ArticlePDF Available

Mevalonic Aciduria in a Child Featuring Hepatic Fibrosis and Novel Mevalonate Kinase Mutations


Abstract and Figures

Mevalonic aciduria (MVA) is an inborn error of isoprene biosynthesis caused by mevalonate kinase (MVK) gene mutations. Described below is a case of a Palestinian MVA patient suffering from prolonged fevers as well as from hepatic fibrosis -a rare feature of MVA. Also demonstrated is a unique genotype -heterozigosity of two novel MVK mu-tations; V8F (t25a), and F38I (t112a).
Content may be subject to copyright.
38 The Open Pediatric Medicine Journal, 2009, 3, 38-40
1874-3099/09 2009 Bentham Open
Open Access
Mevalonic Aciduria in a Child Featuring Hepatic Fibrosis and Novel
Mevalonate Kinase Mutations
M. Harel-Meir, Y. Bujanover *, Y. Berkun, N. Goldstein and Y. Anikster
Department of Pediatrics B, Safra Children's Hospital, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel
Abstract: Mevalonic aciduria (MVA) is an inborn error of isoprene biosynthesis caused by mevalonate kinase (MVK)
gene mutations. Described below is a case of a Palestinian MVA patient suffering from prolonged fevers as well as from
hepatic fibrosis - a rare feature of MVA. Also demonstrated is a unique genotype - heterozigosity of two novel MVK mu-
tations; V8F (t25a), and F38I (t112a).
Mevalonic aciduria (MVA) (OMIM 610377) is a rare
inborn error of isoprene biosynthesis, caused by mutations in
the mevalonate kinase (MVK) gene. MVA features recurrent
febrile episodes, developmental delay, ataxia, dysmorphism,
failure to thrive, cataracts, and retinal dystrophy [1]. MVK
mutations are also responsible for the hyperimmunoglobu-
linemia D and periodic fever syndrome (HIDS) (OMIM
260920) [1], an autosomal recessive disorder characterized
by recurrent febrile episodes, abdominal pain, arthritis, rash
and cervical lymphadenopaty [2].
Although HIDS and MVA are considered as separate
clinical entities, many patients illustrate a phenotypic spec-
trum, possibly related to the level of enzyme activity. Me-
valonate kinase activity is less severely impaired in HIDS
patients compared to its activity in MVA patients [1]. Ac-
cordingly, mevalonate is excreted in th e urine of HIDS pa-
tients in low-moderate levels and only during febrile epi-
sodes, while MVA patients continuously excrete high levels
of mevalonate [3]. Moreover, specific genotypes are associ-
ated with resulting different mevalonate kinase activity lev-
els, and thus with either HIDS or MVA [4].
Most of the reported HIDS and MVA patients are of
western European descent [2]. However, cases have been
reported of patients from countries including Portugal [5],
Italy [6] and Turkey [7]. The first Palestinian HIDS patient
was recently reported [8]. The diagnosis was made through
evidence of elevated IgD levels, as well as by DNA sequenc-
ing demonstrating homozigosity of the MVK V377I muta-
The following report describes a Palestinian child with
hepatic fibrosis diagnosed with MVA, featuring novel muta-
tions of the MVK gene.
*Address correspondence to this author at the Department of Pediatrics,
Safra Children's Hospital, B Sheba Medical Center, Tel Hashomer, Ramat
Gan 52621, Israel; Tel: 97235305006; E-mail:
A 1.5 year old Palestinian male was referred to our hospi-
tal from the GAZA strip for the investigation of hepatosple-
nomegaly. He is the third of four healthy children of non-
consanguineous parents (Fig. 1A). Upon detailed history, he
was found to have suffered from monthly episodes of fever
up to 39° C, lasting 7-10 days, since the age of 10 weeks. In
contrast to his normally developed twin sister, at the age of
1.5 years he was unable to stand, and did not use any mean-
ingful words.
Physical examination revealed hepatomegaly, a macu-
lopopular corporal and facial rash, and left elbow arthritis.
Abdominal ultrasonography confirmed the presence of an
enlarged heterogenic liver and a spleen of 9.5 X 8.6 cm. Por-
tal blood flow was normal.
Neurological examination revealed general hypotonia
and a linguistic developmental delay, otherwise being a
normal examination.
No pathology was found in his retina, cornea, uvea or
optic discs.
Serology for CMV, herpes simplex virus (HSV), Vene-
real Disease Research Laboratory (VDRL) tests,
Toxoplasma, hepatitis viruses A, B and C were obtained and
were all found negative. Serology tests for Rubella demon-
strated an immunized individual.
