DO: 0110733;
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 (Mole et al., 2005).
For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (256730).
Schulz et al. (2004) described a ninth variant of juvenile-onset neuronal ceroid lipofuscinosis in 2 Serbian sisters and 2 German brothers. The sisters, whose great-grandmothers came from adjacent villages, developed declining vision, progressive ataxia, and seizures by age 4 years. By age 10 years, they could not walk independently and became mute. The 2 brothers showed a similar course as the sisters, presenting at age 4 years with declining vision and seizures. Cognitive decline was apparent at age 6 years, ataxia and rigidity occurred at age 9 years, and they were mute by age 12 years. The younger brother died at age 15 years following pneumonia, and the older brother, who later had hallucinations and dysphagia, died at age 19 years. All patients had slowed EEGs with polyspike wave discharges. Laboratory studies in 1 of the brothers showed neurons ballooned with autofluorescent fine granular material. A brain biopsy from 1 sister showed neurons with granular and curvilinear bodies. Fibroblasts from all patients were small and rounded with prominent nucleoli, attached poorly, and were highly apoptotic. They showed increased DNA synthesis and increased expression of several cyclins. Patient fibroblasts also showed a decrease in ceramide, sphingomyelin, lactosylceramide, ceramide trihexoside, and globoside, indicating a perturbation of sphingolipid metabolism. Enzyme screening and genetic testing ruled out other NCL types and lysosomal storage disorders.
Schulz et al. (2006) found that fibroblasts derived from patients with neuronal ceroid lipofuscinosis-9 showed markedly decreased levels of dihydroceramide and decreased dihydroceramide synthase activity. The cells showed partial correction of growth defects and apoptosis when transfected with CLN8 (607837) and several human LASS genes (see, e.g., LASS1; 606919), all of which increase dihydroceramide synthase activity. Schulz et al. (2006) concluded that the CLN9 protein may be a regulator of dihydroceramide synthase.
The transmission pattern of CLN9 in the families reported by Schulz et al. (2004) was consistent with autosomal recessive inheritance.
In affected sibs from 1 of the families reported by Schulz et al. (2004), El Haddad et al. (2012) identified a homozygous nonsense mutation in the CLN5 gene (Q232X; 608102.0010). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. This family was thus reclassified as having neuronal ceroid lipofuscinosis-5 (CLN5; 256731). The same region of homozygosity on chromosome 13 was found uniquely in probands of the second family; however, exon and promoter sequencing in the second family did not reveal mutations in the CLN5 gene, suggesting that the mutation is probably intronic or in a different gene altogether.
El Haddad, S., Khoury, M., Daoud, M., Kantar, R., Harati, H., Mousallem, T., Alzate, O., Meyer, B., Boustany, R.-M. CLN5 and CLN8 protein association with ceramide synthase: biochemical and proteomic approaches. Electrophoresis 33: 3798-3809, 2012. [PubMed: 23160995] [Full Text: https://doi.org/10.1002/elps.201200472]
Mole, S. E., Williams, R. E., Goebel, H. H. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 6: 107-126, 2005. [PubMed: 15965709] [Full Text: https://doi.org/10.1007/s10048-005-0218-3]
Schulz, A., Dhar, S., Rylova, S., Dbaibo, G., Alroy, J., Hagel, C., Artacho, I., Kohlschutter, A., Lin, S., Boustany, R.-M. Impaired cell adhesion and apoptosis in a novel CLN9 Batten disease variant. Ann. Neurol. 56: 342-350, 2004. [PubMed: 15349861] [Full Text: https://doi.org/10.1002/ana.20187]
Schulz, A., Mousallem, T., Venkataramani, M., Persaud-Sawin, D.-A., Zucker, A., Luberto, C., Bielawska, A., Bielawski, J., Holthuis, J. C. M., Jazwinski, S. M., Kozhaya, L., Dbaibo, G. S., Boustany, R.-M. N. The CLN9 protein, a regulator of dihydroceramide synthase. J. Biol. Chem. 281: 2784-2794, 2006. [PubMed: 16303764] [Full Text: https://doi.org/10.1074/jbc.M509483200]