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

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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).
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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).
INTRODUCTION
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-
tion.
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: bujyoram@netvision.net.il
CASE REPORT
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-
tion.
DISCUSSION
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.
ABBREVIATIONS
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
antibodies
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
antibodies
TNF- = Tumor necrosis factor alpha
VDRL = Venereal disease research laboratory tests
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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 (http://creativecommons.org/licenses/by-
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... 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. ...
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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.