Neuronal ceroid lipofuscinosis type CLN2: A new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America |
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Authors: | Romina Kohan,Marí a Noelia Carabelos,Winnie Xin,Katherine Sims,Norberto Guelbert,Iné s Adriana Cismondi,Patricia Pons,Graciela Irene Alonso,Mó nica Troncoso,Scarlet Witting,David A. Pearce,Raquel Dodelson de Kremer,Ana Marí a Oller-Ramí rez,Iné s Noher de Halac |
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Affiliation: | 1. 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;2. Facultad de Odontología, Universidad Nacional de Córdoba. Haya de la Torre s/n, (5000) Córdoba, Argentina;3. Secretaría de Ciencia y Tecnología (SECyT), Universidad Nacional de Córdoba. Juan Filloy s/n, (5000) Córdoba, Argentina;4. Massachussets General Hospital, Neurogenetics DNA Diagnostic Laboratory, Simches Research Building, 5 300, 185 Cambridge St., Boston, MA 02114, USA;5. Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Haya de la Torre esq. Enrique Barros, 1º piso, (5000) Córdoba, Argentina;6. Servicio de Neuropsiquiatría Infantil. Hospital Clínico San Borja Arriarán, Avenida Santa Rosa 1234, Santiago, Chile;g Sanford Childrens Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota, USA;h Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Rivadavia 1917, C1033AAJ CABA, Argentina |
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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. |
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Keywords: | CB, curvilinear body DBS, dried blood spot FP, fingerprint profile GROD, granular osmiophilic deposit J-NCL, juvenile NCL LD, lysosomal disorder LI-NCL, late-infantile NCL NCLs, neuronal ceroid lipofuscinoses PDB, protein data bank PolyPhen-2, polymorphism phenotyping-2 PPT1, palmitoyl protein thioesterase 1 RB, rectilinear body SIFT, sorting intolerant from tolerant SNP, single nucleotide polymorphism TEM, transmission electron microscopy TPP1, tripeptidyl-peptidase 1 vI-NCL, variant infantile NCL vJ-NCL, variant juvenile NCL |
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