Abstracts

Rationale:
CLN3 Disease is one of the commoner neuronal ceroid lipofuscinoses (NCLs). Classic CLN3 disease is characterised by childhood onset progressive visual loss, followed by seizures, rapid motor and cognitive decline, and death prior to 20 years of age. It is an autosomal recessive condition, and 80% of pathogenic alleles are a CLN3 deletion c.461-280_677+382del966, termed the ‘common 1 kilobase pair deletion’. A rarer phenotype, known as protracted CLN3 disease has adolescent or adult onset of seizures and neurological decline.  We noted that the etiological association with earlier visual loss was not always appreciated, especially if the blindness was attributed to a non-specific retinal degeneration.  We aimed to further explore phenotype and genotype characteristics of a series of previously unreported patients with protracted CLN3 disease.
Method:
We assembled a cohort of nine Australian patients, including two sib-pairs and one pair of twins with protracted CLN3 disease.  Five were retrospectively ascertained and four were suspected clinically and then genetically confirmed.
Results:
Onset of visual impairment was 5-9 years, similar to Classic CLN3 disease. Time from onset of visual impairment to seizures was more prolonged (mean 12 years, range 6-41years). Four patients had developmental delay, and all developed cognitive impairment. A variety of seizure types was reported, most commonly generalised tonic clonic seizures (GTCS), though focal seizures were also seen. Progressive myoclonus epilepsy was not seen. Seizure frequency was variable; most patients had at least several GTCS per year with variable response to antiepileptic medication. One patient never had any seizures. Cerebellar and extrapyramidal features were the most common associated neurological features.   EEG data was available in six patients. EEG typically revealed mild background slowing and 2.5-3.5Hz generalized spike wave discharges. Independent bilateral fronto-temporal epileptiform discharges were seen in three patients.  Ages of death for the three deceased patients were 31, 31 and 52 years of age. All other patients were between 19 and 49 years of age at last review. Molecular testing revealed four patients were homozygous for the common 1 kilobase pair deletion. The remaining patients were compound heterozygotes for various pathogenic CLN3 variants.
Conclusion:
This case series provides insight into protracted CLN3 disease, highlighting an adult phenotype of a disease generally associated with death in adolescence. Unlike CLN2, CLN4 and CLN6 diseases, progressive myoclonus epilepsy is not typical. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures with earlier visual failure.  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 other modifying factors may be important in determining the phenotype. 
Funding:
:Nil