Alternative titles; symbols
ORPHA: 168491, 79262; DO: 0110729;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q23 | Ceroid lipofuscinosis, neuronal, 6A | 601780 | Autosomal recessive | 3 | CLN6 | 606725 |
A number sign (#) is used with this entry because of evidence that neuronal ceroid lipofuscinosis-6A (CLN6A) is caused by homozygous or compound heterozygous mutation in the CLN6 gene (606725) on chromosome 15q23.
Biallelic mutation in the CLN6 gene can also cause juvenile or adult-onset CLN, known as Kufs disease (CLN6B; 204300).
Neuronal ceroid lipofuscinosis-6A (CLN6A) is an autosomal recessive neurodegenerative disorder with a variable age at onset in the first years of life after normal early development. Affected individuals have progressive decline of neurologic function, including visual deterioration in most, cognitive impairment, loss of motor function, and seizures. As with all CLNs, CLN6A is characterized pathologically by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN6A comprises mixed combinations of 'curvilinear' and 'fingerprint' profiles (summary by Sharp et al., 2003; Mole et al., 2005).
For a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
Historically, the CLNs were originally classified broadly by age at onset: CLN1 as the infantile-onset form, or the infantile-onset Finnish form, having first been described in that population; CLN2 as the late infantile-onset form; CLN3 as the juvenile-onset form; and CLN4 as the adult-onset form. With the identification of molecular defects, however, the CLNs are now classified numerically according to the underlying gene defect (Mole et al., 2005).
Sharp et al. (1997) studied 2 consanguineous families with a variant form of late infantile neuronal ceroid lipofuscinosis (vLINCL). Both families originated from the Indian subcontinent. The affected individuals demonstrated a similar clinical course to the classic late infantile form (CLN2; 204500), but their histology included storage bodies typical of both the CLN2 and juvenile (CLN3; 204200) forms: curvilinear bodies typical of CLN2 and fingerprint profiles more typical of CLN3. Haines et al. (1998) stated that the phenotype reported by Sharp et al. (1997) was similar to that described by Lake and Cavanagh (1978), who described an 'early-juvenile' form with onset around 5 years of age after normal early development. Features included ataxia, drop attacks, myoclonus, cognitive decline, loss of motor skills, abnormal eye movements, dementia, and pyramidal/extrapyramidal signs. Histology showed fingerprint profiles in patient neurons and smooth muscle cells.
Haines et al. (1998) studied 8 families from Costa Rica with variant late infantile NCL. The patients had onset between 5 and 7 years of age and lived until the middle of the second decade. Skin biopsies showed curvilinear bodies and lamellated membrane structures. The families were descendants of Spanish settlers in a small geographic region of Costa Rica.
Sharp et al. (2003) reported the clinical features of 26 families from 9 different countries with CLN6A confirmed by genetic analysis. Some of the patients and mutations had previously been reported. Disease onset ranged from 1.5 to 5 years of age. Seizures occurred between 3 and 6 years of age, although some had later onset. Progressive visual failure was observed between 3 and 6 years, loss of ambulation between 2 and 8 years, and death between 9 and 16.8 years. Several geographically related groups were described, including patients from Costa Rica, Portugal, Pakistan, and the Czech Republic, including Roma Gypsy families.
Siintola et al. (2005) reported a girl (patient 9124), born of unrelated Turkish parents (family 4), who had normal early motor development with mild language delay until age 4 years, when she developed dementia with loss of language, seizures with EEG abnormalities, and brain atrophy on MRI. Mixed curvilinear and fingerprint inclusions were found in skin biopsy. Two sibs in another consanguineous Turkish family (family 3) presented in early childhood with progressive neurodegenerative features, seizures, and cerebral and cerebellar atrophy.
