P10 Unique insights from a national multidisciplinary rare disease service: expanding the phenotype of late-onset ERCC6-related cockayne syndrome with hemiplegic migraine as a novel clinical feature

Cockayne Syndrome (CS) is a rare autosomal recessive neuro-progressive disorder caused by pathogenic variants in DNA repair genes (e.g ERCC6 and ERCC8). Since 2019, the National Service for Cockayne Syndrome/Trichothiodystrophy has enabled comprehensive clinical and molecular profiling of over 70 patients. Late-onset cases of CS are uncommon and often misdiagnosed.Here we report six patients with genetically confirmed ERCC6-related CS with a normal clinical course during the first two decades of life, followed by neurocognitive decline and hemiplegic migraine. Symptoms onset ranged from age 16 to the mid-30s, with diagnosis established between ages 20 and 59. Initial presentations included hemiplegic migraine (n=3) without variants in known familial hemiplegic migraine genes, early neurocognitive decline (n=3), and tremor, speech, and balance difficulties (n=3). MRI findings were consistent across all patients, showing diffuse leukoencephalopathy, basal ganglia calcifications, and cerebral and cerebellar atrophy.All patients were compound heterozygotes for the splice donor site variant c.2286+5G>A in ERCC6. We hypothesise that this variant results in aberrant splicing and deletion of exon 11 from the ERCC6/CSB mRNA and that a residual amount of normal splicing produces enough ERCC6/CSB protein to delay symptoms onset. We are currently testing this hypothesis.These findings expand the late-onset CS phenotype.