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216 Letter to the Editor
Late onset of isovaleric acidemia presenting
with bicytopenia
Bisitopeni ile birliktelik gösteren geç başlangıçlı izovalerik asidemi
Barış Malbora1, Zekai Avcı1, Alev Hasanoğlu2, Füsun Alehan3, Namık Özbek1
1Department of Pediatric Hematology, Başkent University Faculty of Medicine, Ankara, Turkey
2Department of Pediatric Metabolism, Gazi University Faculty of Medicine, Ankara, Turkey
3Department of Pediatric Neurology, Başkent University Faculty of Medicine, Ankara, Turkey
Address for Correspondence: M.D. Barış Malbora, Başkent University Faculty of Medicine, Department of Pediatric Hematology, 6. Cadde,
No: 72/3, Bahcelievler 06490 Ankara, Turkey Phone: +90 312 212 68 68 E-mail: barismalbora@gmail.com
doi:10.5152/tjh.2010.34
To the Editor,
Isovaleric academia (IVA) is an autosomal reces-
sive inborn error of leucine metabolism caused by
a deficiency of isovaleryl-CoA dehydrogenase. In
the acute phase of this disease, thrombocytopenia,
neutropenia or pancytopenia may be common fea-
tures [1-4]. However, the physiopathology of the
bone marrow suppression in this disease is still
unclear. Here, we report the case of an IVA patient
who presented with thrombocytopenia and neutro-
penia at the age of 31 months.
A 31-month-old male patient had been admitted
to our hospital with fever, vomiting, fatigue, and loss
of appetite. There was no history of any drug use.
On physical examination, the patient was lethargic.
Vital signs were normal except for mild tachycardia
and tachypnea. Skin turgor and tonus were found to
be decreased.
The results of a complete blood count revealed
the following: white blood cells (WBC) count
1.4x109/L; absolute neutrophil count 0.92x109/L;
hemoglobin 11 g/dl; and platelet count 57.5x109/L.
The bone marrow aspiration showed normal matu-
ration of three lineages without any hemophagocy-
tosis, megaloblastic cells, extramyeloid cells, fatty
changes, or myelodysplasia. There were numerous
necrotic cells. The number and the morphology of
megakaryocytes were normal. In the aspiration
smear, 18% myelocyte, 35% metamyelocyte, 11%
polymorphonuclear leukocyte, 28% lymphocyte, 2%
normoblast, 1% monocyte, 1% eosinophil, and 4%
lymphoblast-like cells were present. Bone marrow
flow cytometry did not reveal lymphoblasts.
Biochemical analyses were within normal limits
except for hypocalcemia, hyperammonemia, and
mildly increased aspartate aminotransferase and
lactate dehydrogenase. Serum C-reactive protein
and erythrocyte sedimentation rate were in normal
range. Ketonuria was determined. The results of
blood, throat, urine, stool, and cerebrospinal fluid
cultures were negative. Viral serology of the cere-
brospinal fluid and serum were also negative.
Serum Brucella agglutination and Salmonella agglu-
tination were negative. Serum lactate and pyruvate
levels were 4 mmol/L (normal range: 0.7-2.1
mmol/L), and 2.74 mg/dl (normal range: 0.3-1 mg/
dl), respectively. The urine organic acid examina-
tion showed that the excretions of isovaleryl glycine
and methyl malonic acid were significantly
increased: 1299 mmol/mol creatinine (normal: 0
mmol/mol creatinine) and 42.7 mmol/mol creati-
nine (normal: 0 mmol/mol creatinine), respectively.
Tandem mass spectrometry of spot serum, free car-
nitine and amino acid profiles were normal. There
was an increase in the isovaleryl and 3-OH butyryl
carnitine levels, whereas there was a decrease in
the levels of acetyl, propionyl, and palmitoylcarni-
tine. Lymphocyte isovaleryl-CoA dehydrogenase
activity was 0.02 nmol/min.mg [controls mean±SD:
1.51±0.31 nmol/min.mg].
We initiated antibiotic therapy and protein-poor
diet. Carnitine and L-glycine were added to the treat-
ment. During this period, his laboratory examination
revealed WBC count of 0.64x109/L (absolute neutro-
phil count, 0.43x109/L); a hemoglobin level of 10.7 g/
dl; and a platelet count of 31.8x109/L. On the fifth day
of antibiotics, his fever was controlled, and the WBC
number and platelet count began to increase. His
blood count was completely normal one week after
the end of antibiotic treatment (Figure 1a, b).
Hematologic problems can be seen in patients
with inborn errors of branched-chain amino acid
metabolism. Various cytopenias have been reported
in IVA [5]. However, the physiopathology of myelo-
suppression in this disease is not well known. Some
infections may also result in myelosuppression, but
in our patient, we did not determine any serologic
or microbiologic evidence of infection. There is also
a report of a patient with IVA with promyelocytic
myeloproliferative syndrome [6,7]. In patients with
IVA, hematologic problems are usually reported in
early infancy [1,2,6]. Compatible with this, no
patients have been reported in the English literature
with IVA diagnosed later in childhood with neutro-
penia, thrombocytopenia or pancytopenia.
In some patients, this disorder may be diagnosed
as late as 5 years [8]. However, hematologic prob-
lems are not observed at that age. Another interest-
ing finding in our patient was the lymphoblast-like
cells observed in the bone marrow. We believe that
the lymphoblast-like cells observed in our patient’s
bone marrow were due to maturation arrest in the
normal lymphoblastic series caused by IVA.
Although both forms of IVA often occur in the first
year of life, IVA may be observed later in childhood.
Hematologic problems frequently observed in the acute
form of the disease can be seen in the chronic intermit-
tent form, as was the case in our patient. Thus, in such
cytopenias, inborn errors of branched -chain amino acid
metabolism, like IVA, should be kept in mind.
Acknowledgement
This study conforms to the principles outlined in
the Declaration of Helsinki (1975) and later revisions,
and was approved by Ethical Committee of Baskent
University Faculty of Medicine, Ankara, Turkey.
Conflict of Interest
No author of this paper has a conflict of interest,
including specific financial interests, relationships,
and/or affiliations relevant to the subject matter or
materials included in this manuscript.
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Malbora et al.
Hematologic problems in isovaleric acidemia
Turk J Hematol 2010; 27: 216-8 217
Figure 1. The hematologic parameters of the patient during isovaleric acidemia episode. A) WBC (white blood cell) and ANC (absolute
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218
