LINCL, INCLUDED
CEROID LIPOFUSCINOSIS, NEURONAL, 2, VARIABLE AGE AT ONSET
JANSKY-BIELSCHOWSKY DISEASE NEURONAL CEROID LIPOFUSCINOSIS, LATE INFANTILE, INCLUDED
CLN2
The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and ... The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure. The lipopigment pattern seen most often in CLN2 consists of 'curvilinear' profiles (Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
MacLeod et al. (1985) reported on the successful prenatal diagnosis of this form of NCL. A fetus was studied by electron microscopy at 16 weeks of gestation because of an affected sib. About ... - Prenatal Diagnosis MacLeod et al. (1985) reported on the successful prenatal diagnosis of this form of NCL. A fetus was studied by electron microscopy at 16 weeks of gestation because of an affected sib. About one-third of a subpopulation of dark, elongated amniotic fluid cells contained one or more deposits of curvilinear cytosomes bound by a single unit membrane. After delivery at term, a punch biopsy and buffy coat preparation from the baby showed similar characteristic inclusions. Berry-Kravis et al. (2000) used mutation analysis for prenatal diagnosis. Previously, prenatal testing for LINCL had been accomplished through electron microscopic examination of uncultured amniocytes for typical curvilinear bodies. They reported success in 2 cases and described a new private mutation in the CLN2 gene in one of the families (607998.0006).
Hassin (1926) reviewed the pathology of late infantile NCL. Seitelberger et al. (1957) collected 28 cases from the world's literature. Some cases reported as LINCL may have been instances of generalized gangliosidosis (Donahue et al., 1967).
... Hassin (1926) reviewed the pathology of late infantile NCL. Seitelberger et al. (1957) collected 28 cases from the world's literature. Some cases reported as LINCL may have been instances of generalized gangliosidosis (Donahue et al., 1967). Gonatas et al. (1968) described the gross and microscopic findings in LINCL. Brain weight was severely diminished and there was neuronal loss as well as intraneuronal accumulation of an eosinophilic material. Ultrastructural examination showed curvilinear bodies of a lysosomal nature. The characteristic inclusions may be found in other tissue types. On the basis of electron microscopic findings of 'multilamellar cytosomes,' Gonatas et al. (1968) suggested that 2 cases they studied and 4 cases reported by others represented a different type of late infantile cerebral lipidosis. Elfenbein and Cantor (1969) and Richardson and Bornhofen (1968) also reported cases of LINCL with multilamellar cytosomes. By electron microscopy, Dolman and Chang (1972) found curvilinear bodies not only in the central and autonomic nervous system but also in the cells of virtually every organ examined. In the provinces of Quebec and Newfoundland, Andermann et al. (1977) ascertained 46 cases of cerebromacular degeneration (CMD) in 30 sibships: 27 cases of late infantile CMD (Jansky-Bielschowsky), 17 cases of juvenile CMD (Spielmeyer-Vogt), and 2 cases in 1 family of the adolescent form (Kufs) (204300). Two-thirds were Newfoundlanders of Anglo-Saxon descent. Andermann et al. (1988) described further the Newfoundland aggregate of LINCL. Age of onset was 2.5 to 3.5 years with seizures, rapid mental deterioration, ataxia, dementia, and quadriparesis. Retinal blood vessels were narrowed and optic atrophy was common. Ultrastructural study showed curvilinear profiles. Taratuto et al. (1995) reported 24 cases of LINCL that had been diagnosed in Argentina from 1985 to 1993. Age of onset ranged from 1 to 6 years (mean 3.1). The clinical findings were homogeneous, including refractory epilepsy, mental regression and deterioration, ataxia, myoclonus, and visual loss. Affected patients demonstrated abnormal electroretinography (ERG), visual evoked potentials (VEP), and electroencephalograms (EEG). Brain biopsies from 3 patients showed neuronal loss, distended neurons with granular PAS-positive material, and curvilinear inclusions on electron microscopy. Children affected with LINCL have retinal degeneration which is most visible in the macula, and the entire retina is involved as reflected by extinction of the electroretinogram (ERG) early in the disease (Brodsky et al., 1996). The cherry red spot typical of the infantile form of Tay-Sachs disease (272800) is not observed. Usual features are a strikingly enlarged VEP and large photically driven spikes on EEG.
