Kuper Willemijn F E, van Alfen Claudia, van Eck Linda, de Man Stella A, Willemsen Marjolein H, van Gassen Koen L I, Losekoot Monique, van Hasselt Peter M
Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University Utrecht The Netherlands.
Bartiméus Institute for the Visually Impaired Zeist, Doorn The Netherlands.
JIMD Rep. 2020 Feb 7;52(1):23-27. doi: 10.1002/jmd2.12097. eCollection 2020 Mar.
CLN3 disease is a disorder of lysosomal homeostasis predominantly affecting the retina and the brain. The severity of the underlying mutations in 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 to give rise to the classical, that is, severe, phenotype.
We present three patients with an identical 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 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.
CLN3病是一种溶酶体稳态紊乱疾病，主要影响视网膜和大脑。特别是潜在突变的严重程度决定了神经功能恶化的发病时间和病程。鉴于真核生物物种之间起始密码子编码高度保守，我们预计CLN3起始密码子中的一个变体将导致典型的，即严重的表型。
我们报告了三名具有相同CLN3基因型的患者（常见的1 kb缺失的复合杂合子与c.1A＞C起始密码子变体），他们均表现出比预期更轻的表型。虽然他们的视网膜表型与经典CLN3病预期的相似，但他们的神经表型出现延迟。两名患者早期出现认知障碍，但随后恶化特别缓慢，且无明显运动障碍。第三名患者认知障碍也起病较晚。
与我们最初的预期相反，CLN3起始密码子变体的患者可能表现出病程延长的表型。未来的研究将不得不揭示假定的残余蛋白质合成背后的确切机制，并确定这是否可能适用于起始密码子靶向治疗。
