Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America

• Published in: Gene Vol. 516; no. 1; pp. 114 - 121
• Main Authors: Kohan, Romina, Carabelos, María Noelia, Xin, Winnie, Sims, Katherine, Guelbert, Norberto, Cismondi, Inés Adriana, Pons, Patricia, Alonso, Graciela Irene, Troncoso, Mónica, Witting, Scarlet, Pearce, David A., Dodelson de Kremer, Raquel, Oller-Ramírez, Ana María, Noher de Halac, Inés
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2013
• Subjects: Adolescent; Adult; Alleles; Alternative Splicing; Aminopeptidases - genetics; Aminopeptidases - metabolism; Argentina; Child; Child, Preschool; Computational Biology; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - metabolism; disease course; enzyme activity; Female; heterozygosity; Humans; Introns; leukocytes; Male; Microscopy, Electron, Transmission; Mutation; Mutational spectrum; Neuronal ceroid lipofuscinoses; Neuronal Ceroid-Lipofuscinoses - enzymology; Neuronal Ceroid-Lipofuscinoses - genetics; Neuronal Ceroid-Lipofuscinoses - pathology; patients; Pedigree; Phenotype; Prospective Studies; Reproducibility of Results; Retrospective Studies; Serine Proteases - genetics; Serine Proteases - metabolism; South America; South American population; surveys; TPP1/CLN2 gene; Tripeptidyl-Peptidase 1; Young Adult; South America; Argentina; GROD; SIFT; FP; vI-NCL; LI-NCL; PDB; PolyPhen-2; RB; Phenotype; South American population; DBS; SNP; Tripeptidyl-peptidase 1; LD; NCLs; PPT1; TPP1; vJ-NCL; Mutational spectrum; J-NCL; TEM; TPP1/CLN2 gene; CB; Neuronal ceroid lipofuscinoses
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2012.12.058

Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60–15.85nmol/h/mg (nr 110–476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887−10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at non-conserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity. ► CLN2 is the most frequent neuronal ceroid lipofuscinosis in South America. ► Two CLN2 groups have been recognized: I-null TPP1 activity; II-residual TPP1 activity. ► The variant juvenile phenotype comprises approximately 50% of CLN2 in South America. ► Slight residual TPP1 activity had an effect on the attenuation of the phenotype. ► The five most frequent South American mutations comprise 66% of pathological alleles.