Levels of immunoglobulins were tested and proved to be
mildly elevated: IgG 1980 mg/dL (N:420-1200), IgA 189
mg/dL (N:12-150), IgM 328 mg/dL (N:45-200). Comple-
ment levels were normal or mildly elevated. C-reactive pro-
tein level was 30 mg/dL. Serology for ANA, P-ANCA, C-
ANCA, anti-LKM, anti-actin, ANF, anti-M2 and ASMA
were all negative.
Liver biopsy was performed next and revealed an in-
flammatory lymphocytic infiltrate, associated with portal
fibrosis (Fig. 2). Due to a thus suspected inflammatory-
mediated condition, steroid therapy was begun. This
Mevalonic Aciduria and Hepatic Fibrosis The Open Pediatric Medicine Journal, 2009, Volume 3 39
treatment diminished both arthritis and fevers, although upon
weeks of follow-up had little effect on the child's general
well being. Upon the reduction of steroid dose, the fevers
and arthritis reappeared. A trial of imuran treatmen t had no
clinical effect.
Due to the combination of hepatosplenomegaly, recurrent
fevers, and arthritis the diagnosis of MVA was considered
and sought by urine organic-acid analysis. Mevalonate levels
were 2250 mmol/mol Cr (N < 0.03) thus confirming the di-
agnosis. Levels of IgD, however, were only slightly elevated
- 8.2 mg/dL (N 0-4.5). Genetic sequence analysis revealed
the patient to be a compound heterozygote of two novel mu-
tations on exon 1 of the MVK gene (Fig. 1C): V8F (t25a),
and F38I (t112a). The patient's father was found to be the
carrier of the V8F mutation (Fig. 1B). Hence the F38I mu-
Fig. (1). (A) The patient's family pedigree. Noteworthy is the lack of consanguinity. (B) Sequencing of Exon 1F of the paternal MVK gene,
demonstrating the V8F mutation. (C) Sequencing of Exon 1F of the patient's MVK gene, demonstrating compound hetrozygosity of two mu-
tations: V8F (t25a), and F38I (t112a).
Fig. (2). A photomicrograph showing the patient's H&E stained liver tissue, demonstrating hepatic fibrosis, an unfamiliar feature of MVA.
40 The Open Pediatric Medicine Journal, 2009, Volume 3 Harel-Meir et al.
taion is most likely maternal in origin (DNA sample for se-
quencing was unavailable), or less likely, a de-novo muta-
This case demonstrates the phenotypic continuum be-
tween MVA and HIDS; this patient presented with a mild
developmental delay, daily as opposed to periodic fevers,
slightly elevated IgD blood levels and high urine mevalonate
levels - all supporting diagnsosis of MVA [1, 2]. Still, other
features of MVA such as ataxia, dysmorphic features or cata-
racts [1] were absent, although none are considered to be
sine qua non to MVA. One might argue that ataxia has not
yet developed in this patient due to his young age, however,
central cataracts and unusual facies have been previously
described in MVA patients as young as 2 years of age [9].
One of the diagnostic challenges presented in this patient
was the presence of hepatic fibrosis in liver biopsy, which
temporarily shifted the differential diagnosis to more com-
mon inflammatory hepatic diseases. Although previously
described in MVA patients [10], hepatic fibrosis is far from
being considered a hallmark of the disease, and is scantly
described in the literature, perhaps due to the infrequent ex-
ercise of liver biopsy in these patients.
Another remarkable finding in this patient was his geno-
type, as he was found to be a compound heterozygote of two
novel MVK mutations: V8F (t25a), and F38I (t112a). Al-
though mutations in MVK have been previously described in
a HIDS patient of Palestinian descent [8], our reported case
is, to our knowledge, the first described Palestinian MVA
patient. In general the phenotypic severity of mevalonic
aciduria correlates with the activ ity of the enzyme me-
valonate kinase(1). In the case described the two novel muta-
tions cause a change from the aliphatic(V,I) amino acid to
aromatic(V,F) and vice versa. It is possible that this struc-
tural change affects the enzyme activity.
As of now, medical treatment presents the principal chal-
lenge in MVA. Previously reported treatments includin g
statins, the tumor necrosis factor alpha (TNF- ) inhibitor
etanercept, and Anakinra, an interleukin-1 receptor antago-
nist [1] were all found to be of limited value. Recently,
Neven, et al. [1] described a successful allogeneic bone mar-
row transp lantation in an MVA patien t. However, as this is a
fairly new treatment, no evidence is present regarding its
effect on neurological development.
