Ceroid Lipofuscinosis, Neuronal, 6

A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-6 (CLN6) is caused by homozygous or compound heterozygous mutation in the CLN6 gene (606725) on chromosome 15q23.

Description

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 lipopigment patterns observed most often in CLN6 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (Mole et al., 2005).

Adult-onset neuronal ceroid lipofuscinosis, also known as Kufs disease, is a neurodegenerative disorder without retinal involvement. There are 2 overlapping phenotypes: type A, characterized by progressive myoclonic epilepsy, and type B, characterized by dementia and a variety of motor-system signs (summary by Arsov et al., 2011).

For a discussion of genetic heterogeneity of CLN, see CLN1 (256730).

Nomenclature

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).

CLN6 refers to CLN caused by mutation in the CLN6 gene, regardless of the age at onset. Thus, what was formerly called CLN4A, an adult-onset form of autosomal recessive neuronal ceroid lipofuscinosis, is now referred to as CLN6.

Clinical Features

Sharp et al. (1997) studied 2 consanguineous families with a variant form of late-onset 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; they showed curvilinear bodies typical of CLN2 and fingerprint profiles more typical of CLN3.

Kufs (1925) reported a case of adult-onset neuronal ceroid lipofuscinosis with onset at age 26 and death at age 38. Fine et al. (1960) found reports of 18 complete histologic descriptions. Chou and Thompson (1970) reported the morphologic changes in a man who was well until age 17 and died at age 32. A sister was said to have died of a similar clinical picture characterized by seizures, intellectual deterioration, lack of motor control, and development of athetoid movements. The parents were well and were related as first cousins, indicating autosomal recessive inheritance.

Dom et al. (1979) described 2 brothers with Kufs disease. In both, the first manifestation took the form of generalized epileptic seizures, at ages 30 and 32, followed by a cerebellar syndrome with myoclonic jerks and extrapyramidal symptoms. Postmortem examination of 1 brother showed extensive storage of ceroid lipofuscin as curvilinear bodies in the central nervous system and in hepatocytes, heart muscle, and retina. The surviving younger brother showed lipofuscin accumulation on peroneal muscle biopsy. The eye grounds were normal.

Tobo et al. (1984) reported adult-onset CLN in a 49-year-old man and his 51-year-old sister, characterized by episodic stuporous and psychotic states, mental retardation, generalized convulsions, and ichthyosis vulgaris. Postmortem examination of the woman showed excessive accumulation of lipofuscin throughout the central nervous system, particularly in neurons of the thalamus, substantia nigra, inferior olivary nuclei, brainstem motor nuclei, and cerebral cortex.

Of 118 cases in the literature that had been reported as Kufs disease, Berkovic et al. (1988) concluded that only 50 cases fulfilled strict clinical and pathologic criteria for the diagnosis. The 68 cases that were excluded had inadequate data, evidence for a storage disease other than Kufs disease, or atypical clinical features. Berkovic et al. (1988) noted that diagnostic confusion in the earlier literature may have resulted from lipofuscin accumulation with normal aging or from the fact that electron microscopy was not yet available for definitive diagnosis. Berkovic et al. (1988) delineated 2 clinical phenotypes of Kufs disease: type A begins with a progressive myoclonic epilepsy, with later development of dementia and ataxia, and type B is characterized by dementia with cerebellar and/or extrapyramidal motor symptoms. Both types have onset around age 30 years, and both have absence of retinal degeneration or blindness.

Goebel and Braak (1989) provided a detailed review of adult-onset NCL. Psychiatric and behavioral changes, mental deterioration, seizures, extrapyramidal symptoms, and ataxia dominate the clinical picture, while ocular symptoms are conspicuously absent.

Nardocci et al. (1995) reported findings on 4 patients with adult-onset NCL evaluated at the National Neurological Institute of Milan from 1984 to 1993. Two patients were sibs and 2 were isolated cases. The sibs had onset at ages 38 and 40 years, and the 2 isolated cases had onset at ages 50 and 12 years. The older patients presented with mental deterioration and later developed dystonia, bradykinesia, and ataxia. The younger patient, who was considered to have an adolescent onset of Kufs disease, presented with seizures and myoclonus, and later developed ataxia and mental deterioration. In all patients, visual acuity and funduscopic findings were normal, and MRI showed cerebral and cerebellar atrophy within 6 years of disease onset. All patients showed fingerprint profiles in skin cells.

Sadzot et al. (2000) reported 2 brothers with Kufs disease who presented with progressive myoclonic epilepsy. The first manifestations occurred before age 20 years in both patients, but did not progress significantly until after age 20. Both patients developed dementia and were in a vegetative state by age 30. Postmortem examination of 1 patient showed characteristic autofluorescent storage material in neurons with fingerprint profiles and strong immunoreactivit y against subunit c of mitochondrial ATP synthase (603192).

Arsov et al. (2011) reported 6 unrelated families with type A Kufs disease. Age at onset ranged from 16 to 51 years. Most had initial tonic-clonic seizures or action myoclonus, followed by cognitive decline or dementia. Some had ataxia.

Mapping

Sharp et al. (1997) excluded linkage of vLINCL in 2 families to the CLN3 locus on chromosome 16 and the CLN5 (608102) locus on chromosome 13. By homozygosity mapping, they mapped the locus for the disorder in these families to chromosome 15q. Further analyses in these families and study of 7 additional vLINCL families localized the gene to 15q21-q23. A maximum total lod score of 6.0 was obtained at marker D15S1020 (theta = 0.00).

From haplotype and disequilibrium analyses, Haines et al. (1998) concluded that the gene underlying a variant form of late-onset infantile neuronal ceroid lipofuscinosis, found among the descendants of Spanish settlers in a small geographic area in Costa Rica, maps to 15q21-q23 and therefore may be allelic to CLN6.

Molecular Genetics

In 2 families with a variant form of LINCL, one from Costa Rica and the other from Venezuela, Gao et al. (2002) identified mutations in the CLN6 gene (606725.0001-606725.0002). Wheeler et al. (2002) independently and simultaneously identified 6 different mutations in the CLN6 gene in patients with vLINCL.

Siintola et al. (2005) identified 2 different mutations in the CLN6 gene (606725.0008; 606725.0009) in affected members of 2 Turkish families with CLN6. The findings indicated that a subset of patients with the so-called 'Turkish variant' of late-infantile CLN (CLN7; see 600143), actually have CLN6.

By genomewide mapping followed by candidate gene sequencing in 3 families with autosomal recessive Kufs disease, Arsov et al. (2011) identified homozygous or compound heterozygous mutations in the CLN6 gene (see, e.g., 606725.0011-606725.0014). Mutations were also found in affected members from 4 additional families with Kufs disease, yielding a total of 9 different pathogenic mutations in the CLN6 gene. All patients from the 7 families had progressive myoclonic epilepsy followed by dementia, consistent with a type A phenotype. There were no apparent genotype/phenotype correlations. Mutation in the CLN6 gene was not found in 1 family with a type B phenotype. Arsov et al. (2011) noted the striking phenotypic differences between patients with earlier onset CLN6 and patients with Kufs disease. Patients with CLN6 have retinal involvement, whereas none of the Kufs syndrome patients had retinal involvement. The authors suggested that Kufs syndrome patients may have some residual mutant protein function or that there are other disease modifiers.

Animal Model

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.