Two brothers with mild congenital erythropoietic porphyria due to a novel genotype.
BACKGROUND
Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease caused by the deficient activity of the heme biosynthetic enzyme, uroporphyrinogen III synthase (URO-synthase), and the accumulation of the nonphysiologic and phototoxic porphyrin I isomers. Clinical manifestations range from severe mutilation to mild erosions and blisters on sun-exposed areas. Evaluation of the URO-synthase mutation and residual enzyme activity has been correlated with the phenotypic expression of the disease.


METHODS
We describe 16- and 4-year-old brothers with CEP with a mild phenotype due to a novel genotype, one allele having a promoter mutation (-76G-->A) and the other having an exonic missense mutation (G225S). The father and a 4-year-old fraternal twin brother were carriers of the -76G-->A mutation, whereas the mother and a 15-year-old brother were carriers of the G225S mutation. Previous in vitro expression studies demonstrated that the G225S mutation severely decreased URO-synthase activity to 1.2% of normal, whereas the promoter mutation decreased the activity to approximately 50% of wild type, accounting for the mild clinical phenotype.


CONCLUSIONS
The mild disease phenotype in these patients is a further example of the clinical heterogeneity seen in CEP and is additional proof that in vitro enzyme expression studies provide dependable genotype-phenotype correlations.
Berry
Ali A
AA
Department of Dermatology, Ford Medical Center, Henry Ford Hospital, New Center One, 3031 W. Grand Boulevard, Ste, 800, Detroit, MI 48202, USA.
Desnick
Robert J
RJ
Astrin
Kenneth H
KH
Shabbeer
Junard
J
Lucky
Anne W
AW
Lim
Henry W
HW
D000293:Adolescent; D000409:Alanine; D002675:Child, Preschool; D005091:Exons; D005817:Genetic Counseling; D005838:Genotype; D005998:Glycine; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017092:Porphyria, Erythropoietic / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D011166:Porphyrins / Q000032:analysis; D011401:Promoter Regions, Genetic; D012694:Serine; D035781:Siblings; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics / Q000378:metabolism*
D011166:Porphyrins; D012694:Serine; D014576:Uroporphyrinogen III Synthetase; D000409:Alanine; D005998:Glycine