Foveal hypoplasia is a common feature in ACHM cohorts: all reported subjects with
ATF6-ACHM,
23 and two thirds of the reported
CNGA3- and
CNGB3-ACHM subjects, have foveal hypoplasia.
10,22,28 In our cohort of
GNAT2-ACHM, no case of foveal hypoplasia was observed, a finding similar to
PDE6C-ACHM.
24 GNAT2 encodes guanine nucleotide-binding protein G(t) subunit alpha-2, which is part of the transducin complex, a G-protein participating in the visual cycle.
48,49 The α-subunit is released from βγ subunits after the interaction with light activated photopigment in cone cells and the exchange of GDP for GTP. The released α-subunit activates the cGMP phosphodiesterase (PDE6C), which lowers the cGMP and hyperpolarizes photoreceptors.
50 Interestingly, despite both molecules being involved in a sequential path in the phototransduction cascade and both causing ACHM,
PDE6C-ACHM presents with far more severe structural defects than
GNAT2-ACHM.
24 Structural integrity of the EZ on OCT was evident in all
GNAT2 subjects (
Fig. 1), with the exception of subject P6 (
Fig. 3) - representing an example of the structural intrafamilial variability commonplace in inherited retinal diseases.
49 The other four affected individuals from the same pedigree showed a continuous EZ, with three of the subjects being older. Functional intrafamilial variability has also been reported in the same pedigree.
7 Similar structural intrafamilial variability has also been reported in pedigrees of
CNGA3-ACHM.
22 Due to the recessive inheritance and the rarity of ACHM, data for intrafamilial variability are limited. The above finding of loss of foveal EZ in patient P6, combined with the stable imaging findings over follow-up (
Fig. 3), supports the notion that major EZ loss is an event during early childhood,
51 rather than a progressive phenomenon later in life.
52 In the on-going debate about the stationary or progressive nature of ACHM, different genotypes should be studied individually.
PDE6C-ACHM was recently reported as a slowly progressive maculopathy.
24 ACHM studies with different proportions of patients with
GNAT2 and
PDE6C have shown conflicting results.
52,53 Thiadens et al., in a cohort with five patients with
PDE6C (20%) and no
GNAT2, concluded that ACHM was often a progressive disease.
53 Hirji et al., in a cohort with one subject with
PDE6C (2%) and two subjects with
GNAT2 (4%), concluded that ACHM was predominantly stationary.
52