Objective:

To investigate the genetic and biochemical basis of retinitis pigmentosa in individuals with variants affecting both copies of IDUA.

Approach:

• Participants: Researchers studied 14 people from 12 families with retinitis pigmentosa.
• Testing: The study combined clinical evaluation, genetic analysis, enzyme activity testing in nine participants, and long-read RNA sequencing of a recurrent IDUA variant.

Key Findings:

• All participants carried variants affecting both copies of IDUA, the gene associated with mucopolysaccharidosis type I (MPS I).
• Seven participants, aged 46–73 at their latest assessments, had no systemic features consistent with MPS I despite comprehensive evaluation.
• Enzyme activity was detectable but greatly reduced; some variants retained approximately 0.5%–1.5% of normal activity.
• RNA sequencing showed abnormal splicing of a recurrent variant, with only a small proportion of transcripts processed correctly.

Interpretation:

The authors report that IDUA-related disease may present predominantly as retinal degeneration, without the typical systemic features of MPS I. They recommend including IDUA and other MPS-associated genes in inherited retinal disease panels and considering biochemical follow-up when variants affect both gene copies.

Limitations:

• The cohort was small.
• Longitudinal follow-up was incomplete.

Conclusion:

The authors state that genomic, enzyme, and functional testing together can help interpret uncertain variants and identify this atypical presentation.

Sources:

• The American Journal of Human Genetics study, as described in the supplied article context