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.
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