Chin et al. (2019) reported 2 sibs and an unrelated patient with common features of CLN6A but without visual impairment. Proband 1 had symptom onset at 6 years of age with myoclonus, epilepsy, and developmental regression. Ataxia developed at age 8 years. Although she did not have visual impairment, she had enlargement of the optic nerve cup concerning for glaucoma. Brain MRI showed a thin corpus callosum, atrophy of the cerebellum, cerebral cortex and ventral pons, and enlargement of ventricles. Proband 2 had symptom onset at 6 years of age with developmental regression and an episode of psychosis. She developed epilepsy at age 6 years and myoclonus and ataxia between ages 6 and 8. Brain MRI showed periventricular white matter loss, abnormal signal in the occipital lobes, mild thinning of the corpus callosum, hypomyelination of the internal capsule, and mild cerebral cortex atrophy. The younger brother of proband 2 reportedly had developmental regression at age 5 years and ataxia, dysarthria, and cognitive regression, but no visual impairment, at age 12.
The transmission pattern of CLN6A in the families reported by Gao et al. (2002) was consistent with autosomal recessive inheritance.
By linkage analysis of 2 consanguineous Indian families with vLINCL, Sharp et al. (1997) identified a 12-cM critical region on chromosome 15q21-23, which was designated CLN6. A maximum total lod score of 6.0 was obtained at marker D15S1020 (theta = 0.00).
From haplotype and disequilibrium analyses of 8 families from a small geographic region in Costa Rica with vLINCL, Haines et al. (1998) identified a candidate region on chromosome 15q21-q23, close to the region identified by Sharp et al. (1997).
In 2 families with a variant form of LINCL, one from Costa Rica and the other from Venezuela, Gao et al. (2002) identified homozygous mutations in the CLN6 gene (E72X; 606725.0001 and tyr171del; 606725.0002, respectively). Wheeler et al. (2002) independently and simultaneously identified 6 different mutations in the CLN6 gene in patients with vLINCL (606725.0001; 606725.0003-606725.0007).
Sharp et al. (2003) identified 8 mutations in the CLN6 gene in patients with CLN6A, bringing to 18 the total number of CLN6 mutations found in this disorder. Ten mutations affected single amino acids, all of which are conserved across the vertebrate species. Minor differences in the pattern of disease symptom evolution could be identified. One patient with a more protected disease course was compound heterozygous for a missense mutation and an unidentified mutation. Fifteen mutations occurred in 1 or 2 families only, and families from the same country did not all share the same mutation. No major founder mutation was identified, but the E72X mutation (606725.0001) was significantly more common in patients in Costa Rica than 2 other mutations present in that same population. A group of Roma Gypsy families from the Czech Republic shared 2 disease associated haplotypes, one of which was also present in a Pakistani family, consistent with the proposed migration of the Roma from the Indian subcontinent 1,000 years ago.
Siintola et al. (2005) identified 2 different mutations in the CLN6 gene (606725.0008; 606725.0009) in affected members of 2 Turkish families with CLN6A. The findings indicated that a subset of patients with the so-called 'Turkish variant' of late infantile CLN (CLN7; see 600143) actually have CLN6A.
In 2 sibs and an unrelated patient with CLN6A without visual impairment, Chin et al. (2019) identified homozygous and compound heterozygous mutations in the CLN6 gene (606725.0015-606725.0017), respectively. The mutations were found by whole-exome sequencing.
Sharp et al. (2003) reported 26 families from 9 different countries with CLN6 confirmed by genetic analysis. Several geographically related groups were described, including patients from Costa Rica, Portugal, Pakistan, and the Czech Republic, including Roma Gypsy families. Although many families from Costa Rica shared the same nonsense mutation (E72X), families from the same country did not necessarily share the same mutation. There was also evidence of compound heterozygosity within ethnic groups and shared mutations or disease haplotypes among different ethnic groups, suggesting that this gene is highly mutable. The authors emphasized that CLN6 has a worldwide geographic distribution.
Broom et al. (1998) showed linkage of the naturally occurring OCL mutant in South Hampshire sheep, the best-described animal model of NCL, to a region syntenic to human chromosome 15q21-q23.
