Fig. 6.1
North Carolina macular dystrophy (NCMD) (MCDR1). Colour fundus photographs showing both the typical drusen-associated phenotype that can be seen in NCMD (above) and the characteristic grade 3 pigmented atrophic lesion (below)
Histopathology is available of one patient with MCDR1, which showed accumulation of lipofuscin in the retinal pigment epithelium (RPE) within the atrophic macular lesion [3].
Linkage studies have mapped MCDR1 to a locus on chromosome 6q16 [1]. To date, MCDR1 has been described in various countries and no evidence of genetic heterogeneity has been reported [3–7]. The disease interval has been refined to 3 cM (1.8mb) between markers D6S1716 and D6S1671 [7]. All 11 annotated genes within the interval were analysed by mutation screening of coding regions, with no mutation identified [7]. There are several plausible explanations for the failure to identify the causative mutation in this study. The mutation may have been missed and may be located in a non-coding or regulatory region, or in an as yet unrecognised exon of one of the identified positional candidate genes, or in an as yet unidentified gene. Alternatively, MCDR1 may be caused by another mechanism such as copy number variation. The advent of next-generation sequencing should lead to the identification of the causative gene; this will improve our understanding of the pathogenesis of drusen and CNVM in MCDR1 and will provide new insights into the biology of human macular development.
Stefko et al. have mapped a dominantly inherited macular dystrophy in a North American family to chromosome 6q14, adjacent to but likely distinct from the MCDR1 locus [8, 9]. This macular dystrophy has a highly variable clinical phenotype, described as an autosomal dominant drusen disorder with macular degeneration (DD). Most young adults had fine macular drusen and good vision. Some affected individuals have congenital atrophic maculopathy and drusen and are symptomatic in infancy or early childhood.
Progressive bifocal chorioretinal atrophy (PBCRA) has also been linked to 6q14–q16.2 and the disease locus overlaps with the established MCDR1 interval [10, 11]. These two autosomal dominant macular dystrophies have some phenotypic similarities and both are thought to result from a failure of normal macular development. However, PBCRA differs significantly from MCDR1 in several important respects, including more severe visual loss, slow progression, abnormal colour vision, extensive nasal as well as macular atrophy and abnormal ERG and EOG. Therefore, if allelic, it is likely that different mutations are involved in their aetiology. An alternative explanation is that PBCRA and MCDR1 are caused by mutations in two different adjacent developmental genes.
6.2 North Carolina Macular Dystrophy-Like Phenotypes
Three North Carolina macular dystrophy-like phenotypes mapping to different genetic loci than MCDR1 have been described, suggesting further genetic heterogeneity in the MCDR1 phenotype.
6.2.1 Autosomal Dominant Macular Dystrophy (MCDR3) Resembling North Carolina Macular Dystrophy
A British pedigree has been described with an early-onset autosomal dominant macular dystrophy (MCDR3) [12]. Visual acuity ranged from 6/5 to 6/60. The retinal changes were confined to the macular region and vary from mild RPE pigmentary change to atrophy. Drusen-like deposits were present to varying degrees and were characteristic of the phenotype (Fig. 6.2). Choroidal neovascular membrane formation was an established complication. The EOG and ERG were normal, indicating that there is no generalised retinal dysfunction. The only significant differences between this phenotype and MCDR1 are that in MCDR3, colour vision is abnormal in the majority of affected individuals and there was evidence of disease progression, albeit in a single case.
Fig. 6.2
Autosomal dominant macular dystrophy (MCDR3) resembling North Carolina macular dystrophy. Colour fundus photographs showing bilateral typical fine macular drusen-like deposits (above), which are associated with increased autofluorescence (middle), and bilateral macular RPE atrophy and pigment clumping, with surrounding drusen-like deposits (below)
6.2.2 North Carolina-Like Macular Dystrophy and Progressive Sensorineural Hearing Loss (MCDR4)
A British family characterised by a nonprogressive MCDR1-like macular dystrophy in association with progressive sensorineural hearing loss has been reported (MCDR4) [14]. Visual acuity ranged from 6/9 to hand movements. In keeping with MCDR1 and MCDR3, the EOG and full-field ERG were normal. Progressive sensorineural deafness was present in all affected individuals over the age of 20 years.
Genotyping excluded linkage to the MCDR1 locus and established linkage to chromosome 14q.
6.2.3 North Carolina-Like Macular Dystrophy and Digital Anomalies (Sorsby Syndrome)
A British and a French family have been described with a dominantly inherited condition characterised by bilateral macular dysplasia in association with apical dystrophy or brachydactyly (Fig. 6.3) [15–17]. Visual acuity ranged from 6/12 to 4/60. The maculopathy was nonprogressive and variable in severity, ranging from mild RPE pigmentary changes to excavated chorioretinal atrophic lesions. There was no evidence of generalised retinal dysfunction.
