| #610003 | ||||||||||||||||||||||||
| CEROID LIPOFUSCINOSIS, NEURONAL, 8, NORTHERN EPILEPSY VARIANT | ||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||
| NORTHERN EPILEPSY EPILEPSY, PROGRESSIVE, WITH MENTAL RETARDATION; EPMR | ||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||
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| Phenotypic Series | ||||||||||||||||||||||||
| Clinical Synopsis | ||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||
| A number sign (#) is used with this entry because Northern epilepsy, also known as progressive epilepsy with mental retardation (EPMR), is caused by a Finnish founder mutation in the CLN8 gene (607837.0001). Northern epilepsy is a form of neuronal ceroid lipofuscinosis (NCL, CLN) and is a variant of CLN8 (600143). | ||||||||||||||||||||||||
| 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 CLN8 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles (Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). | ||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||
| Hirvasniemi et al. (1994) presented genealogic and phenotypic features of a recessively inherited form of childhood epilepsy occurring in the population of northern Finland, referred to as 'Northern epilepsy.' With 1 exception, both parents of all 11 sibships with affected individuals descended from 1 or 2 founding couples. The patients were normal at birth and developed normally until school age. Age at onset ranged from 5 to 10 years (mean, 6.7 years) with generalized tonic-clonic seizures. The seizures increased in frequency reaching a maximum of approximately 1 or 2 seizures per week by puberty. After puberty, the frequency of seizures began to decline unrelated to changes in medication. In early adulthood, seizure frequency was between 6 and 25 attacks per year, and after 35 years of age many patients were virtually seizure-free. EEG showed focal and nonfocal paroxysmal seizures. Mental development, which was originally normal, began to deteriorate 2 to 5 years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age. Haltia et al. (1999) and Herva et al. (2000) recognized Northern epilepsy as a subtype of neuronal ceroid lipofuscinosis. Herva et al. (2000) reported neuropathologic findings of 3 patients with Northern epilepsy. There was intraneuronal accumulation of cytoplasmic autofluorescent granules that were immunoreactive to subunit C of mitochondrial ATP synthase. Membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. The findings confirmed Northern epilepsy as a form of CLN with an exceptionally protracted course. Ranta et al. (2004) noted that although Northern epilepsy is allelic to CLN8, the clinical phenotype is distinct. Northern epilepsy presents between 5 and 10 years of age with frequent tonic-clonic seizures followed by progressive mental retardation. Visual loss is not a prominent feature of Northern epilepsy, there is no myoclonus, and the clinical progression is slower. | ||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||
| Tahvanainen et al. (1994) assigned the locus for Northern epilepsy to the telomeric region of 8p by linkage. Analyses of recombinations placed the locus in a 7-cM interval between 2 markers. Haplotypes comprising alleles at 5 loci in this interval supported the hypothesis of a single founding mutation for all affected chromosomes except the one belonging to the unrelated parent, who had a very different haplotype, suggesting another mutation or a very old ancestry of a single mutation. One of the markers that was closely linked to EPMR was the most distal Genethon marker on 8p known at that time. In general, the linked markers were known to be in the 8pter-p22 region. Ranta et al. (1996) reported that a recombination detected with a new microsatellite marker narrowed the EPMR critical region to 4 cM. They constructed a YAC contig containing 22 YACs across the disease gene region. They characterized the YAC contig by a collection of 19 YAC-end sequence-tagged sites together with 7 microsatellite markers. The entire YAC contig spanned a minimum of 3 Mb. | ||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||
| In 22 Finnish patients with Northern epilepsy, Ranta et al. (1999) identified homozygosity for an arg24-to-gly mutation in the CLN8 gene (R24G; 607837.0001). The carrier frequency was 1 in 135, compatible with a founder effect. | ||||||||||||||||||||||||
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