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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. 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. 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. © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.


Willemijn F E Kuper, Claudia van Alfen, Linda van Eck, Stella A de Man, Marjolein H Willemsen, Koen L I van Gassen, Monique Losekoot, Peter M van Hasselt. The c.1A > C start codon mutation in CLN3 is associated with a protracted disease course. JIMD reports. 2020 Mar;52(1):23-27

PMID: 32154056

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