Abstract
ABSTRACT Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of inherited lysosomal storage disorders characterized by the intracellular accumulation of ceroid-lipofuscin compounds and neurodegeneration. Fourteen genes are currently recognized with disease-causing DNA variants: PPT1/CLN1, TPP1/CLN2, CLN3, DNAJC5/CLN4, CLN5, CLN6, MFSD8/CLN7, CLN8, CTSD/CN10, GRN/CLN11, ATP13A2/CLN12, CTSF/CLN13, KCTD7/CLN14, TBCK/CLN15. In the frame of the Cordoba cohort, we studied N=51 cases. The aim of this paper is the observational and retrospective analysis of the “atypical” phenotypes. PCR-Sanger sequencing and/or massive exome sequencing were used as a screening methodology. One CLN1 subject showed an atypical prolonged (P) phenotype with null PPT1 activity and a heterozygous compound genotype: E5 c.451C>T, p.Arg151*/g.6302T>G (I3 c.363-3T>G). Other 11 CLN2 individuals (except one girl) showed TPP1 activity decreased to around 10% of the minimum value of the reference interval in leukocytes and saliva. The DNA variants E7 c.827A>T, p.Asp276Val and I7 c.887-10A>G were the most prevalent. One CLN8 individual showed an atypical congenital phenotype with a heterozygous combination of DNA variants: E2 c.1A>G, p.?/E3 c.792C>G, p.Asn264Lys. Massive sequencing was installed as a screening methodology for the precision diagnosis of atypical CLN1, CLN2, and CLN8 phenotypes. A genetic/phenotypic local registry is under construction.
Highlights
Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of lysosomal storage diseases characterized by the intracellular accumulation of lipofuscin-like compounds.[1]
Study strategy (Figure 3): the clinical suspicion was emitted at any age based on the clinical signs and symptoms, studied through a set of clinical analysis, such as brain imaging (MRI), neurophysiology studies (EEG, OF, ERG, VEP, and others); transmission electronic microscopy (TEM), and light microscopy of a blood smear (LM), enzymology (PPT1 and tripeptidyl peptidase 1 (TPP1) activity measurement in leukocyte pellet, saliva, and dried blood spots [DBS]), and genomics according to our published algorithm, and to symptomatology.[8,27]
Short after the early observation of more than one of the clinical markers of the NCL diseases, massive genomic analysis is performed with parallel palmitoyl protein thioesterase 1 (PPT1) and TPP1 enzyme assays and clinical evaluation through electrophysiological and image analyses of eyes and brain
Summary
Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of lysosomal storage diseases characterized by the intracellular accumulation of lipofuscin-like compounds.[1] Even though these accumulations can be observed in all cells, neurons are the most affected, resulting in neuronal death and neurodegenerative syndrome. There is no cure for these disorders, except a treatment for one of the forms (CLN2 disease) approved in 2017 by the US Food and Drug Administration (https://www.ninds.nih.gov/disorders/patientcaregiver-education/fact-sheets/batten-disease-fact-sheet).[3] In most NCL forms, the affected individuals die prematurely around the second or third decade of life. Variations in the life span occur in the different forms.[4]. Científicas y Técnicas, Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas, Campus Universitario UCC, Av. Armada Argentina, 3555, 5017, Córdoba, Argentina. 7 Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Centro de Microscopía Electrónica, Bv. de la Reforma y Enfermera Gordillo, Ciudad Universitaria, 5016, Córdoba, Argentina Armada Argentina, 3555, 5017, Córdoba, Argentina. 7 Universidad Nacional de Córdoba, Facultad de Ciencias Médicas, Centro de Microscopía Electrónica, Bv. de la Reforma y Enfermera Gordillo, Ciudad Universitaria, 5016, Córdoba, Argentina
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