Residual electroretinograms in young Leber congenital amaurosis patients with mutations of AIPL1.

Leber congenital amaurosis (LCA) is a severe congenital or early-onset inherited retinal dystrophy that classically presents with searching nystagmus, absence of normal pupil responses, flat electroretinograms (ERGs), minimal, if any, vision beyond infancy, and an initially normal fundus appearance, followed by the development of pigmentary changes over time. The term LCA has traditionally been used when these features present within the first 6 months of life, whereas a variety of terms such as juvenile retinitis pigmentosa,1 early childhood onset retinitis pigmentosa,2 or severe early childhood onset retinal dystrophy (SECORD)3 have been used to describe milder forms of the disease that present after 1 year. LCA and SECORD are genetically extremely heterogeneous, and are caused by >16 genes (AIPL1, CEP290, CRX, CRB1, GUCY2D, IMPDH1, IQCB1, LCA5, LRAT, MERTK, RD3, RDH12, RPGRIP1, RPE65, SPATA7, and TULP1). All except CRX and IMPDH1 exhibit autosomal recessive inheritance in which some de novo mutations result in an autosomal dominant trait.3–5 The gene AIPL1 encodes aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), a 384-amino acid protein with three tetratricopeptide repeat motifs. AIPL1 has been suggested to play a role in photoreceptor development6 and protein farnesylation7 and as a chaperone for NUB1, Hsp70, Hsp90, and photoreceptor-specific phosphodiesterases (PDE6β).8–12 Although AIPL1 was initially thought to be expressed only in adult rod photoreceptors,13 its expression in adult rodent cones has now been demonstrated.14 Mutations in AIPL1 are estimated to account for approximately 5% to 10% of all cases of LCA.4,15 Patients usually have severe vision loss (ranging from 20/200 to LP), but milder forms that would fit the definition of a later onset rod-cone dystrophy have also been reported.2,16–19 Other typical features include poorly responsive pupils, nystagmus, hyperopia, and unrecordable ERGs. The fundus appearance in patients with AIPL1 mutations can appear normal early in the disease, but most patients eventually demonstrate a pigmentary retinopathy with a high prevalence of macular atrophy. One series demonstrated that cataracts and keratoconus were common in those with homozygous AIPL1 mutations.18 Spectral domain-optical coherence tomography (SD-OCT) has shown severe loss of outer retinal thickness in the macula, lamellar disorganization, and increased inner retinal thickness.16 Successful gene replacement therapy in AIPL1-deficient mouse models has raised the hope that such methods could be translated for human treatment.20,21 However, Jacobson et al.16 recently studied the feasibility of treatment in a series of patients with AIPL1 mutations and concluded that the severe photoreceptor degeneration seen might mean they were not good candidates for gene replacement therapy unless and that evidence would be needed in much younger patients of some photoreceptor preservation. We herein report three young patients with mutations in AIPL1 who presented with the clinical features of LCA but had residual electroretinograms characterized by slow insensitive scotopic responses and absent photopic responses. The presence of these residual ERG responses potentially indicated greater photoreceptor preservation than seen in older patients and suggested that these patients might be better candidates for gene replacement therapy than previously considered.