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

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.