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Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 1093-1094
CORRESPONDENCE
UGT1 Promoter Polymorphism Accounts for Increased Neonatal
Appearance of Hereditary Spherocytosis
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LETTER |
To the Editor:
Hereditary spherocytosis (HS) is a common inherited hemolytic anemia
with a prevalence of at least 1 in 5,000 people.1 The
clinical features of HS are anemia, jaundice, and splenomegaly. The
clinical forms in adulthood are mild, typical, and severe. However, HS
is commonly symptomatic in the neonatal period (65% of cases).
Jaundice is the first and more frequent symptom, often requiring
phototherapy and sometimes exchange-transfusion.2
The presence of neonatal symptoms is not strictly predictive of the
adult form, nor is it associated within specific erythrocyte membrane
alteration.3 Hemolysis in the neonatal period has been
partially attributed to the presence of free 2,3-diphosphoglycerate (2,3-DPG) which further destabilizes the membrane skeleton. The worsening of the jaundice is also due to the interaction between hemolysis of spherocytes and the reduced capacity of the neonatal liver
to conjugate bilirubin.1
Gilbert's syndrome is a benign unconjugated hyperbilirubinemia
characterized by episodes of mild intermittent jaundice. It is the most
common inherited disorder of hepatic bilirubin metabolism, occurring in 2% to 13% of the population.4,5 Recently
a correlation between homozygosity for a 2-bp insertion in the
promoter of the UDP-glucuronosyltransferase 1 (UGT1) exon 1 and
Gilbert's syndrome was demonstrated. This insertion lies within the
TATA box sequence and causes a less efficient binding of transcription
regulatory proteins. Hepatic glucuronidating activity is reduced to
about 30% of normal.
We examined retrospectively 178 newborns affected with HS (98 males and
80 females); all were at term and their weight ranged between 3.000 and
3.500 g; 160 of 178 newborns were breast fed. Diagnosis of HS was
performed by means of osmotic fragility test and red blood cell protein
assay. Analysis of the presence of two (TA) extranucleotide elements in
the promoter of UDP1 gene was performed by means of polymerase chain
reaction and analysis of the amplified DNA fragments in a 6%
polyacrylamide gel. Analysis of bilirubin level was performed daily
during the first week of life. Hyperbilirubinemia was classified as a
total bilirubin level higher than 2 SD of normal value and these levels
required phototherapy. We excluded all the newborns affected by
infections or presenting any illness associated with increased
bilirubin levels.
According to the UDP1 genotype, two groups of subjects were identified:
the first was composed of 148 6/6 [homozygotes for the common allelele
bearing the sequence (TA)6TAA] or 6/7 genotype; whereas
the second group was composed by 30 individuals homozygotes 7/7
[homozygotes for the rarer allele with the sequence
(TA)7TAA].
The frequency of 7/7 genotype in the Italian population was
16.9%, higher than that observed in Northern European
population. In the examined HS population 112 (63%) patients
added phototherapy during the first days of life. Jaundice
requiring phototherapy was present in 97% of HS patients homozygous
for Gilbert's gene, whereas about one half on the patients with at
least one UDP1 normal gene had total bilirubin levels not higher
than 2 SD of normal value (Table 1).
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Table 1.
Correlation Between Bilirubin Levels Requiring
Phototherapy (jaundice) and Length of TATAA Element in the Promoter
Region of UGT1 Gene in a Population of Newborns Affected With
HS
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Certainly the increased clinical manifestation of HS in neonatal period
is a very complex process in part due to the intracellular metabolic
causes; however, our results suggest that the genetic variation
in bilirubin UDP1 gene promoter plays a role in the enhanced
clinical manifestation (jaundice) of HS
newborns.
A. Iolascon
M.F. Faienza
A. Moretti
Dipartimento di Biomedicina dell'Età
Evolutiva
Università di Bari
Bari, Italy
S. Perrotta
E. Miraglia del Giudice
Dipartimento di Pediatria
II
Università di Napoli
Napoli, Italy
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