Researchers have identified an unexpected connection between inherited blindness and a gene known for causing a rare metabolic disorder.
The study, published in The American Journal of Human Genetics, examined 14 individuals from 12 families with retinitis pigmentosa, a progressive inherited condition that damages the retina and causes vision loss. They all carried variants affecting both copies of the IDUA gene, which encodes the enzyme α-L-iduronidase.
Deficiency of this enzyme typically causes mucopolysaccharidosis type I(MPS I), a rare inherited metabolic disorder characterized by the accumulation of complex sugars within cells. Classical MPS I affects multiple organs, including the skeleton, heart, and eyes, and can cause severe physical disability.
However, seven participants, aged 46 to 73 years at their latest assessments, showed no systemic features consistent with MPS I, despite comprehensive clinical evaluation.
Biochemical testing of nine individuals revealed that α-L-iduronidase activity was detectable but greatly reduced. Several genetic variants retained approximately 0.5 percent to 1.5 percent of normal enzyme activity, potentially explaining why some patients developed retinal disease without widespread systemic involvement.
Corresponding author Gavin Arno said, “Genetic conditions do not always follow the patterns we expect. Our findings show that changes in the same gene can sometimes affect the retina while leaving other parts of the body largely unaffected. This phenomenon may represent a significant cause of blindness in patients who remain undiagnosed.”
The researchers also used long-read RNA sequencing to investigate a recurrent IDUA variant. Although conventional protein-based testing suggested little functional impact, RNA analysis revealed abnormal gene splicing, with only a small proportion of transcripts processed correctly.
These findings demonstrate the value of combining genomic sequencing, enzyme activity measurements, and functional studies to interpret variants that might otherwise remain diagnostically uncertain.
The authors recommend including IDUA and other MPS-associated genes in inherited retinal disease testing panels. When variants affecting both gene copies are identified, follow-up biochemical investigations, including leukocyte enzyme activity and urinary glycosaminoglycan analysis, may help establish the diagnosis and guide referral for metabolic assessment.
Although the study was limited by its small cohort and incomplete longitudinal follow-up, the findings suggest that apparently isolated retinal degeneration can represent an unusually mild presentation of inherited metabolic disease, with implications for genetic counseling, diagnostic classification, and clinical surveillance.
Newsletters
Receive the latest pathologist news, personalities, education, and career development – weekly to your inbox.
