LAUSR

OBJECTIVE To analyse phenotypic features of a cohort of patients with protracted CLN3 disease to improve recognition of the disorder. METHODS We analysed phenotypic data of ten patients from six families with protracted CLN3 disease. Haplotype analysis was performed in three reportedly unrelated families. RESULTS Visual impairment was the initial symptom with onset at 5-9 years, similar to classic CLN3 disease. Mean time from onset of visual impairment to seizures was 12 years (range 6-41 years). Various seizure types were reported, most commonly generalized tonic-clonic seizures (GTCS); focal seizures were present in four patients. Progressive myoclonus epilepsy was not seen. Inter-ictal EEG revealed mild background slowing and 2.5-3.5Hz spontaneous generalized spike-wave discharges. Additional inter-ictal focal epileptiform discharges were noted in some patients. Age at death for the three deceased patients was 31, 31 and 52 years. Molecular testing revealed five individuals were homozygous for c.461-280_677+382del966, the 'common 1 kilobase pair' CLN3 deletion. The remaining individuals were compound heterozygous for various combinations of recurrent pathogenic CLN3 variants. Haplotype analysis demonstrated evidence of a common founder for the common 1 kb deletion. Dating analysis suggested the deletion arose approximately 1,500 years ago. and thus did not represent cryptic familial relationship in this Australian cohort. SIGNIFICANCE We highlight the protracted phenotype of a disease generally associated with death in adolescence, which is a combined focal and generalized epilepsy syndrome with progressive neurological deterioration. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures preceded by progressive visual loss. The common 1kB deletion has been typically associated with classic CLN3 disease, and the protracted phenotype has not previously been reported with this genotype. This suggests that modifying genetic factors may be important in determining this somewhat milder phenotype and identification of these factors should be the subject of future research.