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

Abstract

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 0.60-15.85 nmol/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.

• Authors: Romina Kohan, María Noelia Carabelos, Winnie Xin, Katherine Sims, Norberto Guelbert, Inés Adriana Cismondi, Patricia Pons, Graciela Irene Alonso, Mónica Troncoso, Scarlet Witting, David A Pearce, Raquel Dodelson de Kremer, Ana María Oller-Ramírez, Inés Noher de Halac
• Journal: Gene (Gene) Vol. 516 Issue 1 Pg. 114-21 (Mar 01 2013) ISSN: 1879-0038 [Electronic] Netherlands
• PMID: 23266810 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Tripeptidyl-Peptidase 1
• Serine Proteases
• Aminopeptidases
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• TPP1 protein, human

Topics

• Adolescent
• Adult
• Alleles
• Alternative Splicing
• Aminopeptidases (genetics, metabolism)
• Argentina
• Child
• Child, Preschool
• Computational Biology
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (genetics, metabolism)
• Female
• Humans
• Introns
• Male
• Microscopy, Electron, Transmission
• Mutation
• Neuronal Ceroid-Lipofuscinoses (enzymology, genetics, pathology)
• Pedigree
• Phenotype
• Prospective Studies
• Reproducibility of Results
• Retrospective Studies
• Serine Proteases (genetics, metabolism)
• South America
• Tripeptidyl-Peptidase 1
• Young Adult