Hereditary Systemic Diseases Can Have a Predominant Ocular Phenotype, but They Are Still Systemic Diseases

This issue of JAMA Ophthalmology contains 2 articles^1,2 that emphasize the occurrence of a predominant ocular phenotype in adult patients with 2 forms of neuronal ceroid lipofuscinosis (NCL), which is classically recognized as a group of severe neurodegenerative disorders of childhood. Smirnov et al¹ demonstrate the presence of a phenotype-genotype correlation in 15 adult patients with biallelic pathogenic variants in CLN3 drawn from a cohort of 1533 patients and described as having nonsyndromic inherited retinal disease. The authors¹ divide them into 2 groups: 6 patients with mild rod-cone degeneration of middle-aged onset and legal blindness in their 70s and 9 patients with a severe retinal degeneration involving early macular atrophic changes and legal blindness by their 40s. While none of the patients reportedly had any neurological symptoms, the details of their neurological workups and specific questions about mental functions that are generally affected in NCL are lacking. No investigations of cardiac function or the spine, both recently recognized as affected organs in NCL type 3,³ were conducted. Also, the authors did not compare retinal findings among siblings in the 4 sibships in this report.¹ If the clinical course of the disease is consistent within pedigrees, this will give even more credence to their demonstration that the CLN3 pathogenic variants in these 2 groups of patients are associated with phenotypes that are milder than those of patients with classic juvenile NCL. Patients with classic juvenile NCL or Batten disease present with rapidly progressive loss of visual acuity followed by neurological deterioration in the first decade of life and demise as young adults.⁴ Of the patients with this phenotype, 73% are homozygous for a common homozygous deletion variation of 966 basepairs involving exons 7 and 8 of CLN3, as opposed to the mostly missense CLN3 variations in the 15 patients¹ with a predominant retinal phenotype.⁵ Furthermore, the gene sequence variants in the milder cases were distinct from those in the more severe cases, indicating an even more refined genotype-phenotype correlation.