GENOTYPE–PHENOTYPE CORRELATIONS OF OCULAR, CEREBRAL, AND KIDNEY MANIFESTATIONS IN LOWE SYNDROME

Lowe syndrome is an X-linked genetic disorder caused by OCRL pathogenic variants, characterized by ocular, central nervous system (CNS), and kidney involvement. Previous studies have reported no clear genotype–phenotype correlations in kidney manifestations. However, correlations with ocular and neurological features have not been systematically investigated.

A nationwide questionnaire survey was distributed to nephrologists and pediatric nephrologists across 1,814 institutions in Japan. A total of 29 patients (26 families) aged ≥6 years with genetically or clinically confirmed Lowe syndrome—defined by the triad of congenital cataracts, central nervous system involvement, and Fanconi syndrome—were included. Medical records were reviewed to assess ocular, CNS, developmental, activities of daily living (ADL) and kidney findings. ADL was evaluated using the Barthel Index (range, 0–100; ≥85 defined as independent). Data were retrospectively analyzed according to OCRL variant type. Continuous data were presented as median (interquartile range). Group comparisons were performed using the Mann–Whitney U test or Fisher’s exact test. Time-to-event analyses were conducted using the Kaplan–Meier method, and group differences were evaluated by the generalized Wilcoxon and log-rank tests. 

The median age at evaluation was 16.8 (10.6–23.0) years, and all patients were male. All patients had congenital cataracts. Glaucoma was observed in 8 of 29 patients (28%), and visual acuity was <0.3 in 16 of 24 patients (67%). Regarding neurodevelopmental milestones, the median ages for acquisition of single words, two-word phrases, and independent walking were 35 (18–81), 74 (48–122), and 51 (30–78) months, respectively. The median estimated glomerular filtration rate (eGFR) was 42.9 mL/min/1.73 m² (25.9–55.5), and urinary β₂-microglobulin levels were 82,876 µg/L (54,954–118,747). Nephrocalcinosis or urolithiasis was detected in 14 of 29 patients (48%). Genetic analysis identified OCRL variants in all 24 tested patients: 11 truncating/large-deletion variants (Group A), 11 non-truncating variants (Group B), and 2 unclassified variants. Compared with Group B, Group A tended to have more severe ocular manifestations, including visual acuity <0.3 (89% vs 44%; P = 0.13) and glaucoma (45% vs 9%; P = 0.15). Neurodevelopmental milestones were delayed in Group A, with later acquisition of single words (median, 60 vs 18 months; log-rank P = 0.08; Wilcoxon P = 0.07) and significantly delayed acquisition of two-word phrases (median, 108 vs 48 months; log-rank P = 0.009; Wilcoxon P = 0.004) and independent walking (median, 66 vs 31 months; log-rank P = 0.09; Wilcoxon P = 0.04). Both Barthel Index scores (median, 55 vs 98; P = 0.03) and the proportion of patients achieving ADL independence (0% vs 70%; P = 0.03) were significantly lower in Group A. No significant differences were observed in eGFR, urinary β₂-microglobulin, and the prevalence of nephrocalcinosis or urolithiasis between the two groups.

This study is the first to evaluate genotype–phenotype correlations of ocular and CNS involvement in Lowe syndrome. Developmental milestones were achieved earlier than previously reported. Truncating or large-deletion variants were associated with more severe ocular involvement and significantly delayed neurodevelopment, resulting in reduced ADL independence.

Acknowledgment

This study was supported by “Research on Rare and Intractable Diseases, Health and Labour Sciences Research Grants” from the Ministry of Health, Labour and Welfare of Japan.