The c.1A > C start codon mutation in CLN3 is associated with a protracted disease course

Abstract

Background CLN3 disease is a disorder of lysosomal homeostasis predominantly affecting the retina and the brain. The severity of the underlying mutations in CLN3 particularly determines onset and course of neurological deterioration. Given the highly conserved start codon code among eukaryotic species, we expected a variant in the start codon of CLN3 to give rise to the classical, that is, severe, phenotype. Case series We present three patients with an identical CLN3 genotype (compound heterozygosity for the common 1 kb deletion in combination with a c.1A > C start codon variant) who all displayed a more attenuated phenotype than expected. While their retinal phenotype was similar to as expected in classical CLN3 disease, their neurological phenotype was delayed. Two patients had an early onset of cognitive impairment, but a particularly slow deterioration afterwards without any obvious motor impairment. The third patient also had a late onset of cognitive impairment. Conclusions Contrasting our initial expectations, patients with a start codon variant in CLN3 may display a protracted phenotype. Future work will have to reveal the exact mechanism behind the assumed residual protein synthesis, and determine whether this may be eligible to start codon targeted therapy.

Tagless LysoIP method for molecular profiling of lysosomal content in clinical samples

“…This individual still had elevated GPD metabolites within the lysosome, but at least 5-fold (between 4.8 to 43-fold) lower than in CLN3 patients that are homozygous for the common 1 kb deletion that results in a complete loss of function. This example illustrates the quantitative nature of the tagless LysoIP and its potential to measure lysosome-restricted biomarkers and correlate them to disease phenotypes, especially in cases with atypical mutations (19,20).…”

Early recognition of CLN3 disease facilitated by visual electrophysiology and multimodal imaging

“…Various neurological signs and symptoms have been reported, including: dementia, seizures, speech delay, mood fluctuations, difficult behaviour, balance, or memory changes, cognitive decline, sleep disturbances, feeding difficulties, clumsiness, and poor concentration [13,18,41] with seizure as the most common [13]. CLN3 has a variable phenotype as illustrated by those presenting with mild or delayed neurological defects ranging from 3-to 18-year interval between ocular and neurological onset [53][54][55][56], or no systemic features [9,10,15]. Ocular and neurological phenotypic variability also is frequently reported in those with the same mutations [57][58][59].…”

Recognition and epileptology of protracted CLN3 disease

“…A rarer phenotype, known as protracted CLN3 disease, has been described more recently 9–12 . We identified 20 published cases of protracted CLN3 disease in the literature 9–15 . Protracted CLN3 disease is also associated with childhood onset progressive visual loss; however, seizures and other neurological manifestations do not typically develop until the third decade of life or later.…”

“… 9 , 10 , 11 , 12 We identified 20 published cases of protracted CLN3 disease in the literature. 9 , 10 , 11 , 12 , 13 , 14 , 15 Protracted CLN3 disease is also associated with childhood onset progressive visual loss; however, seizures and other neurological manifestations do not typically develop until the third decade of life or later. Although early mortality is still seen in this cohort, the life expectancy is longer than that of classic CLN3 disease.…”