Nclf is a spontaneous mouse mutation causing a recessively inherited NCL-like disease with hallmark storage deposits, retinal atrophy, and paralysis (Bronson et al., 1998). Both Gao et al. (2002) and Wheeler et al. (2002) identified mutations in the Cln6 gene in the nclf mouse.
Bronson, R. T., Donahue, L. R., Johnson, K. R., Tanner, A., Lane, P. W., Faust, J. R. Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9. Am. J. Med. Genet. 77: 289-297, 1998. [PubMed: 9600738] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980526)77:4<289::aid-ajmg8>3.0.co;2-i]
Broom, M. F., Zhou, C., Broom, J. E., Barwell, K. J., Jolly, R. D., Hill, D. F. Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6. J. Med. Genet. 35: 717-721, 1998. [PubMed: 9733028] [Full Text: https://doi.org/10.1136/jmg.35.9.717]
Chin, J. J., Behnam, B., Davids, M., Sharma, P., Zein, W. M., Wang, C., Chepa-Lotrea, X., Gallantine, W. B., Toro, C., Adams, D. R. Tifft, C. J., Gahl, W. A., Malicdan, M. C. V. Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients. Molec. Genet. Metab. 126: 188-195, 2019. [PubMed: 30528883] [Full Text: https://doi.org/10.1016/j.ymgme.2018.12.001]
Gao, H., Boustany, R.-M. N., Espinola, J. A., Cotman, S. L., Srinidhi, L., Antonellis, K. A., Gillis, T., Qin, X., Liu, S., Donahue, L. R., Bronson, R. T., Faust, J. R., Stout, D., Haines, J. L., Lerner, T. J., MacDonald, M. E. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am. J. Hum. Genet. 70: 324-335, 2002. [PubMed: 11791207] [Full Text: https://doi.org/10.1086/338190]
Haines, J. L., Boustany, R.-M. N., Alroy, J., Auger, K. J., Shook, K. S., Terwedow, H., Lerner, T. J. Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis. Neurogenetics 1: 217-222, 1998. [PubMed: 10737126] [Full Text: https://doi.org/10.1007/s100480050032]
Lake, B. D., Cavanagh, N. P. C. Early-juvenile Batten's disease--a recognisable sub-group distinct from other forms of Batten's disease: analysis of 5 patients. J. Neurol. Sci. 36: 265-271, 1978. [PubMed: 650259] [Full Text: https://doi.org/10.1016/0022-510x(78)90087-4]
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]
Sharp, J. D., Wheeler, R. B., Lake, B. D., Savukoski, M., Jarvela, I. E., Peltonen, L., Gardiner, R. M., Williams, R. E. Loci for classical and a variant late infantile neuronal ceroid lipofuscinosis map to chromosomes 11p15 and 15q21-23. Hum. Molec. Genet. 6: 591-595, 1997. [PubMed: 9097964] [Full Text: https://doi.org/10.1093/hmg/6.4.591]
Sharp, J. D., Wheeler, R. B., Parker, K. A., Gardiner, R. M., Williams, R. E., Mole, S. E. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 22: 35-42, 2003. [PubMed: 12815591] [Full Text: https://doi.org/10.1002/humu.10227]
Siintola, E., Topcu, M., Kohlschutter, A., Salonen, T., Joensuu, T., Anttonen, A.-K., Lehesjoki, A.-E. Two novel CLN6 mutations in variant late-infantile neuronal ceroid lipofuscinosis patients of Turkish origin. Clin. Genet. 68: 167-173, 2005. [PubMed: 15996215] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00471.x]
Wheeler, R. B., Sharp, J. D., Schultz, R. A., Joslin, J. M., Williams, R. E., Mole, S. E. The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am. J. Hum. Genet. 70: 537-542, 2002. [PubMed: 11727201] [Full Text: https://doi.org/10.1086/338708]
Zeman, W., Hoffman, J. Juvenile and late forms of amaurotic idiocy in one family. J. Neurol. Neurosurg. Psychiat. 25: 352-362, 1962. [PubMed: 14003453] [Full Text: https://doi.org/10.1136/jnnp.25.4.352]