In summary, this case highlights phenotypic features of
MVA, such as hepatic fibrosis, and demonstrates the clinical
spectrum of the disease. The reported unique genotype in
this patient, as well as his unique ancestry, will hopefully
enable earlier accurate diagnoses of future cases.
ANA = Antinuclear antibodies
Anti-LKM = Anti- liver kidney microsomal antibodies
ANF = Antinuclear factor
Anti-M2 = Antimitochondrial protein 2
ASMA = Anti- smooth muscle antibodies
C-ANCA = Cytoplasmic antineutrophil cytoplasmic
CMV = Cytomegalovirus
HIDS = Hyperimmunoglobulinemia D and periodic
fever syndrome
HSV = Herpes simplex virus
IgD = Immunoglobulin D
IgG = Immunoglobulin G
IgM = Immunoglobulin M
IgA = Immunoglobulin A
MVA = Mevalonic aciduria
MVK = Mevalonate kinase gene
P-ANCA = Perinuclear antineutrophil cytoplasmic
TNF- = Tumor necrosis factor alpha
VDRL = Venereal disease research laboratory tests
[1] Neven B, Valayannopoulos V, Quartier P, et al. Allogeneic bone
marrow transplantation in mevalonic aciduria. N Engl J Med 2007;
356: 2700-3.
[2] Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobu-
linemia D and periodic fever syndrome: the clinical spectrum in a
series of 50 patients. Medicine (Baltimore) 1994; 73: 13 3-44.
[3] Houten SM, Wanders RJ, Waterham HR. Biochemical and genetic
aspects of mevalonate kinase and its deficiency. Biochim Biophys
Acta 2000; 1529: 19-32.
[4] Simon A, Kremer HP, Wevers RA, et al. Mevalonate kinase defi-
ciency: Evidence for a phenotypic continuum. Neurology 2004; 62:
[5] Abreu TT. Periodic fever: the first Portuguese case-report of hyper-
IgD syndrome (HIDS). Acta Med Port 2004; 17: 391-4.
[6] Ostuni PA, Lazzarin P, Ongaro G, Gusi R, Todesco S, Gambari PF.
Hyper-IGD syndrome: a new case treated with colchicine. Clin
Rheumatol 1988; 7: 398-401.
[7] Coban E, Terziolu E. A patient with hyper-IgD syndrome in Anta-
lya, Turkey. Clin Rheumatol 2004; 23: 177-8.
[8] Hammoudeh M. Hyperimmunoglobulinemia D syndrome in an
Arab child. Clin Rheumatol 2005 ; 24: 92-4.
[9] Hoffmann G, Gibson KM, Brandt IK, Bader PI, Wappner RS,
Sweetman L. Mevalonic aciduria--an inborn error of cholesterol
and nonsterol isoprene biosynthesis. New Eng J Med 1986; 314:
[10] Hinson DD, Rogers ZR, Hoffmann GF, et al. Hematological ab-
normalities and cholestatic liver disease in two patients with me-
valonate kinase deficiency. Am J Med Genet 1998; 78: 408-12.
Received: March 11, 2009 Revised: March 26, 2009 Accepted: April 22, 2009
© Harel-Meir et al.; Licensee Bentham Open.
This is an open acc ess article licen sed under the terms of the Creative Commons Attribution Non-Commercial License (
nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
... Generally, hepatosplenomegaly is detected in mevalonic aciduria, along with dysmorphic features and severe neurologic impairment, absent in our case [5]. Liver involvement in MVK may manifest as neonatal hepatitis, hepatomegaly or hepatosplenomegaly, cholestatic liver dysfunction, hepatic fibrosis, or even hepatic failure [6][7][8]. MVK mimicks metabolic, infectious, chromosomial, hematologic, or neoplastic diseases [1,3]. Liver biopsy reveals an inflammatory lymphocytic infiltrate, such as in our case, associated with portal fibrosis [7] or histiocyte infiltration with hemophagocytosis [8]. ...
... MVK mimicks metabolic, infectious, chromosomial, hematologic, or neoplastic diseases [1,3]. Liver biopsy reveals an inflammatory lymphocytic infiltrate, such as in our case, associated with portal fibrosis [7] or histiocyte infiltration with hemophagocytosis [8]. ...
... There are few data regarding ultrasonography in pediatric patients with HIDS/MVK, although it may be fig. 1 (arrows); b) 4 months later the spleen parenchyma had a homogenous structure. (table II) as heterogenous hepatosplenomegaly may be seen [7]. In our patient, the hypoechoic hepatosplenic masses with rapid regression were likely inflammatory pseudotumors, mass-forming lesions characterized by a prominent inflammatory infiltrate. ...
