactants persisted.

After some months, however, the child developed a persistent vasculitic rash, gross hematuria, proteinuria (urinary protein/creatinine: 1.17 mg/dL; Cameron index: <0.1), and hypertension (119/55 mmHg). A kidney biopsy showed a picture suggesting membranoproliferative glomerulonephritis (Fig 1). Focal areas of increased mesangial cells and matrix were observed in which the glomerular capillary walls appeared thickened (because of interposition of mesangial matrix), minimal interstitial lymphocytic infiltrates were present, and no glomerular IgA was detected by immunohistochemistry. A continuous treatment with corticosteroids (prednisone 1 mg/kg per day) and enalapril (0.1 mg/kg per day) did not improve the nephritis. Considering the severe clinical involvement, the inefficacy of steroid therapy, and the recent reports about the efficacy of IL-1ra (anakinra) in other severe autoinflammatory syndromes (chronic infantile neurologic cutaneous and articular syndrome and Muckle-Wells syndrome^19–23), we began a therapeutic trial with anakinra (30 mg/day). After a few days of treatment, a dramatic improvement in clinical symptoms was reported, with normalization of the CRP, a rise in the hemoglobin value (8.8 g/dL), and disappearance of proteinuria. Hematuria disappeared after 2 months of treatment.

View larger version (124K): [in this window] [in a new window]   FIGURE 1 Focal areas of increased mesangial cells and matrix, with thickened glomerular capillary and lymphocytic infiltrates (x66 hematoxylin-eosin coloration).

 
In the following 12 months, the child presented with few mild febrile episodes, and steroids were administered in only 2 cases to reduce significant general malaise. One of the 2 episodes was associated with vomiting, diarrhea, and severe abdominal pain, with a marked elevation in the inflammatory markers, and the other episode was associated with sore throat. A possible concomitant viral illness was suspected, and both cases were managed with a single administration of steroids and prudential suspension of anakinra for few days (Fig 2).

View larger version (20K): [in this window] [in a new window]   FIGURE 2 Febrile attacks, hemoglobin, and CRP during follow-up in respect to the antiinflammatory therapy.

 

MATERIALS AND METHODS

Mutation screening was performed on DNA extracted from peripheral blood cells. All coding regions and intronic flanking sequences of MVK were amplified by polymerase chain reaction and analyzed by means of denaturing high-performance liquid chromatography (DHPLC) as described previously.¹⁰ Polymerase chain reaction products characterized by the heteroduplex DHPLC profile were sequenced by using the BigDye kit 3.0 (Applied Biosystems, Foster City, CA). To validate new mutations, 50 healthy controls were analyzed.

Urinary mevalonic acid was dosed by means of gas chromatography/mass spectrometry. Spectra were obtained with a Hewlett Packard (Palo Alto, CA) gas chromatograph 6890 series equipped with a Hewlett Packard 5973 quadrupole operating in electron-impact mode at 70 eV as described previously.²⁴

MK activity was determined in the patient's fibroblasts by using ¹⁴C-labeled mevalonate as the substrate²⁵ and expressed as the percentage of average MK activity determined simultaneously in fibroblasts from healthy control subjects.

IgD levels were measured by means of an enzyme-linked immunosorbent assay sandwich kit (Bethyl Laboratories, Inc, Montgomery, TX) as described elsewhere.¹¹ The diagnostic criteria for HIDS require IgD values of >100 IU/mL⁷ or>141 mg/L.²⁶

DISCUSSION

MKD is known to be responsible for the 2 distinct phenotypes MA and HIDS but has, in fact, a wider spectrum of clinical manifestations,^4,5,7 and many MKD cases could remain undiagnosed, as previously stated by Bodar et al¹⁴ and Hoffmann.²⁷ Although it is a rare disorder, knowledge of it is very important for avoiding useless invasive investigations and providing effective new therapies, such as those based on biological inhibition of inflammatory cytokines (IL-1ra).¹⁴ A practical diagnostic strategy (proposed by Drenth²⁸) includes clinical evaluation, IgA and IgD determination, and genetic confirmation by means of screening for the V377I mutation in MVK. In case of high clinical suspicion, analysis of the entire MVK is indicated, and measurement of the mevalonic acid level in the urine is not considered very useful.

As far as diagnostic issues are concerned, our case emphasizes the importance of a comprehensive genetic analysis in children with severe illness that is compatible with MKD regardless of other laboratory data (the IgD level was within the reference range in our case). In fact, it was observed that although high IgA and IgD values can help in the diagnosis, they are neither sensitive nor specific for this condition.^7,29 Screening for only the V377I variation is probably not a good strategy outside the Netherlands, considering that a wider distribution of mutations has been described in Italy.¹⁰ While waiting for wider clinical experiences, we suggest that in such severe cases the patient suspected of having MKD deserves a more comprehensive genetic-testing protocol. Furthermore, in those with new mutations, a dosage of urinary mevalonic acid may help the clinician to select cases for MK activity dosage. In our case, the novel G335S mutation was associated with a measurable, although very low (<1%), level of MK activity, which indicates a very severe phenotype but not a definite MA diagnosis. Only clinical and radiologic follow-up (cerebellar involvement) will allow us to evaluate the role of this defect in psychomotor development.

What remains to be defined, apart from the experience of single physicians, is the concept of "strong clinical suspicion" for MKD. We believe that this should not include only the typical picture originally described for HIDS or MA but also that each patient with an infant onset of a severe inflammatory disorder with recurrent fever and no clear alternative diagnosis could be considered for MVK mutation screening. Values of acute-phase reactants that are in the reference range between crises are not a sine qua non condition for MKD. In our case, an index of inflammation and anemia were present also between febrile attacks, which suggests the diagnosis of a chronic inflammatory disease, but no specific diagnosis was made in this sense.

The case we have described also presents new insights into therapeutics of MKD. We confirmed the dramatic efficacy of anakinra in a patient with a severe case of MKD. It is very important to note that the treatment was associated not only with the disappearance of inflammatory attacks but also the improvement of nephritis, a rare manifestation of MKD.

CONCLUSIONS

MKD has to be considered in children with an early onset of inflammatory complaints that are associated with recurrent fever, and a genetic analysis has to be performed irrespective of laboratory data to facilitate diagnosis. Although these data have to be confirmed in larger series, IL-1 blockade therapy with anakinra could dramatically improve the quality of life in patients with severe MKD.

FOOTNOTES

Accepted Sep 13, 2006.

Address correspondence to Alberto Tommasini, MD, Institute of Child Health IRCCS Burlo Garofolo, University of Trieste, Via dell'Istria 65/1, 34137 Trieste, Italy. E-mail: tommasini{at}burlo.trieste.it

The authors have indicated they have no financial relationships relevant to this article to disclose.

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