An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients

Centre for the Study of Inherited Metabolic Diseases (CEMECO), Children's Hospital, School of Medicine, National University Cordoba, Cordoba, Argentina.
Clinical Genetics (Impact Factor: 3.93). 10/2009; 76(4):372-82. DOI: 10.1111/j.1399-0004.2009.01214.x
Source: PubMed


The neuronal ceroid lipofuscinoses (NCLs) are a family of progressive neurodegenerative diseases that are characterized by the cellular accumulation of ceroid lipofuscin-like bodies. NCL type 1 (CLN1) and type 2 (CLN2) are caused by deficiencies of the lysosomal enzymes palmitoyl-protein thioesterase 1 (PPT-1) and tripeptidyl peptidase 1 (TPP-1), respectively. In this study, 118 Latin American patients were examined for NCL using an integrated multidisciplinary program. This revealed two patients affected by CLN1 and nine by CLN2. Both CLN1 patients had a juvenile-onset phenotype with mutation studies of one patient demonstrating the known mutation p.Arg151X and a novel mutation in intron 3, c.363-3T>G. Six of the CLN2 patients presented with the 'classical' late-infantile phenotype. The remaining three patients, who were siblings, presented with a 'protracted' phenotype and had a higher level of residual TPP-1 activity than the 'classical' CLN2 patients. Genotype analysis of the TPP1 gene in the 'classical' CLN2 patients showed the presence of the known mutation p.Arg208X and the novel mutations p.Leu104X, p.Asp276Val, and p.Ala453Val. The siblings with the 'protracted' phenotype were heterozygous for two known TPP1 mutations, p.Gln66X and c.887-10A>G. This multidisciplinary program is also being used to diagnose other NCL types.

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Available from: Inés Noher de Halac, Mar 20, 2014
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    • "I2, c.89 + 5G N C [63] E3, p.Gln66* [54] E4, p.Leu104* [4] [64] I5, c.509-1G N C [54] b E6, p.Arg208* [54] b E7, p.Asp276Val [4] I7, c.887-10A N G [65] E8, p.Arg339Gln [63] E8, p.Glu343Asp [this publication] E8, p.Arg350Trp [32] E9, c.1107-1108delTG [32] E11, p.Arg447His [54] E11, p.Ala453Val [4] E11, p. Ala453Asp [32] E11, p.Ser475Leu [54] E13, p.Gly535Arg [32] CLN3 n = 6 (11.6%) CLN3 disease, juvenile, n = 6 (4–7 y) Visual loss, rapidly progressing to blindness secondary to a pigmentary retinopathy; intellectual decline. "
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    ABSTRACT: The Argentinean program was initiated more than a decade ago as the first experience of systematic translational research focused on NCL in Latin America. The aim was to overcome misdiagnoses and underdiagnoses in the region. 216 NCL suspected individuals from 8 different countries and their direct family members. Clinical assessment, enzyme testing, electron microscopy, DNA screening. 1) The study confirmed NCL disease in 122 subjects. Phenotypic studies comprised epileptic seizures and movement disorders, ophthalmology, neurophysiology, image analysis, rating scales, enzyme testing, and electron microscopy, carried out under a consensus algorithm; 2) DNA screening and validation of mutations in genes PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), and CLN8: characterization of variant types, novel/known mutations and polymorphisms; 3) Progress of the epidemiological picture in Latin America; 4) NCL-like pathology studies in progress. The Translational Research Program was highly efficient in addressing the misdiagnosis/ underdiagnosis in the NCL disorders. The study of "orphan diseases" in a public administrated hospital should be adopted by the health systems, as it positively impacts upon the family's quality of life, the collection of epidemiological data, and triggers research advances. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease). Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; 1852(10 Pt B). DOI:10.1016/j.bbadis.2015.05.003 · 4.66 Impact Factor
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    • "For those mutations, it is worthwhile to study RNA to verify the predicted truncating effect. Another category of variant are those located within the active site of the protein (c.827A>T [Kohan et al., 2009], c.1424C>T [Sleat et al., 1999]), so even a minor change might affect the function of the protein significantly. "
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    ABSTRACT: Spinocerebellar ataxias are phenotypically, neuropathologically and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1-variants to SCAR7. In spite of the limited sample size and measurements a putative genotype-phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, while variants that diminish TPP1 enzyme activity lead to SCAR7.
    Human Mutation 05/2013; 34(5). DOI:10.1002/humu.22292 · 5.14 Impact Factor
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    • "We profiled the phenotypes and genotypes of 25 CLN2 individuals (n= 9 retrospective (Kohan et al., 2009) and n = 16 prospective) belonging to Argentinean and Chilean families. Controls for enzyme and molecular studies were obtained from volunteer donors from a similar ethnic population. "
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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 0.60-15.85nmol/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.
    Gene 12/2012; 516(1). DOI:10.1016/j.gene.2012.12.058 · 2.14 Impact Factor
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