“Atypical” Phenotypes of Neuronal Ceroid Lipofuscinosis: The Argentine Experience in the Genomic Era

• Published in: Journal of inborn errors of metabolism and screening Vol. 9
• Main Authors: Pesaola, Favio, Guelbert, Guillermo, Venier, Ana Clara, Cismondi, Inés Adriana, Becerra, Adriana, Vazquez, Juan Carlos G., Fernandez, Elmer, De Paul, Ana Lucia, Guelbert, Norberto, Noher, Inés
• Format: Journal Article
• Language: English
• Published: Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) 2021; SciELO
• Subjects: Atypical Phenotypes; CLN1; CLN2; CLN8; GENETICS & HEREDITY; Genomics; Neuronal CeroidLipofuscinosis; CLN2; Neuronal CeroidLipofuscinosis; CLN1; CLN8; Genomics; Atypical Phenotypes
• ISSN: 2326-4594; 2326-4594
• DOI: 10.1590/2326-4594-jiems-2021-0009

ABSTRACT Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of inherited lysosomal storage disorders characterized by the intracellular accumulation of ceroid-lipofuscin compounds and neurodegeneration. Fourteen genes are currently recognized with disease-causing DNA variants: PPT1/CLN1, TPP1/CLN2, CLN3, DNAJC5/CLN4, CLN5, CLN6, MFSD8/CLN7, CLN8, CTSD/CN10, GRN/CLN11, ATP13A2/CLN12, CTSF/CLN13, KCTD7/CLN14, TBCK/CLN15. In the frame of the Cordoba cohort, we studied N=51 cases. The aim of this paper is the observational and retrospective analysis of the “atypical” phenotypes. PCR-Sanger sequencing and/or massive exome sequencing were used as a screening methodology. One CLN1 subject showed an atypical prolonged (P) phenotype with null PPT1 activity and a heterozygous compound genotype: E5 c.451C>T, p.Arg151*/g.6302T>G (I3 c.363-3T>G). Other 11 CLN2 individuals (except one girl) showed TPP1 activity decreased to around 10% of the minimum value of the reference interval in leukocytes and saliva. The DNA variants E7 c.827A>T, p.Asp276Val and I7 c.887-10A>G were the most prevalent. One CLN8 individual showed an atypical congenital phenotype with a heterozygous combination of DNA variants: E2 c.1A>G, p.?/E3 c.792C>G, p.Asn264Lys. Massive sequencing was installed as a screening methodology for the precision diagnosis of atypical CLN1, CLN2, and CLN8 phenotypes. A genetic/phenotypic local registry is under construction.