Northern epilepsy syndrome (NES, CLN8)--MRI and electrophysiological studies.

Northern epilepsy syndrome (NES, EPMR, progressive epilepsy with mental retardation, CLN8), an inherited childhood-onset epilepsy with mental retardation, has been recently characterized to belong to the family of neuronal ceroid lipofuscinoses (NCLs). In this study, four patients (ages 26-44 years) with NES and eight healthy controls underwent magnetic resonance imaging (MRI) and electrophysiological evaluation with somatosensory evoked magnetic field (SEF) studies. The findings in NES were compared with the known findings in juvenile NCL (JNCL, CLN3) and Finnish variant late infantile NCL (vLINCLFIN, CLN5) that manifest around the same age as NES. Also postmortem MRI was performed on one brain. On the MRIs, slight to moderate cerebellar atrophy was seen in all patients, whereas only two patients had slightly enlarged cerebral sulci. None of the MRIs demonstrated signal intensity abnormalities that are commonly seen in JNCL and vLINCLFIN and are considered to reflect the Wallerian degeneration after neuronal death. Generally SEFs in NES were within normal limits, indicating that the disease had not impaired the function of the neurons on the somatosensory pathway. In conclusion, MRI imaging and SEF findings suggest that the cerebral neuronal death and dysfunction in NES are minimal compared with JNCL and vLINCLFIN.

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

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.

Northern epilepsy: a novel form of neuronal ceroid-lipofuscinosis.

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.

The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8.

The neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues. Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype (CLN8). It is an autosomal recessive disorder characterized by onset of generalized seizures between 5 and 10 years, and subsequent progressive mental retardation. Here we report the positional cloning of a novel gene, CLN8, which is mutated in EPMR. It encodes a putative transmembrane protein. EPMR patients were homozygous for a missense mutation (70C-->G, R24G) that was not found in homozygosity in 433 controls. We also cloned the mouse Cln8 sequence. It displays 82% nucleotide identity with CLN8, conservation of the codon harbouring the human mutation and is localized to the same region as the motor neuron degeneration mouse, mnd, a naturally occurring mouse NCL (ref. 4). In mnd/mnd mice, we identified a homozygous 1-bp insertion (267-268insC, codon 90) predicting a frameshift and a truncated protein. Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL.

High-resolution mapping and transcript identification at the progressive epilepsy with mental retardation locus on chromosome 8p.

Progressive epilepsy with mental retardation (EPMR) is an autosomal recessive central nervous system disorder characterized by childhood onset epilepsy and subsequent mental retardation. The locus for EPMR has been mapped to human chromosome 8p23. We recently reported the construction of a YAC contig across the 4 centimorgan minimum genetic region that harbors the disease locus. We now report further delineation of the critical region to <700 kb. Our mapping strategy relied on the identification of nine novel microsatellite markers and the construction of a complete BAC contig across the critical region. Several partial gene sequences have been identified from the region and are being analyzed as candidate genes for EPMR.

Neurophysiological findings in the northern epilepsy syndrome.

We describe the neurophysiological findings in the northern epilepsy syndrome (NES), an autosomal recessively inherited childhood onset epilepsy with associated mental deterioration. Sixty-five EEGs of 18 patients (10 females and 8 males) from the age of 5 years to 52 years were analyzed. EEG showed relatively slight changes at the outbreak of epilepsy at the mean age of 6.6 years (range 5-10 years). Slowing of the background activity to 6-7 Hz theta activity, abundant diffuse or intermittent theta and delta activity and disappearance of sleep-specific activity characterized the EEGs at puberty. The amount of diffuse delta and theta activity diminished in adulthood. Epileptiform findings were scanty. Spikes and sharp waves occurred in 43% of the recordings with varying localization, form and extent. Intermittent 2-4 Hz sharp and slow wave rhythm was seen in 32% of the recordings. Of the three ictal recordings, one showed a primarily generalized discharge pattern, while two were clearly asymmetric. Clonazepam was the most effective antiepileptic drug, and it also normalized the EEG when started in childhood or at the onset of puberty. Visual evoked potentials were abnormal in 44% and brainstem auditory evoked potentials in 35%. The neurophysiological findings suggest an extensive, probably multifocal degenerative brain process, which reaches its peak at puberty. Although the abnormal features of EEG often decreased in adulthood, the clinical course of NES showed slow progression throughout the lifetime.

Genetic and physical mapping of the progressive epilepsy with mental retardation (EPMR) locus on chromosome 8p.

Progressive epilepsy with mental retardation (EPMR) is an autosomal recessive disorder discovered recently from an isolated region in Finland. The disorder is characterized by normal early development, generalized tonic-clonic seizures with onset at 5-10 years of age, and progressive mental retardation beginning 2-5 years after the onset of seizures. We recently mapped the EPMR locus to a 7-cM region on chromosome 8p between markers AFM185xb2 and D8S262. A recombination detected with a new microsatellite marker AFMa054td9 narrows the region to 4 cM. A yeast artificial chromosome (YAC) contig containing 22 YACs was constructed across the disease gene region. The YAC contig is characterized by a collection of 19 YAC-end sequence-tag sites together with seven microsatellite markers. The entire YAC contig spans a minimum of 3 Mb. Moreover, the distal end of the contig contains a subtelomeric YAC yRM2205 that anchors the contig to the telomere. Construction of a YAC contig across the disease gene region is an essential step toward the isolation of the EPMR gene.

Northern epilepsy syndrome: clinical course and the effect of medication on seizures.

We describe the clinical course and treatment of 19 patients with the Northern epilepsy syndrome, an autosomal recessively inherited epilepsy with associated mental deterioration. The clinical course could be divided into three successive stages. The first stage continued from the onset of epilepsy until puberty. Seizures began at a mean age of 6.6 years and consisted predominantly of generalized tonic-clonic convulsions (GTC) and, transiently, also of complex partial seizures (CPS). Until puberty, seizure frequency increased in most patients from one attack in 1-2 months to one to two attacks weekly. Seizures did not respond to phenytoin (PHT) or carbamazepine (CBZ), were transiently controlled by valproate (VPA) and phenobarbital (PB), but were effectively treated only by clonazepam (CZP). Mental deterioration began 2-5 years after the onset of epilepsy and was most rapid before adulthood, a time when the seizures were also most frequent. The second stage is marked by fewer seizures, further mental deterioration, and less rapid progression. All patients were demented (I.Q. < 70) by age of 30 years. The first signs of motor clumsiness also appeared then. The third stage was one of permanent disability and usually began in middle age. Seizures were few, but the patients were clumsy and had marked equilibrium difficulties.

Neuroradiological findings in the northern epilepsy syndrome.

Neuroradiological findings are presented of 19 patients with the northern epilepsy syndrome, a recessively inherited childhood epilepsy with associated mental deterioration. The first signs of cerebellar-brainstem atrophy already appeared in young adulthood, with atrophy tending to increase with age. Findings of cerebral atrophy were detected later: four of the seven patients under 30 years of age displayed central or cortical atrophy, while all 12 patients over 30 were affected. The degree of mental deterioration correlated well with the severity of cerebral atrophy. One half of the patients with either central or cortical atrophy were moderately to severely retarded, whereas all patients with both central and cortical atrophy were moderately to profoundly retarded.

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

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.

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

A new autosomal recessively inherited disease of the central nervous system involving childhood epilepsy and mental deterioration is described. Twenty three patients (11 males and 12 females) belonging to 11 families from northern Finland have been identified. A common ancestor has been found for nine families. The mean age of onset of epilepsy was 6.7 years (range 5-10 years) and the epilepsy was characterised by generalised tonic-clonic seizures increasing in frequency up to puberty. One third of the patients also had complex partial seizures during childhood. During young adulthood the epileptic activity began to decrease, but complete remission did not occur. Electroencephalography showed progressive slowing of the background activity with relatively scanty epileptiform activity. Out of four ictal recordings the paroxysmal activity was initiated focally in two cases. Clonazepam and sodium valproate had some antiepileptic effect, clonazepam being the more beneficial of the two. Mental development, which was originally normal, began to deteriorate two to five 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. The pathogenesis of the disorder, called the Northern epilepsy syndrome, is unknown. Linkage analysis using DNA markers linked to the EPM1 gene for progressive myoclonus epilepsy of Unverricht-Lundborg type showed that the Northern epilepsy syndrome is not allelic to EPM1.

Nonketotic hyperglycinemia. A genetic study of 13 Finnish families.

In Finland, 19 children, born 1964--1977, from 13 families, have been diagnosed as suffering from nonketotic hyperglycinemia (NKH). This gives an incidence for NKH in the Finnish population of 1:55,000 newborns. The majority of these children were born in the northern part of the country, where the incidence is 1:12,000. The geographical distribution of the birth-places of the grandparents also seems to point towards an enrichment of the gene in northern Finland. An autosomal recessive mode of inheritance for this disease seems probable, since the corrected proportion of affected siblings (Apert's a priori method) is 0.288. Abnormally high plasma glycine concentration and elevated glycine urinary excretion in the parents of the NKH-children suggest the existence of a minor metabolic defect in heterozygotes of this disease. Some of the healthy siblings of the NKH-patients also show similary elevated levels. However, a definite diagnosis of the NKH-heterozygote state cannot easily be made on the basis of these laboratory findings, as the levels in some individuals are very close to, or even overlap corresponding values in a normal material.