Disease progression in IMPDH1 gene-associated rod-cone dystrophy caused by a rare p.Thr244Pro heterozygous variant

A hallmark of the IMPDH1-related rod-cone dystrophy is the highly variable expressivity. Disease onset, severity and progression are variant-dependent due to specific affected photoreceptor mechanisms, underscoring the importance of genotype-phenotype correlations. We provide a detailed clinical characterization of a patient with rod-cone dystrophy caused by a rare de novo missense IMPDH1 variant.

A 33-year-old female patient was assessed over a period of four years following the onset of her symptoms. A multimodal evaluation of both structural and functional aspects, along with molecular analysis, was performed. We identified a rare de novo missense variant in the IMPDH1 gene (NM_000883.4:c.730A > C, p.Thr244Pro), which had been previously reported in one patient. Threonine 244 is located at the interface between the catalytic domain and the regulatory Bateman domain. This region is crucial for GDP/GTP nucleotide binding and mediates feedback regulation, putatively influencing allosteric regulation. The SD-OCT imaging revealed a symmetrically preserved ellipsoid zone in the central retina, alongside noticeable neuroretinal layer loss beyond the temporal vascular arcades. Functional examinations showed normal BCVA, microperimetric macular thresholds, and color vision thresholds in both eyes. Multifocal ERG was slightly reduced, and full-field ERGs were affected in both dark- and light-adapted responses, consistent with the peripheral sensitivity loss in the 80° automated visual field. No significant changes were observed throughout the follow-up period.

The IMPDH1 p.Thr244Pro variant was associated with preserved central retina structure and function with stable peripheral dysfunction in the fourth decade of life, suggesting a relatively stationary disease course that starkly contrasts the rapid progression of retinal dystrophies caused by other IMPDH1 variants.