Cone–rod dystrophy (CORD) is a heterogeneous group of disorders characterized by cone degeneration that is more significant and occurs earlier than the degeneration of rods. The estimated prevalence ranges from 1:30,000 to 1:40,000. Individuals with CORD typically complain of progressive central or paracentral visual loss associated with photophobia and color vision anomalies. Nyctalopia and peripheral visual field constriction also occur but may be delayed in onset. Nystagmus can also be present.
Patients usually present in childhood or early adulthood. The average onset age is 10 years, with some patients diagnosed as early as the age of 5 years. Vision ranges from 20/20 to 20/800, averaging usually at 20/70. Night blindness often does not occur until 10 years after the first vision symptoms. Severely constricted visual field can develop on average by the age of 50 years. Early age of onset of the disease is associated with worse visual defects. Early in the onset of the disease, patients may be indistinguishable from pure cone dystrophies until the later onset of rod involvement. Examination of older affected family members may be useful to make this distinction. Although end-stage CORD may look similar to retinitis pigmentosa (RP) on full-field (ff) electroretinogram (ERG), patients with RP will tend to have better preservation of central responses on the multifocal (mf) ERG and corresponding preservation of central vision.
The majority of CORD patients present with decreased visual acuity, photophobia impaired color vision, central or paracentral scotomas, and fundus examination revealing maculopathy. With the progression of the disease, patients develop nyctalopia, peripheral visual field contraction, and decreasing scotopic responses on ffERG. On fundus examination, the macular appearance can be normal in the early stages or patients may have mild to moderate vessel attenuation, bull’s eye maculopathy, macular atrophy, pigmentary alterations in the perifovea, and macula and/or pigmentary changes in the midperiphery (▶ Fig. 20.1). Temporal optic nerve pallor may be an early sign. Although there are no pathognomonic findings for each subtype, X-linked CORD can be associated with high myopia photophobia.
Fig. 20.1 Patient with cone–rod dystrophy caused by heterozygous mutation of the ABCA4 gene (c.5929G>A and c.*55G>A). (a) Wide angle fundus picture showing pigmented macular chorioretinal atrophy associated with vessel attenuation and preretinal gliosis. (b) Fundus autofluorescence of same patient revealing nummular hypo-autofluorescent patches in the macula associated with a hyperfluorescent granular ring on the midperiphery.
20.2 Molecular Genetics
The genetic basis of CORD is complex and highly heterogeneous (▶ Table 20.1). Inheritance can be either autosomal recessive (AR; up to 80%), autosomal dominant (AD; up to 20%), or X-linked recessive (1%). Approximately 30 genes have been implicated in CORD (sph.uth.edu/retnet/; March 2015). Most mutations are missense (up to 80%), but splicing defects (up to 25%) and nonsense mutations (up to 15%) also occur. Frameshift insertions or deletions have rarely been reported (▶ Table 20.1).
Associated with NF1b
aOther genes described in CORD: (1) AD inheritance—AIPL1, PRPH2, and UNC119; (2) AR inheritance—ATF6, C21orf2, CACNA2D4, CERKL, CNGA3, CNGB3, CNNM4, GNAT2, KCNV2, PDE6C, PDE6H, and RDH5.
bOne case of CORD associated with neurofibromatosis type 1.
The most frequent genes associated with each inheritance pattern are ABCA4 (AR), GUCY2D (AD), and RPGR (X-linked recessive). Depending on the population, mutations in ABCA4 and GUCY2D can be as high as 65 and 30%, respectively. Depending on the reported clinical series, 25 to 60% of AR CORD patients have an identifiable mutation. This number is nearly 100% for AD CORD.
In approximately half of CORD3 patients, biallelic ABCA4 mutations are found, whereas the other half show only heterozygous mutations. Deep intronic sequencing can increase the detection rate by an additional 30%. The molecular etiology of the remaining patients remains unknown and could theoretically include digenic disease, epigenetic effects, or an unknown regulator of ABCA4. The amount of residual ABCA4 function appears to determine the phenotype. Whereas ABCA4 null alleles produce RP, the combination of a null allele and a moderately affected allele may produce CORD. Sometimes this clinical continuum can be defined only on the basis of the ERG patterns.
Despite genetic heterogeneity, some phenotype–genotype correlation can be observed. CORD2, CORD8, and CORD13 frequently present with profound visual loss. CORD8 additionally can have severe photophobia and epiphora, with a high degree of fundus granularity and marked macular degeneration. In addition to childhood onset, moderate myopia and pendular nystagmus have been seen in CORD6. Patients with CORD7 may present with late-onset symptoms between the ages of 20 and 40 years, with difficulty in bright light, foveal pigmentary changes, and macular atrophy. Patients with CORD11 have electronegative b-waves. CORD15 has been associated with coexistent oculocutaneous albinism in the absence of mutations in TYR