To the Editor:

Many mutations in the α- and β-spectrin genes are known to be associated with hereditary elliptocytosis (HE). Spectrin abnormalities are detected as abnormal peptides after limited trypsin digestion of spectrin (Sp).1 We had an opportunity to study a Filipino family living in Kuwait. The proband first presented with hemolysis at the age of 4 months and he was transfusion dependent until he was 12 months old. This family was referred to us when the proband was 16 months old. The parents are unrelated and there is no hemolytic history on either side (Table 1). The proband’s blood film showed obvious elliptocytes with few poikilocytes. His mother’s red blood cells were elliptocytic whereas the father’s red blood cell morphology was apparently normal. In osmotic gradient ektacytometry, red blood cells from all three members produced trapezoidal deformability curves, which are typical of HE with reduced DIiso values2 (Table 1). Spectrin analysis showed that all three individuals are heterozygous for the HE SpαI/74 variant and have defective Sp dimer self-association process (shown as increased percent of spectrin dimer content in the cold low-ionic-strength membrane extracts) (Table 1). The SpV41 polymorphism3 was also identified in the proband and his mother. This polymorphism is associated with the low-expressed α-SpLely allele.4 The high percentage of the αV41 peptide in the mother is related to homozygosity for α-SpLely allele (Table 1).

Direct sequencing of exon 2 in α-Sp gene and exon 30 in β-Sp gene5 has shown that the mother is heterozygous for a previously described mutation in codon 28 of α-Sp gene (CGT → TGT; R28C).6 The father is heterozygous for a new β-Sp gene mutation in codon 2018 (GCC → GAC; A2018D), which we designate as β-SpKuwaitino. Another point mutation previously reported in this codon was β-SpCagliari(GCC → GGC; A2018G).7 The proband was found to be heterozygous for both mutations (α-Sp R28C and β-Sp A2018D). The homozygosity for α-SpLely allele in the mother has nullified the expected reduced expression of SpαI/74variant when this HE allele is inherited in cis to an α-SpLely allele.8 In analogy to another α-Sp HE mutation,9 the low percentage of the αV41 peptide in the proband’s tryptic digest can be accounted for by the cis inheritance of the α-SpLely in respect to the deleterious HE α-Sp allele.

The appearance of HE SpαI/74 variants can be due to impairment of either spectrin genes, and more precisely exon 2 in α-Sp gene and exon 30 in β-Sp gene.1,10 Although the two point mutations detected in the heterozygous HE parents involve the codons of the Sp genes already known to be mutated in other HE cases, the present study is the first report describing an HE patient who has co-inherited both α- and β-gene mutations. The molecular combinations of these two mutations, including the presence of the α-spectrin mutation (R28C) on a low-expressed α-SpLely, have produced in the proband a hematological and biochemical picture of an apparently heterozygous HE phenotype, which is similar to that of his heterozygous HE parents, without any Sp deficiency (Table 1). The absence of typical elliptocytic cells in the father, despite his typical HE trapezoidal deformability curve, has already been observed in another HE family with a point mutation in β-spectrin.11 Because no more transfusions were needed 1 year after birth, the severity of the proband’s disease in the first year of life appears consistent with a transient poikilocytosis in infancy.10 However, such diagnosis has to be confirmed by an accurate clinical follow-up of the proband, especially as the percentage of αI/74 peptide being incorporated into his red blood cell membranes was found to be slightly higher than those observed in both parents (Table 1).

1
Gallagher
PG
Forget
BG
Hematologically important mutations; spectrin variants in hereditary elliptocytosis and hereditary pyropoikilocytosis.
Blood Cells Mol Dis
22
1996
254
2
Cynober
T
Mohandas
N
Tchemia
G
Red cell abnormalities in hereditary spherocytosis. Relevance of diagnosis and for understanding the variable expression of clinical severity.
J Lab Clin Med
128
1996
259
3
Alloisio
N
Morle
L
Marechal
J
Roux
AF
Ducluzeau
MT
Guetarni
D
Pothier
B
Baklouti
F
Ghanem
A
Kastally
R
Sp alpha V/41: A common spectrin polymorphism at the alpha IV-alpha V domain junction. Relevance to the expression level of hereditary elliptocytosis due to alpha-spectrin variants located in trans.
J Clin Invest
87
1991
2169
4
Wilmotte
R
Maréchal
J
Morlé
L
Baklouti
F
Philippe
N
Kastally
R
Kotula
L
Delaunay
J
Alloisio
N
Low expression allele αLELY of red cell spectrin is associated with mutations in exon 40 (αV/41 polymorphism) and intron 45 and with partial skipping of exon 46.
J Clin Invest
91
1993
2091
5
Parquet
N
Devaux
I
Boulanger
L
Galand
C
Boivin
P
Lecomte
MC
Dhermy
D
Garbarz
M
Identification of three novel spectrin αI/74 mutations in hereditary elliptocytosis: Further support for a triple-standed folding unit model of the spectrin heterodimer contact site.
Blood
84
1994
303
6
Coetzer
T
Palek
J
Lawler
J
Liu
SC
Jarolim
P
Lahav
M
Prchal
JT
Wang
W
Alter
BP
Schewitz
G
Mankad
V
Gallanello
R
Cao
A
Structural and functional heterogeneity of α spectrin mutations involving the spectrin heterodimer self-association site: Relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis.
Blood
75
1990
2235
7
Sahr
FE
Coetzer
TL
Moy
LS
Derick
LH
Chishi
AH
Jarolim
P
Lorenzo
F
Miraglia del Giudice
M
Iolascon
A
Gallanello
R
Cao
A
Delaunay
J
Liu
SC
Palek
J
Spectrin Cagliari. An ALA → GLY substitution in helix 1 of β spectrin repeat 17 that severely disrupts the structure and self-association of the erythrocyte spectrin heterodimer.
J Biol Chem
268
1993
22656
8
Randon
J
Boulanger
L
Marechal
J
Garbarz
M
Vallier
A
Ribeiro
L
Tamagnini
G
Dhermy
D
A variant of spectrin low-expression allele αLELY carrying a hereditary elliptocytosis mutation in codon 28.
Br J Haematol
88
1994
534
9
Dalla Venezia
N
Wilmotte
R
Morlé
L
Forissier
A
Parquet
N
Garbarz
M
Rousset
T
Dhermy
D
Alloisio
N
Delaunay
J
An α-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the αV/41 polymorphism.
Hum Genet
90
1993
641
10
Lux
SE
Palek
J
Disorders of the red cell membrane
Blood: Principles and Practice of Hematology.
Handin
RI
Lux
SE
Stossel
TP
1995
1701
Lippincott
Philadelphia, PA
11
Tse
WT
Lecomte
MC
Costa
FF
Garbarz
M
Feo
C
Boivin
P
Dhermy
D
Forget
BG
Point mutation in the beta-spectrin gene associated with alpha I/74 hereditary elliptocytosis. Implications for the mechanism of spectrin dimer self-association.
J Clin Invest
86
1990
909
Sign in via your Institution