Steinfeld et al. (2002) described the natural progression of LINCL in 22 German patients with CLN2 mutations, using a scoring system that allowed quantification of the motor, visual, and verbal performances over long periods of time. Sixteen of ... Steinfeld et al. (2002) described the natural progression of LINCL in 22 German patients with CLN2 mutations, using a scoring system that allowed quantification of the motor, visual, and verbal performances over long periods of time. Sixteen of the patients, who were grouped together in the study, were homozygous or compound heterozygous for common mutations that result in complete loss of enzymatic activity. Bessa et al. (2008) reported a 40-year-old Portuguese man with a mild protracted form of CLN2 who was homozygous for a mutation that created a potential acceptor site in intron 7 of the TPP1 gene (IVS7AS-10A-G; 607998.0009), predicted to result in a protein with 3 extra amino acids between codons 295 and 296 and not affecting the wildtype splice site. The patient had onset at age 10 years of progressive cognitive and motor dysfunction and seizures. Western blot analysis detected a 60% reduction in overall TPP1 protein levels, suggesting that the mutant protein had decreased stability. Bessa et al. (2008) concluded that the mutant protein retained enzyme activity, which was consistent with the milder phenotype.
In 2 unrelated patients with LINCL, Sleat et al. (1997) identified mutations in the CLN2 gene (607998.0001 and 607998.0002).
Zhong et al. (1998) screened 16 LINCL probands for 4 previously described CLN2 mutations. The intronic mutation ... In 2 unrelated patients with LINCL, Sleat et al. (1997) identified mutations in the CLN2 gene (607998.0001 and 607998.0002). Zhong et al. (1998) screened 16 LINCL probands for 4 previously described CLN2 mutations. The intronic mutation IVS5-1G-C (607998.0004) was found in 9 of the 16 patients, of whom 2 were homozygous, and accounted for 34% (11 of 32) of CLN2 chromosomes. A nonsense mutation (607998.0003) was found in 31% (5 of 16) of the patients, including 1 homozygote, and accounted for 19% (6 of 32) of the CLN2 chromosomes. Together, one or both of these mutations were seen in 11 (69%) cases. The 2 other missense mutations were not found in any of the 16 probands, and no mutation was identified in 5. To better understand the molecular pathology of LINCL, Sleat et al. (1999) conducted a genetic survey of the CLN2 gene in 74 LINCL families. In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL. Both pathogenic alleles were identified in 57 of the other 60 LINCL families studied. In total, 24 mutations were associated with LINCL, comprising 6 splice junction mutations, 11 missense mutations, 3 nonsense mutations, 3 small deletions, and 1 single-nucleotide insertion. Two previously reported mutations were particularly common: a splice junction mutation (607998.0004), found in 38 of 115 alleles, and a stop mutation (607998.0003), found in 32 of 115 alleles.
Moore et al. (2008) observed extensive genetic heterogeneity for NCL in Newfoundland. In total, 52 patients from 34 families were identified clinically. Of the 28 families with available DNA, 18 had 5 different mutations in the CLN2 gene ... Moore et al. (2008) observed extensive genetic heterogeneity for NCL in Newfoundland. In total, 52 patients from 34 families were identified clinically. Of the 28 families with available DNA, 18 had 5 different mutations in the CLN2 gene (see, e.g., 607998.0007). One family had a CLN3 mutation (607042.0001), another had a CLN5 mutation (608102.0005), and 5 families shared the same mutation in CLN6 (606725.0010). One family was misdiagnosed, and molecular testing was inconclusive in 2 families. Patients with CLN2 had an earlier presentation and seizure onset compared to those with CLN6 mutations. There was a slower clinical course for those with CLN5 mutations compared with CLN2 mutations. Moore et al. (2008) estimated that NCL in Newfoundland has an incidence of 1 in 7,353 live births. The incidence of CLN2 was 9.0 per 100,000, or 1 in 11,161 live births, the highest reported in the world.