CLN2 is the most frequent NCL in latin america. Update of the phenotypes and mutational spectrum.

ROMINA KOHAN, MARÍA NOELIA CARABELOS, INÉS ADRIANA CISMONDI, NORBERTO GUELBERT, VERÓNICA TAPIA ANZOLINI, GRACIELA ALONSO, WINNIE XIN, KATHERINE SIMS, DAVID A. PEARCE, RAQUEL DODELSON DE KREMER, ANA MARÍA OLLER-RAMÍREZ, INÉS NOHER DE HALAC

London,UK

Congreso; 13th International Conference on Neuronal Ceroid Lipofusinoses(Batten Disease) & Patient Organisation Meeting; 2012

13th International Conference on Neuronal Ceroid Lipofusinoses(Batten Disease) & Patient Organisation Meeting

The Neuronal Ceroid Lipofuscinoses (NCLs) are metabolic lysosomal disorders characterized by the intracellular accumulation of autofluorescent ceroid-lipofuscin like bodies in peripheral tissues and in the brain. Ten human disease genes have been identified: CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN4/DNAJC5, CLN5, CLN6, CLN7/MFSD8, CLN8 and CLCN6, with more than 380 mutations and 49 polymorphisms reported (http://www.ucl.ac.uk/ncl). In the Center for the Study of Inborn Errors of Metabolism of the Children´s Hospital, Córdoba-Argentina 82 patients were diagnosed since 2003: CLN1 (2; 2.4%); CLN2 (23; 28.2%); CLN3 (6; 7.3%); CLN5 (2; 2.4%); CLN6 (2; 2.4%); CLN7 (3; 3.7%); CLN8 (2; 2.4%). The remaining 42 (51.2%) individuals showed clinical and electron microscopy data compatible with NCL but do not have molecular diagnosis. Among the 23 CLN2 patients, the majority (16, 69.6%) showed the classic phenotype but the remainder (7, 30.4%) evidenced a more protracted course. This juvenile phenotype was however clinically distinguishable from the JNCL “classical” CLN3, beginning with severe seizures at 5-9 years, residual TPP-I activity, and with visual decline appearing later on in the evolution of the disease; whilst the classical CLN3 generally initiates with visual impairment. The CLN2 mutation spectrum included: 6 new missense mutations, E7 p.Asp276Val, E8 p.Arg339Gln, E8 p.Arg350Trp, E11 p.Ala453Val, E11 p.Ala453Asp, and E13 p.Gly535Arg; 3 nonsense, including the new: E4 p.Leu104X and previously known, E6 p.Arg208X and E3 p.Gln66X; 3 known intronic, I2 c.89+5G>C, I5 c.509-1G>C and I8 c.887-10A>G; and 1 new deletion, E9 c.1107-1108delTG. The most frequent mutation (p.Asp276Val) was found in 15 alleles (35.7%). The next frequent mutations were the p.Arg208X in 4 alleles (9.5%), followed by p.Leu104X, p.Gln66X and c.887-10A>G in 3 alleles (7% each). The new missense changes were validated in 200 chromosomes of controls with same ethnicity by PCR and sequencing, restriction enzymes or ASO. The prediction of mutation pathogenicity was supported by analysis using bioinformatics resources: ClustalW2, PolyPhen-2, SIFT, PoPMusic 2.1, and PDB/PyMol 1.1. Founder effects were assumed for the most frequent mutations, and all others appeared private.