Cone-Rod Dystrophy 3

A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-3 (CORD3) is caused by homozygous or compound heterozygous mutation in the ABCA4 (601691) on chromosome 1p22.

For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.

Klevering et al. (2002) analyzed phenotype information from the charts of 12 patients with autosomal recessive CORD caused by mutations in the ABCA4 gene and found that although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Klevering et al. (2002) concluded that given the wide clinical spectrum of CORD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassification is difficult and may not be very useful.

Fishman et al. (2003) examined 30 patients with autosomal recessive CORD, 16 of whom harbored plausible disease-causing variations in the ABCA4 gene. Among the mutation-positive patients, 2 distinctly different fundus phenotypes were observed: 12 showed diffuse pigmentary degenerative changes (type 1), whereas 4 showed either no pigmentary changes or only a mild degree of peripheral pigment degeneration (type 2). All 16 patients showed either a central scotoma (6 patients) or both a central scotoma and some degree of peripheral field loss (10 patients). Both cone and rod a- and b-wave electroretinogram (ERG) amplitudes were reduced in all patients, which is diagnostic for CORD.

Cideciyan et al. (2004) studied surrogate measures of retinoid cycle kinetics, lipofuscin accumulation, and rod and cone photoreceptor and RPE loss in STGD1 and CORD3 patients with ABCA4 mutations and a wide spectrum of disease severity. There were different extents of photoreceptor/RPE loss and lipofuscin accumulation in different regions of the retina. Slowing of retinoid cycle kinetics was not present in all patients; when present, it was not homogeneous across the retina; and the extent of slowing correlated well with the degree of degeneration. The orderly relationship between these phenotypic features permitted the development of a model of disease sequence in retinal degeneration due to ABCA4 mutation, which predicted lipofuscin accumulation as a key early component of disease expression with abnormal slowing of the rod and cone retinoid cycle occurring at later stages of the disease sequence.

Cremers et al. (1998) performed ophthalmologic examination and haplotype analysis in a consanguineous family with individuals showing either retinitis pigmentosa (RP) (601718) or cone-rod dystrophy (CORD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at chromosome 1p21-p13 (lod score, 4.22), a genomic segment that harbors the ABCA4 gene, known to be involved in Stargardt disease and age-related macular degeneration.

Cremers et al. (1998) analyzed the ABCA4 gene in a consanguineous family with RP and CORD and identified homozygosity for a 5-prime splice site mutation in intron 30 (601691.0009) in the 4 RP patients; the 5 patients with CORD were compound heterozygotes for the mutation in intron 30 and a 5-prime splice site mutation in intron 40 (601691.0010). Four unaffected members of this family were heterozygous for the mutation in intron 40. Both splice site mutations were found in heterozygosity in 2 unrelated patients with Stargardt disease (STGD1; 248200) in whom the second mutation was either a missense mutation or unknown, but not in 100 control individuals. Cremers et al. (1998) suggested that the intron 30 splice site mutation represents a true null allele, whereas the intron 40 mutation probably renders the exon 40 5-prime splice site partially functional.

To evaluate the importance of the ABCA4 gene as a cause of autosomal recessive CORD, Maugeri et al. (2000) studied 5 patients with autosomal recessive CORD and 15 patients with isolated CORD, all from Germany and the Netherlands. They found 19 ABCA4 mutations in 13 (65%) of 20 patients. In 6 patients, mutations were identified in both ABCA4 alleles; in 7 patients, mutations were detected in 1 allele. The complex ABCA4 allele L541P/A1038V (601691.0023) was found exclusively in German patients with CORD; 1 patient carried this complex allele in homozygous state, and 5 others were compound heterozygotes.

Ducroq et al. (2002) evaluated the prevalence of ABCA4 mutations in a cohort of 55 patients with autosomal recessive or sporadic cone-rod dystrophy. They screened the 50 exons of the ABCA4 gene as well as the flanking intronic sequences using DHPLC and identified 16 different mutant alleles in 13 (23.6%) of 55 patients. Among these 13 patients, 2 were homozygotes (from 2 consanguineous families; see, e.g., 601691.0024), 4 were compound heterozygotes, and 7 were simple heterozygotes. There was no significant difference in the frequency of ABCA4 mutations between autosomal recessive and sporadic cases of CORD (6 of 29 versus 7 of 26 cases, respectively). Ducroq et al. (2002) estimated that this screen detected approximately 80% of mutations present in these families, with unidentified mutations potentially located in promoter or intron sequences or in undiscovered exons, and stated that the corrected mutation frequency would then be 29.5% of all CORD cases. For a sporadic case of cone-rod dystrophy with no ABCA4 mutation, they estimated that the risk of the disease being inherited as an autosomal recessive condition can be estimated to be 15.6% using the Bayesian calculation.

Fishman et al. (2003) examined 16 patients with autosomal recessive CORD and ABCA4 mutation and observed 2 distinctly different fundus phenotypes: 12 showed diffuse pigmentary degenerative changes (type 1), whereas 4 showed either no pigmentary changes or only a mild degree of peripheral pigment degeneration (type 2). Of the 12 patients classified as type 1, 4 harbored an A1038V change (601691.0016): in 2 this was the only sequence variation identified; in 1 case, it was observed in compound heterozygosity with a nonsense mutation; and in 1 case it was found as a complex allele with an L541P mutation (see 601691.0023). In the additional 8 patients classified as type 1, 2 showed 2 different heterozygous missense mutations, 3 had a single heterozygous missense mutation, and 3 had a heterozygous splice site mutation within intron 40 (601691.0010). In the 4 patients with considerably less funduscopically apparent pigmentary change (type 2), a heterozygous missense mutation was observed: in 2 instances L1201R (601691.0025), and in another 2 L2027F (601691.0004).

Ducroq et al. (2006) analyzed a large multiplex Christian Arab family with presumed autosomal recessive CORD and 6 consanguineous loops and found segregation of 3 distinct haplotypes at the CORD3 locus. Sequencing of the ABCA4 gene revealed 3 different mutations segregating with the disease in this family: 4 patients were homozygous for a splice-site mutation; 4 were compound heterozygous for the splice-site mutation and 1 of 2 missense mutations, respectively; and 1 patient was compound heterozygous for the 2 missense mutations. Review of clinical data from the 9 affected individuals confirmed the diagnosis of CORD in 8 of them, but the patient who was compound heterozygous for 2 missense mutations was found to exhibit typical signs of Stargardt disease without extension to the peripheral retina, with severely reduced photopic responses but normal scotopic amplitudes on ERG. Ducroq et al. (2006) emphasized the pitfalls of homozygosity mapping in highly inbred families when the heterozygote carrier frequency is high in the general population.