Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa.
OBJECTIVE
To investigate the clinical spectrum and molecular causes of retinal dystrophies in 3 families.


METHODS
Family molecular genetics study.


METHODS
Sixteen patients and 15 relatives in 3 families.


METHODS
Members of 3 families with multiple ABCA4-associated retinal disorders were clinically evaluated. Deoxyribonucleic acid samples of all affected individuals and their family members were analyzed for variants in all 50 exons of the ABCA4 gene.


METHODS
ABCA4-associated retinal phenotypes and mutations in the ABCA4 gene.


RESULTS
In family A, 2 sisters were diagnosed with Stargardt's disease (STGD); the eldest sister was compound heterozygous for the mild 2588G-->C and the severe 768G-->T mutation. Another patient in this family with a severe type of retinitis pigmentosa (RP) carried the 768G-->T mutation homozygously. In family B, 2 siblings presented with an RP of severity similar to that encountered in family A. Both were homozygous for the severe IVS33+1G-->A mutation. Two other family members with STGD were compound heterozygous for the 2588G-->C and IVS33+1G-->A mutations. In family C, all 5 siblings of generation II demonstrated age-related macular degeneration (AMD). In generations III and IV, 2 STGD patients and 1 cone-rod dystrophy (CRD) patient were present. In 1 STGD patient we identified a heterozygous 768G-->T mutation. Sequence analysis of the entire ABCA4 gene did not reveal the remaining 2 mutations. Nevertheless, the 2 patients with STGD, the patient with CRD, and 2 of the AMD patients shared a common haplotype spanning the ABCA4 gene.


CONCLUSIONS
Different mutations in the ABCA4 gene are the cause of STGD and RP or CRD in at least 2 and, possibly, 3 families. Patients with RP caused by ABCA4 mutations are characterized by an early onset and rapid progression of their retinal dystrophy, with extensive chorioretinal atrophy resulting in a very low visual acuity. Various combinations of relatively rare retinal disorders such as STGD, CRD, and RP in one family may not be as uncommon as once believed, in view of the relatively high carrier frequency of ABCA4 mutations (about 5%) in the general population.
Klevering
B Jeroen
BJ
Department of Ophthalmology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. B.Klevering@ohk.umcn.nl
Maugeri
Alessandra
A
Wagner
Anja
A
Go
Sioe Lie
SL
Vink
Carolien
C
Cremers
Frans P M
FP
Hoyng
Carel B
CB
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes; D006801:Humans; D008268:Macular Degeneration / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D014792:Visual Acuity
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters