Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental deterioration.

Hirvasniemi, Aune; Lang, H. Beckett; Ae, Lehesjoki; Leisti, J

doi:10.1136/jmg.31.3.177

Cited by 76 publications

(41 citation statements)

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“…Autosomal recessive CLN8 (MIM 607837) mutations are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR; MIM 610003), first identified in Finland [Hirvasniemi et al, 1994;Ranta et al, 1999]; and a variant of late infantile NCL (v-LINCL), first described in a subset of Turkish patients [Mitchell et al, 2001;Topcu et al, 2004]. EPMR, or Northern Epilepsy, is characterized by progressive epilepsy with generalized tonic-clonic seizures with onset at 5 to 10 years of age and progressive mental retardation [Hirvasniemi et al, 1994].…”

Section: Introductionmentioning

confidence: 99%

A novelCLN8mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function

et al. 2009

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The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late-infantile NCL (v-LINCL) described in a subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v-LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited 3-bp deletion in CLN8 gene (c.180_182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death.

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Section: Introductionmentioning

confidence: 99%

A novelCLN8mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function

et al. 2009

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“…However, one was very different and, interestingly, this haplotype belonged to the (10) as well as the two loci for benign neonatal convulsions in chromosomes 20q and 8q (4, 5) as candidate loci for EPMR. Our data confirm the recessive type of inheritance of EPMR suggested by previous pedigree studies (10). The patients chosen for the study were clinically homogeneous with little intra-and interfamilial variation.…”

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confidence: 96%

The gene for a recessively inherited human childhood progressive epilepsy with mental retardation maps to the distal short arm of chromosome 8.

Tahvanainen

Ranta

Hirvasniemi

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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A recently delineated childhood epilepsy has hitherto been observed only in a small geographic region in northern Finland, where, with the exception of one, both parents of all of the 11 sibships with affected individuals descend from one or two founding couples. The disease is characterized by generalized tonic-clonic seizures with onset at 5-10 years and progressive, severe mental retardation with onset 2-5 years after the first seizures. In this study the gene locus is assigned to the telomeric region of chromosome 8p by linkage. Analyses of recombinations place the locus in the 7-centimorgan interval between AFM185xb2 and D8S262 in which three markers, D8S504, D8S264, and AFM077yg5, show no recombinations with the phenotype. Haplotypes comprising alleles at the above five loci support the hypothesis of a single founding mutation for all affected chromosomes except the one belonging to the unrelated parent, who has a very different haplotype, suggesting another mutation or a very old ancestry of a single mutation. This study raises to three the number of heritable epilepsies whose gene loci have been mapped and provides a starting point for the cloning of the gene. It also suggests the possibility that the disease might not be limited to the northern Finnish population.

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“…1 Recently, EPMR was recognised as a new subtype of neuronal ceroid lipofuscinoses (NCLs). 2 We previously assigned the EPMR locus to an approximately 700 kb interval on chromosome 8p (Figure 1), [3][4][5] and constructed a 3412 bp partial cDNA sequence (Genbank AF009204) mapping to this region.…”

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Positional cloning and characterisation of the human DLGAP2 gene and its exclusion in progressive epilepsy with mental retardation

et al. 2000

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In search of the gene for progressive epilepsy with mental retardation (EPMR) we identified DLGAP2, the human homolog of the gene encoding the rat PSD-95/SAP90-associated protein-2 (Dlgap2). We extended the transcript in both the 5' and 3' directions and characterised the genomic structure of the approximately 10 kb gene. Sequence comparisons of human DLGAP2 cDNA sequences obtained from human testis and brain cDNA libraries with homologous rat genes suggest alternative splicing in the 5' end of the gene. The 5' coding sequence of the testis cDNA is complete, whereas based on homology with the rat gene 103 bp of coding sequence may still be missing in the 5' end of the DLGAP2 brain transcript. DLGAP2 was excluded as the gene responsible for EPMR.

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Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental deterioration.

Abstract: A new autosomal recessively inherited disease of the central nervous system

Cited by 76 publications

References 10 publications

A novelCLN8mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function

A novelCLN8mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function

The gene for a recessively inherited human childhood progressive epilepsy with mental retardation maps to the distal short arm of chromosome 8.

Positional cloning and characterisation of the human DLGAP2 gene and its exclusion in progressive epilepsy with mental retardation

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