Limits...
Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease.

Xi Q, Li L, Traboulsi EI, Wang QK - Mol. Vis. (2009)

Bottom Line: Unaffected family members either did not carry either or had only one of the two mutations.We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T.These results expand the wide range of clinical manifestations of ABCA4 mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT

Purpose: To identify the gene causing a severe form of progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease and to characterize clinical features in a large American family.

Methods: We characterized an American family who had an unusual retinal dystrophy with clinical features of Stargardt disease and severe progressive cone-rod dystrophy. Family members underwent complete ocular examinations with evaluation of visual acuity, visual fields, fundus examination, fluorescein angiography, and electroretinography. Genome-wide linkage analysis of the family was performed using 408 microsatellite markers spanning the entire human genome. Direct DNA sequence analysis was used for mutational analysis of the ABCA4 gene in all exons and exon-intron boundary regions and for testing cosegregation of the mutations with the disease in the family. DNA sequence analysis was used to determine the presence of the mutations in 200 unrelated controls.

Results: The proband presented with a clinical phenotype that was initially compatible with Stargardt disease, only to progress to a severe cone-rod dystrophy over the course of a few years. The disease-causing gene in the family was linked to the ABCA4 locus on chromosomal 1p22. One novel mutation, c.655A>T, was identified in exon 6 and another novel splicing mutation, c.5312+3A>T, was identified in intron 37 of ABCA4. The mutations were not present in 200 controls. The two affected sisters in this pedigree were compound heterozygotes for the mutations. Unaffected family members either did not carry either or had only one of the two mutations.

Conclusions: We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T. When present as a compound heterozygous state, the mutations cause a phenotype of retinal dystrophy that initially manifests as Stargardt disease and slowly progresses to a severe cone-rod dystrophy. These results expand the wide range of clinical manifestations of ABCA4 mutations.

Show MeSH

Related in: MedlinePlus

Typical retinal phenotype in affected members A: Left fundus of proband showing temporal optic nerve pallor, attenuated retinal blood vessels, macular pigmentary and atrophic changes, and some fine pigment clumping outside the vascular arcade. B: Mid-transit fluorescein angiogram of left fundus of younger sister reveals a dark choroid sign with some retinal pigment epithelium (RPE) transmission defects in a perifoveal distribution. C and D: Right and left fundus photographs of younger sister at age 12 years show mottling of RPE in macular region but no flagrant pigmentary changes; there is slight temporal pallor of the optic nerve heads, especially in left eye.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2665199&req=5

f1: Typical retinal phenotype in affected members A: Left fundus of proband showing temporal optic nerve pallor, attenuated retinal blood vessels, macular pigmentary and atrophic changes, and some fine pigment clumping outside the vascular arcade. B: Mid-transit fluorescein angiogram of left fundus of younger sister reveals a dark choroid sign with some retinal pigment epithelium (RPE) transmission defects in a perifoveal distribution. C and D: Right and left fundus photographs of younger sister at age 12 years show mottling of RPE in macular region but no flagrant pigmentary changes; there is slight temporal pallor of the optic nerve heads, especially in left eye.

Mentions: The proband’s vision continued to deteriorate slowly, and she developed temporal pallor of her optic nerve head as well as peripheral pigmentary changes in a bony spicule pattern (Figure 1A). She also developed a fine nystagmus. Her macular areas took on a beaten bronze appearance. At the age of 15 she complained of significant difficulties with dark adaptation. An electroretinogram showed no recordable waveforms under scotopic and photopic conditions. At the age of 17 her visual acuity was 20/500 OD and 4/200 OS. The peripheral pigmentary changes had become extensive, and her visual fields showed severe peripheral constriction.


Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease.

Xi Q, Li L, Traboulsi EI, Wang QK - Mol. Vis. (2009)

Typical retinal phenotype in affected members A: Left fundus of proband showing temporal optic nerve pallor, attenuated retinal blood vessels, macular pigmentary and atrophic changes, and some fine pigment clumping outside the vascular arcade. B: Mid-transit fluorescein angiogram of left fundus of younger sister reveals a dark choroid sign with some retinal pigment epithelium (RPE) transmission defects in a perifoveal distribution. C and D: Right and left fundus photographs of younger sister at age 12 years show mottling of RPE in macular region but no flagrant pigmentary changes; there is slight temporal pallor of the optic nerve heads, especially in left eye.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2665199&req=5

f1: Typical retinal phenotype in affected members A: Left fundus of proband showing temporal optic nerve pallor, attenuated retinal blood vessels, macular pigmentary and atrophic changes, and some fine pigment clumping outside the vascular arcade. B: Mid-transit fluorescein angiogram of left fundus of younger sister reveals a dark choroid sign with some retinal pigment epithelium (RPE) transmission defects in a perifoveal distribution. C and D: Right and left fundus photographs of younger sister at age 12 years show mottling of RPE in macular region but no flagrant pigmentary changes; there is slight temporal pallor of the optic nerve heads, especially in left eye.
Mentions: The proband’s vision continued to deteriorate slowly, and she developed temporal pallor of her optic nerve head as well as peripheral pigmentary changes in a bony spicule pattern (Figure 1A). She also developed a fine nystagmus. Her macular areas took on a beaten bronze appearance. At the age of 15 she complained of significant difficulties with dark adaptation. An electroretinogram showed no recordable waveforms under scotopic and photopic conditions. At the age of 17 her visual acuity was 20/500 OD and 4/200 OS. The peripheral pigmentary changes had become extensive, and her visual fields showed severe peripheral constriction.

Bottom Line: Unaffected family members either did not carry either or had only one of the two mutations.We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T.These results expand the wide range of clinical manifestations of ABCA4 mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.

ABSTRACT

Purpose: To identify the gene causing a severe form of progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease and to characterize clinical features in a large American family.

Methods: We characterized an American family who had an unusual retinal dystrophy with clinical features of Stargardt disease and severe progressive cone-rod dystrophy. Family members underwent complete ocular examinations with evaluation of visual acuity, visual fields, fundus examination, fluorescein angiography, and electroretinography. Genome-wide linkage analysis of the family was performed using 408 microsatellite markers spanning the entire human genome. Direct DNA sequence analysis was used for mutational analysis of the ABCA4 gene in all exons and exon-intron boundary regions and for testing cosegregation of the mutations with the disease in the family. DNA sequence analysis was used to determine the presence of the mutations in 200 unrelated controls.

Results: The proband presented with a clinical phenotype that was initially compatible with Stargardt disease, only to progress to a severe cone-rod dystrophy over the course of a few years. The disease-causing gene in the family was linked to the ABCA4 locus on chromosomal 1p22. One novel mutation, c.655A>T, was identified in exon 6 and another novel splicing mutation, c.5312+3A>T, was identified in intron 37 of ABCA4. The mutations were not present in 200 controls. The two affected sisters in this pedigree were compound heterozygotes for the mutations. Unaffected family members either did not carry either or had only one of the two mutations.

Conclusions: We have identified two novel ABCA4 mutations, c.655A>T and c.5312+3A>T. When present as a compound heterozygous state, the mutations cause a phenotype of retinal dystrophy that initially manifests as Stargardt disease and slowly progresses to a severe cone-rod dystrophy. These results expand the wide range of clinical manifestations of ABCA4 mutations.

Show MeSH
Related in: MedlinePlus