Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q

Abstract

Aims-To document the phenotype of an autosomal dominant macular dystrophy diagnosed as having North Carolina macular dystrophy (NCMD) in this British family, and to verify that the disease locus corresponds with that of MCDR1 on chromosome 6q. Methods-37 family members were examined and the phenotype characterised. DNA samples from the aVected members, 19 unaVected and five spouses, were used to perform linkage analysis with six microsatellite marker loci situated within the MCDR1 region of chromosome 6q. Results-Every aVected family member had lesions characteristic of NCMD, which developed early in life and usually remain stable thereafter. Although fundus changes are evident in the periphery, all tests revealed that functional loss is restricted to the macula. Some patients with large macular lesions had good visual acuity with fixation at the edge of the lesion at 5°eccentricity. Significant linkage to the MCDR1 locus on chromosome 6q was obtained with three marker loci, with a maximum lod score of 5.9 (q = 0.00) obtained with D6S249. Conclusion-This family has the typical phenotype NCMD, and the causative gene was linked to the disease locus (MCDR1) on chromosome 6q. Early onset and localisation of the disease to the central macula allow specialisation of eccentric retina in some eyes with resultant good visual acuity.

Genetic linkage analysis of a novel syndrome comprising North Carolina-like macular dystrophy and progressive sensorineural hearing loss

“…22 The drusen-like subretinal deposits with RPE disturbance and the areas of well demarcated chorioretinal atrophy and pigment epithelial hypertrophy would be consistent with grade I and III NCMD lesions, respectively. 10 Furthermore, the presence of normal electrophysiology parallels the findings in NCMD 4 and suggests that the deficit is restricted to the central retina. Also, similar to NCMD reasonable acuity was generally retained even in those with subfoveal chorioretinal lesions.…”

“…It has been hypothesised this might arise if foveal disruption occurs sufficiently early in retinal development to allow neural specialisation at an eccentric point. 10 Holz et al 41 have described an Indian family with autosomal dominant macular dystrophy with appearances that overlapped between NCMD, pattern dystrophy, fundus flavimaculatus, and drusen but there was no associated hearing impairment. Excln θ is the recombination fraction at a lod score of −2; Excln cM is the genetic distance (in centimorgans) around the marker which is excluded from linkage.…”

“…5 Extensive genealogical studies have revealed that several other diseases, thought originally to be distinct entities, central areolar pigment epithelial dystrophy, 6 central pigment epithelial and choroidal degeneration, 7 and central retinal pigment epithelial dystrophy, 8 arise in descendants of the original NCMD founders and are in fact manifestations of the variable expressivity of the condition. 9 Subsequently, families with NCMD unrelated to the original pedigree have been reported in the United Kingdom, 10 Texas, United States, 11 Central America, 12 and France. 13 The gene for NCMD has been shown to reside within a 3.1 cM interval termed the MCDR1 locus on 6q14-q16.2 [14][15] ).…”

“…[21][22] Visual acuity varies from normal to significantly compromised and the posterior segment findings can be classified into one of three grades depending on severity: fine "drusen" within 3°of fixation (grade I); confluent elevated subretinal deposits sometimes associated with retinal pigment epithelial (RPE) changes (grade II); central macular chorioretinal atrophy with hypertrophic fibrous tissue (grade III). 10 Deafness is a common congenital anomaly with an incidence of 1 in 1000 live births. 23 About 50% of cases can be attributed to genetic factors, with hearing impairment which is typically progressive and sensorineural, inherited either as an isolated anomaly or as part of over 400 clinical syndromes.…”

The genetics of inherited macular dystrophies

“…To date, MCDR1 has been described in various countries and no evidence of genetic heterogeneity has been reported. [81][82][83] The identification of the gene The genetics of inherited macular dystrophies responsible for this disorder is keenly awaited as it will help to improve our understanding of the pathogenesis of drusen and SRNVM.…”