Macular Dystrophy, Patterned, 3

A number sign (#) is used with this entry because of evidence that patterned macular dystrophy-3 (MDPT3) is caused by heterozygous mutation in the MAPKAPK3 gene (602130) on chromosome 3p21. One such family has been reported.

Description

Patterned macular dystrophy-3 (MDPT3), also called Martinique crinkled retinal pigment epitheliopathy, appears in the fourth or fifth decade of life and is characterized by a 'dry desert land' pattern of the fundus, involving the posterior pole initially and progressing from the temporal fovea to the periphery of the retina. Polypoid choroidal vasculopathy, choroidal neovascularization, or atrophic fibrous macular scarring can cause reduced visual acuity after age 50. Late-stage MDPT3 consists of a retinitis pigmentosa (RP; see 268000)-like phenotype due to death of retinal pigment epithelium (RPE) and photoreceptor cells. The dry desert land pattern observed on fundus examination corresponds to an irregular thickness of the Bruch membrane and the RPE, with a scalloped elevation ('crinkling') of the RPE observed on optical coherence tomography (OCT). Full-field electroretinography may be normal at preclinical and early stages of the dystrophy, but later cone and rod responses are severely reduced, consistent with progressive photoreceptor cell dysfunction and death at the final state (summary by Meunier et al., 2016).

For a general phenotypic description and discussion of genetic heterogeneity of patterned macular dystrophy, see MDPT1 (169150).

Clinical Features

Jean-Charles et al. (2013) described a 'crinkled' pattern of the RPE in 10 affected individuals over 3 generations of a family, as well as in 1 unrelated patient, from Martinique, an island in the West Indies. In the youngest generation of the family, examination of an asymptomatic 37-year-old man, his 30-year-old sister, and their 20-year-old cousin showed a network of deep whitish lines in the posterior pole, temporal to the fovea in 1 patient and juxtapapillary in the other 2. OCT of the affected areas showed minor changes, with diffuse scalloped shallow elevation of the RPE. In the middle generation, 4 sibs and a cousin with ages ranging from 50 to 63 years showed a deep reticular pattern in the RPE of the posterior pole and midperiphery, characterized by a network of white lines that displayed hyperautofluorescence associated with a few dark polycyclic dots. Fluorescein angiography showed a crinkled pattern of the fundus resembling crocodile skin; indocyanine green angiography also showed this crinkled pattern, but less clearly and only in the late phase of the sequence. The OCT RPE map confirmed localization of the crinkled pattern of white lines to the RPE, and the thickness of the outer nuclear layer was irregular because of the scalloped elevation of the RPE. A fifth sib, a 59-year-old woman, had decreased visual acuity and exhibited a large area of geographic atrophy in the macula; OCT showed retinal atrophy in the macula with outer retinal cavitations. The oldest patient was the 86-year-old grandmother in the first generation, who had severe vision loss consisting of light perception only, with pigmentary clumping in the periphery and a focal area of whitish deep network lines. The unrelated patient was a woman who presented at age 43 and had been followed for 20 years; she showed a juxtafoveal whitish deep network and had reduced vision in her right eye, in which a fibrovascular scar was observed. Polypoid choroidal vasculopathy (PCV) complicated the disorder in 4 patients, including the unrelated woman; another patient had a foveal fibrovascular scar that might represent a late PCV lesion. Noting that PCV is more frequent in black patients and is common in the French West Indies, the authors suggested that the association of PCV with crinkled retinal pigment epitheliopathy might be coincidental. Jean-Charles et al. (2013) called the disorder 'Martinique crinkled retinal pigment epitheliopathy.'

Meunier et al. (2016) studied 42 members of the family from Martinique reported by Jean-Charles et al. (2013), and noted that all 14 clinically affected individuals were older than 30 years at presentation. The 28 asymptomatic family members, 12 of whom were older than 30 years, all had a normal fundus.

Molecular Genetics

In a large 3-generation family from Martinique with MDPT3, previously reported by Jean-Charles et al. (2013), Meunier et al. (2016) performed whole-exome sequencing and identified a heterozygous missense mutation in the MAPKAPK3 gene (L173P; 602130.0001) that segregated with the disease. The mutation was present in only 1 asymptomatic family member, a 21-year-old woman who was likely in the preclinical stage of the disease; all 12 asymptomatic individuals older than 30 years did not carry the mutation. The mutation was not found in 140 control alleles from Martinique individuals over 40 years of age, or in public variant databases.