Full-text available
Hyperimmunoglobulin D syndrome, due to mevalonate kinase deficiency, is a rare autoinflammatory disease with digestive tract involvement. We report an 11-year female child who has presented since the age of 1 year bouts of fever, rash, joint swelling, pulmonary consolidation, lymph node involvement and hepatosplenomegaly, with hyperimmunoglobulin D and increased urinary mevalonic acid. The ultrasonographic features of hepatosplenomegaly ranged from increment in size to pseudotumoral involvement, with hypoechogenic masses without apparent wall. During flares, abdominal CT showed hypodense, hypoenhancing nodular lesions, suggesting metastases. Nevertheless, a thorough search for malignancy was negative and the masses dissapeared after the disease flares. Mevalonate kinase deficiency may add to the causes of hepatosplenic and pulmonary inflammatory pseudotumors.
Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a sporadic disease, characterized by periodic attacks of inflammation. Mutations in the MEFV, the gene associated with familial Mediterranean fever (FMF), may lead to subclinical inflammation in asymptomatic carriers and modify the phenotype of some inflammatory diseases. We aimed at investigating the effect of MEFV gene mutations on disease phenotype in PFAPA. The cohort of this ongoing prospective study consisted of 124 children with PFAPA syndrome, followed in a single referral center, who were tested for MEFV mutations. Demographic data, clinical characteristics, and disease course of 65 PFAPA patients with and 59 without MEFV mutations (M+ and M-, respectively) were compared. PFAPA attacks in carriers of MEFV mutations were shorter compared with patients without mutations (3.8 ± 1.7 versus 4.8 ± 1.9 days, P < 0.01). The difference was more pronounced in those carrying the M694V mutation. In M+ patients, the rates of patients with regularity of their attacks (49.2%) and oral aphthae (24.6%) were lower, compared with M- patients (74.5% and 43.9%, respectively, P < 0.05 for each of the 2 comparisons). M+ patients needed a lower corticosteroid (beclomethasone) dose to abort the attacks (0.16 ± 0.07mg/kg versus 0.19 ± 0.08, P = 0.028). No differences were observed in all other clinical and laboratory parameters, over a follow-up period of 4.3 years. In PFAPA, MEFV is a modifier gene associated with an attenuated disease severity.
Full-text available
Periodic fever can have one of multiple causes. Among the hereditary periodic fever syndromes, hyper-IgD syndrome (HIDS) is a possible diagnosis, although, until now, no cases had been described in Portugal. We report a 25-year-old woman, with periodic fever since she was 8 months old. She had high serum IgD levels, and a molecular study of the mevalonate kinase gene was performed. A compound heterozygote was found for two mutations: V377I and T237S. This last mutation had not been observed before. We analyse the clinical features that made us think on HIDS as a possible diagnosis, and we highlight the features that are important for the differential diagnosis between HIDS and other periodic fevers. HIDS is a possible diagnosis for patients with periodic fever, even in Portugal.
Full-text available
Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.
A two-year-old boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic features. Quantitative analyses of urinary organic acids revealed massive excretion of mevalonic acid, a metabolic precursor of cholesterol and nonsterol isoprenes: 46,000 to 56,200 mmol per mole of creatinine, as compared with 0.2 to 0.3 mmol per mole in normal children. The mevalonic acid concentration in plasma was also greatly increased at 440 mumol per liter (normal, less than 0.05). The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts. In the subsequent pregnancy of the patient's mother, gas chromatography-mass spectrometry demonstrated a marked elevation of mevalonic acid in the mother's urine and a 3000-fold elevation, as compared with control levels in the amniotic fluid, suggesting that the fetus was affected. The diagnosis was confirmed by demonstration of the deficiency of mevalonate kinase in amniocytes and ultimately in liver from the abortus. Intermediate activities of the enzyme in both parents indicated an autosomal recessive mode of inheritance. These observations identify an inherited disorder of cholesterol and nonsterol isoprene biosynthesis in humans.
We report a new case of hyper-IgD syndrome, a recently described disease characterized by recurrent episodes of fever with headache, bilateral cervical lymphadenopathy and, more rarely, abdominal pain and diarrhoea. Polyclonal increase of serum IgD is the most important laboratory finding. Etiopathogenesis and differences with familial Mediterranean fever are discussed. Moreover, good results obtained with colchicine treatment are also reported.
