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

Abstract

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.

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.…”

“…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.…”

“…Noticeable is that the individual with 0% of activity in all the tested samples is a living boy now 21 years old with a juvenile phenotype [4,52] (Table 3). Because of the small number of patients, percentages of enzyme activities could not be valuated regarding the correlation with phenotypes.…”

Myoclonic Epilepsy in Lysosomal Storage Disorders

“…Epilepsy appears later, becoming rapidly intractable and accompanied with cognitive loss, myoclonic jerks and retinopathy. Patient autonomy is completely lost within the age of 6-8 and death occurs within adolescence period (Zhong et al, 2000;Steinfeld et al, 2002;Kohan et al, 2009). Two major distinct phenotypes have been described for classical juvenile phenotype of NCL3 (Batten disease), according to the patient's genotype: a. patients carrying the 1-kb deletion in homozygous, (firstly described in Finland and Northern Europe), and b. patients carrying a compound of 1-kb deletion with other mutations (Munroe et.…”

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

“…It is now recognized that mutations in all genes are distributed across many countries, albeit with higher incidence in some ethnic groups due to founder effects. Among the many recognized variants of NCL human forms (recent reviews in [3,6,11]), eight causal genes have been identified: CLN10/CTSD [12][13][14], CLN1/PPT1 [3,6,[15][16][17][18], CLN2/TPP1 [6,[18][19][20][21], CLN3 [22][23][24][25], CLN5 [26][27][28][29][30], CLN6 [31][32][33][34], CLN7/ MFSD8 [35][36][37][38][39], CLN8 [40][41][42]. The genes CLCN6 [43], and CLCN7 [44], and possibly SGSH [45], may also contribute to rare forms of NCL.…”