title: 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.affiliation: Centro de Estudio de las Metabolopatías Congénitas (CEMECO), Cátedra de Clínica Pediátrica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Ferroviarios 1250, (5014) Córdoba, Argentina.
authors.forename: Romina
authors.initials: R
authors.lastname: Kohan
authors.forename: María Noelia
authors.initials: MN
authors.lastname: Carabelos
authors.forename: Winnie
authors.initials: W
authors.lastname: Xin
authors.forename: Katherine
authors.initials: K
authors.lastname: Sims
authors.forename: Norberto
authors.initials: N
authors.lastname: Guelbert
authors.forename: Inés Adriana
authors.initials: IA
authors.lastname: Cismondi
authors.forename: Patricia
authors.initials: P
authors.lastname: Pons
authors.forename: Graciela Irene
authors.initials: GI
authors.lastname: Alonso
authors.forename: Mónica
authors.initials: M
authors.lastname: Troncoso
authors.forename: Scarlet
authors.initials: S
authors.lastname: Witting
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
authors.forename: Raquel
authors.initials: R
authors.lastname: Dodelson de Kremer
authors.forename: Ana María
authors.initials: AM
authors.lastname: Oller-Ramírez
authors.forename: Inés
authors.initials: I
authors.lastname: Noher de Halac
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D017398:Alternative Splicing; D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism; D001118:Argentina; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D015203:Reproducibility of Results; D012189:Retrospective Studies; D057057:Serine Proteases / Q000235:genetics* / Q000378:metabolism; D013020:South America; D000091346:Tripeptidyl-Peptidase 1; D055815:Young Adult
chemical_list: D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human