We studied 50 patients (28 male and 22 female) with the hyper-IgD and periodic fever syndrome. Most patients originated from Europe, namely The Netherlands (28 cases; 56%), France (10 cases, 20%), and Italy (3 cases, 6%), but 1 patient was from Japan. A hereditary component is suggested by 18 patients coming from 8 families. The syndrome is typified by a very early age at onset (median, 0.5 years) and life-long persistence of periodic fever. Characteristically, attacks occur every 4-8 weeks and continue for 3-7 days, but the individual variation is large. Attacks feature high spiking fever, preceded by chills in 76% of patients. Lymphadenopathy is commonly present (94% of patients). During attacks, 72% of patients complained of abdominal pains, 56% of vomiting, 82% of diarrhea, and 52% of headache. Joint involvement is common in the hyper-IgD syndrome with poly-arthralgia in 80% and a non-destructive arthritis, mainly of the large joints (knee and ankle), in 68% of patients. Eighty-two percent of patients reported skin lesions with some attacks; these demonstrated vasculitis histologically. Serositis has been seen in only 3 patients (6%), while amyloidosis has not been recorded in any of the patients with this syndrome. Immunizations precipitated attacks in 54% of patients. All patients had a persistently elevated serum IgD level (> 100 U/mL), and in 82% of cases the serum IgA was likewise elevated. During attacks there is an acute-phase response adjudged by leukocytosis, neutrophilia, and increased ESR. The etiology remains to be elucidated, and treatment is supportive. The hyper-IgD syndrome is distinct from other periodic fever syndromes like systemic-onset juvenile rheumatoid arthritis, adult-onset Still disease, and familial Mediterranean fever.
Mevalonate kinase (MK) is an essential enzyme in the mevalonate pathway which produces numerous cellular isoprenoids. The enzyme has been characterized both at the biochemical and the molecular level in a variety of organisms. Despite the fact that mevalonate kinase is not the rate-limiting enzyme in isoprenoid biosynthesis, its activity is subject to feedback regulation by the branch-point intermediates geranyldiphosphate, farnesyldiphosphate and geranylgeranyldiphosphate. Recently, the importance of mevalonate kinase was demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited human disorders mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. The pathophysiology of these disorders is not yet understood, but eventually will give insight into the in vivo role of mevalonate kinase and isoprenoid biosynthesis with respect to the acute phase response and fever. The subcellular localization of mevalonate kinase is still a matter of debate. The enzyme could be localized predominantly in the cytosol, or in peroxisomes, or it is associated differentially with peroxisomes. Here we review the biochemical and molecular properties of MK, and discuss its biological significance, the regulation of its enzyme activity and finally its subcellular localization.
Both mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, recurrent fever attacks, and death in early childhood, and hyper-immunoglobulin D (hyper-IgD) syndrome, with recurrent fever attacks without neurologic symptoms, are caused by a functional deficiency of mevalonate kinase. In a systematic review of known mevalonate kinase-deficient patients, the authors identified five adults with phenotypic overlap between these two syndromes, which argues for a continuous spectrum of disease. Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic fever attacks.
Hyper-IgD syndrome is a periodic fever syndrome that presents with recurrent episodes of high fever accompanied by lymphadenopathy, abdominal distress, arthralgias or arthritis, headache and skin lesions. The diagnosis is based on clinical grounds and elevated serum IgD levels (>100 U/ml), but requires a high index of suspicion, and a mevalonate kinase enzyme defect. Most patients are from western Europe but there are others identified in other countries. We describe a 17-year-old patient who had been followed with the diagnosis of familial Mediterranean fever for a long time before she was diagnosed with hyper-IgD syndrome.
Hyperimmunoglobulinemia D syndrome (HIDS) is newly recognized and resembles familial Mediterranean fever (FMF). It is inherited as an autosomal recessive trait. Mutation of the gene coding for mevalonate kinase is responsible for the disease. The gene is located at chromosome 12q24. The patients initially described were of Dutch ancestry. Other cases from Turkey and Armenia were reported. The case we present is the first from Arab countries to be registered in the International HIDS Registry and to our knowledge the first to be reported.
Mevalonic aciduria--an inborn error of cholesterol and nonsterol isoprene biosynthesis Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency
  • G Hoffmann
  • Km Gibson
  • Ik Brandt
  • Pi Bader
  • Rs Wappner
  • L Sweetman
  • Dd Hinson
  • Zr Rogers
  • Gf Hoffmann
Hoffmann G, Gibson KM, Brandt IK, Bader PI, Wappner RS, Sweetman L. Mevalonic aciduria--an inborn error of cholesterol and nonsterol isoprene biosynthesis. New Eng J Med 1986; 314: 1610-4. [10] Hinson DD, Rogers ZR, Hoffmann GF, et al. Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency. Am J Med Genet 1998; 78: 408-12.