Clinicopathological and molecular characterization of neuronal ceroid lipofuscinosis in the Portuguese population

Abstract

A series of 53 Portuguese patients (derived from 43 families) born in the period 1963-1999 have been diagnosed with neuronal ceroid lipofuscinosis (NCL) based on clinicopathological findings. Plotting the cumulative number of new cases per year against the year of birth resulted in a slightly S-shaped curve, with a nearly straight central segment over a period of 14 years (1977-1990) indicating a continuous registration of new cases born during the corresponding time period. In this period the prevalence of overall NCL in the Portuguese population was calculated to be 1.55 per 100.000 live births.Twenty-six patients from 20 unrelated families were further evaluated by combining clinicopathological with biochemical and genetic data. No intra-familial heterogeneity was observed. Four sub-types of childhood NCL were identified: infantile NCL (INCL) with granular osmiophilic inclusions (GROD) and PPT1 deficiency (1/26), classical LINCL with curvilinear (CV) inclusions and tripeptidyl peptidase (TPP1) deficiency (3/26), variant late infantile NCL (LINCL) with fingerprint/curvilinear (FP/CV) inclusions and normal TPP1 enzyme activity (11/26) and juvenile NCL (JNCL) with a mix of FP/CV (11/26). Eight of 11 JNCL patients were homozygous for the 1.02-kb deletion in the CLN3 gene, and 3 were heterozygous with an unidentified mutation in the second allele. The 1.02-kb deletion in the CLN3 gene accounted for 86.3 % (19/22) of CLN3-causing alleles and 36.5 % (19/52) of childhood NCL defects. The causal mutations for CLN1 and CLN2 were V181M (2/2) and R208X (4/6), respectively. CLN1, CLN2 and CLN3 affected 3.8 %, 11.5 % and 42.3 % of NCL Portuguese patients, respectively. In 42.3 % of patients affected by the vLINCL form, CLN3, CLN5 and CLN8 gene defects were excluded by direct sequencing of cDNA. Genetic variants such as CLN6 might therefore cause a significant portion of childhood NCL in the Portuguese population. The relative frequency of classical childhood forms of NCL in the Portuguese population is reported and contributes to the knowledge of genetic epidemiology of these world-widely distributed disorders.

Infantile neuronal ceroid lipofuscinosis: Follow-up on a Spanish series

“…Our series of six patients with INCL is in agreement with other published cases from southern European countries and USA (Baumann and Markesbery, 1982;Cardona and Rosati, 1995;Santorelli et al, 1998;Teixeira et al, 2003;Veneselli et al, 2000).…”

“…There is at present a strategy for the diagnosis of the NCLs (Kohan et al, 2009) and an international online clinical registry for genotype/phenotype correlation: http://www.ucl.ac.uk/ncl. The p.Val181Met mutation in CLN1 gene which has been previously described (Das et al, 2001;Teixeira et al, 2003) was found in homozygosis in family 3. Moreover, the clinical features and the evolution of the disease in our patients confirm that p.Val181Met mutation is associated with the most severe INCL phenotype when present in the homozygous state.…”

A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

“…The most common mutation in CLN6, which leads to vLINCL, results from the insertion of an additional cytosine at base pair 307 in exon 4, leading to a frameshift and premature stop codon. vLINCL disease onset occurs between 18 months and eight years of age, with symptoms of motor delay, vision loss, dystharthia, and ataxia followed by premature death during the second decade of life [16], [17].…”

A clinical rating scale for Batten disease

“…[3][4][5] A number of studies have focused on specific clinical features [6][7][8][9][10][11][12][13][14][15][16] or correlated such features with molecular, pathologic, or imaging characteristics. [17][18][19][20][21][22][23] Therapeutic studies have targeted specific symptoms rather than overall disease progression. [24][25][26][27][28] A scoring system has been used to characterize a small number of patients, but no data are published regarding its interrater reliability.…”