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 nonconserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity.

The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina

“…With the exception of PPT1 and TPP1 [4,32], the molecular data of this paper reflect new published results for the other genotypes. Additional data on DNA variants throughout the world are compiled at https://www.ucl.ac.uk/ncl/mutation.shtml.…”

“…Residual TPP1 activity was demonstrable in leukocytes and saliva, but not in DBS (Table 2). CLN2 disease, juvenile variant phenotypes were more frequently described than expected through the literature (37.5% of the cases), in several cases correlating with residual TPP1 enzyme activity, especially when measured in blood or saliva [4,32]. The heterozygous combination of intronic mutations in nonconsensus sites with missense/nonsense mutations correlated with the residual TPP1 activity [32].…”

“…Complex heterozygosity predominated in our cohort of patients in all the studied genes. Correlations between compound heterozygosity and protracted phenotypes were described for many NCL forms [32,[77][78][79].…”

“…Transmission electron microscopy (EM) confirmed a presumed NCL disease when typical lipofuscin bodies were seen in skin biopsies: granular osmiophilic deposits (GRODs) in CLN1, curvilinear bodies (CL) in CLN2, and fingerprint profiles (FP) in CLN3 [4,6,32]. Variant morphologies were observed in the remaining genotypes.…”

“…To simplify the future genetic analysis of TPP1-deficient patients in our region, we might consider ruling out E7 p.Asp276Val, I7 c.887−10A>G, E6 p.Arg208*, E3 p.Gln66* and E4 p.Leu104* before starting costly complete TPP1 screening. At present, these five most common Latin American mutations comprise 64.8% of the detected pathological alleles [32]. Rare Diseases epidemiology is a novel action field still largely unexplored.…”