Neonatal Hemolytic Anemia Due to Inherited Harderoporphyria:
Clinical Characteristics and Molecular Basis
J. Lamoril,
H. Puy,
L. Gouya,
R. Rosipal,
V. Da Silva,
B. Grandchamp,
T. Foint,
B. Bader-Meunier,
J.P. Dommergues,
J.C. Deybach, and
Y. Nordmann
From the Centre Français des Porphyries, INSERM U409,
Hôpital Louis Mourier, Colombes, France; the Department of
Pediatrics, Faculty of Medicine I, Charles University, Praha, Czech
Republic; the Service de Dermatologie, Centre Hospitalier, La
Flèche, France; and the Service de Pédiatrie, Hôpital
Kremlin Bicêtre, Kremlin Bicêtre, France.
Porphyrias, a group of inborn errors of heme synthesis, are
classified as hepatic or erythropoietic according to clinical data and
the main site of expression of the specific enzymatic defect.
Hereditary coproporphyria (HC) is an acute hepatic porphyria with
autosomal dominant inheritance caused by deficient activity of
coproporphyrinogen III oxidase (COX). Typical clinical manifestations of the disease are acute attacks of neurological dysfunction; skin
photosensitivity may also be present. We report a variant form of HC
characterized by a unifying syndrome in which hematologic disorders
predominate: harderoporphyria. Harderoporphyric patients exhibit
jaundice, severe chronic hemolytic anemia of early onset associated
with hepatosplenomegaly, and skin photosensitivity. Neither abdominal
pain nor neuropsychiatric symptoms are observed. COX activity is
markedly decreased. In a first harderoporphyric family, with three
affected siblings, a homozygous K404E mutation has been previously
characterized. In the present study, molecular investigations in a
second family with neonatal hemolytic anemia and harderoporphyria
revealed two heterozygous point mutations in the COX gene. One allele
bore the missense mutation K404E previously described. The second
allele bore an A
G transition at the third position of the
donor splice site in intron 6. This new COX gene mutation resulted in
exon 6 skipping and the absence of functional protein production. In
contrast with other COX gene defects that produce the classical hepatic
porphyria presentation, our data suggest that the K404E substitution
(either in the homozygous or compound heterozygous state associated
with a mutation leading to the absence of functional mRNA or protein)
is responsible for the specific hematologic clinical manifestations of
harderoporphyria.
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1453-1457
© 1998 by The American Society of Hematology.
