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.
[Show abstract] [Hide abstract] ABSTRACT: Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.0Comments 4Citations
- "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 , . "
- "Indian patients have identified five private CLN6 mutations in an equal number of families, suggesting that CLN6 defects have not been established by a common ancestor in India (Sharp et al., 2003; Wheeler et al., 2002; Teixeira et al., 2003; Table 8). Moreover, the identification of two Indian patients with MFSD8 mutations (Siintola et al., 2007; Table 9) provides further support that Indian LINCL was not established by a founder, but instead is genetically heterogeneous. "
[Show abstract] [Hide abstract] ABSTRACT: A 31-year-old woman presented with dyspnea and left-sided chest discomfort and was found to have biventricular heart failure with impaired ventricular filling. Clinically, she was thought to have restrictive cardiomyopathy or constrictive pericarditis. Transmission electron microscopy of myocardial tissue unexpectedly revealed crosshatched, curvilinear, and fingerprint depositions, which were characteristic for neuronal ceroid lipofuscinosis. Cardiac involvement by this inherited disorder is discussed in light of the findings in this patient and in 15 other reported cases.0Comments 6Citations
- "Cerebral cortical involvement typically correlates with progressive degenerative processes that lead to visual loss, decline in cognitive acuity, and chronic epileptic activity345. Occurrence of the disorder varies regionally, as demonstrated by rates of 1.3, 1.55, and 2.0–7.0 per 100,000 live births in the Czech Republic, Portuguese, and Scandinavian populations, respectively678. The relative occurrence is likely to be higher in areas with high rates of consanguineous marriages . "