Epilepsies with single gene inheritance

doi:10.1016/S0387-7604(96)00060-5

Brain and Development

Volume 19, Issue 1, January 1997, Pages 13-18

https://doi.org/10.1016/S0387-7604(96)00060-5 Get rights and content

Abstract

Single gene disorders offer the best opportunity for identification of genetic linkage and of abnormal genes. Epilepsies with single gene inheritance include symptomatic epilepsies where there is associated diffuse brain dysfunction, and idiopathic epilepsies where seizures are the major neurological abnormality. There are over 200 single gene symptomatic epilepsies; most are rare. Gene identification has been achieved in a number of these conditions but these important advances have not yet led to a better understanding of epileptogenesis, because of the associated brain disease. Idiopathic single gene epilepsies include benign familial neonatal convulsions, where genetic linkage to chromosomes 20q and 8q has been found in different families, and benign familial infantile convulsions where linkage is presently unknown. Recently, four autosomal dominant partial epilepsies have been described. In autosomal dominant nocturnal frontal lobe epilepsy a genetic defect in the a4 subunit of the nicotinic acetylcholine receptor was found in one family. This is the first genetic defect described in an idiopathic epilepsy. The other three syndromes are autosomal dominant partial epilepsy with variable foci, autosomal dominant rolandic epilepsy with speech dyspraxia, and familial temporal lobe epilepsy. In the latter condition, linkage to chromosome 10q has been reported in one family, but the genetic defect is unknown. It is likely that other idiopathic single gene epilepsies will be identified. Molecular genetic study of these disorders is likely to lead to discovery of other epilepsy genes. This will lead to an improved understanding of human epileptogenesis with implications for clinical diagnosis, genetic counselling, pharmacological therapy and possibly prevention of epilepsy.

Reference (63)

HauserW.A. et al.
Genetics of epilepsy
AndermannE.
Multifactorial inheritance of generalized and focal epilepsy
McKusickV.A.
Online Mendelian Inheritance in Man, OMIM (TM)
(1996)
The European Chromosome 16 Tuberous Sclerosis Consortium
Identification and characterization of the tuberous sclerosis gene on chromosome 16
Cell
(1993)
JanssenB. et al.
Refined localization of TSC1 by combined analysis of 9834 and 16p13 data in 14 tuberous sclerosis families
Hum. Genet.
(1994)
MarchukD.A. et al.
A locus for cerebral cavernous malformations maps to chromosome 7q in two families
Genomics
(1995)
KoideR. et al.
Unstable expansion of CAG repeat in hereditary dentaeorubral-pallidoluysian atrophy (DRPLA)
Nat. Genet.
(1994)
NagafuchiS. et al.
Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p
Nat. Genet.
(1994)
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
Cell
(1993)
DobynsW.B. et al.
Causal heterogeneity in isolated lissencephaly
Neurology
(1992)

ReinerO. et al.

Isolation of a Miller-Dieker lissencephaly gene conttining G protein β-subunit-like repeats

Nature

(1993)

BrunelliS. et al.

Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly

Nat. Genet.

(1996)

TahvanainenE. et al.

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

YuS. et al.

The fragile X genotype is characterized by an unstable region of DNA

Science

(1991)

EksiogluY.Z. et al.

Periventricular heterotopias: an X-linked dominant epilepsy locus causing aberrant cortical development

Neuron

(1996)

PinardJ.-M. et al.

Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene

J. Neurol. Neurosurg. Psychiatry

(1994)

BerkovicS.F. et al.

Progressive myoclonus epilepsies: clinical and genetic aspects

Epilepsia

(1993)

PennacchioL.A. et al.

Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPMI)

Science

(1996)

GreenbergD.A. et al.

Juvenile myoclonic epilepsy may be linked to the Bf and HLA loci on human chromosome 6

Am. J. Med. Genet.

(1988)

SanderT. et al.

The phenotypic spectrum related to the human epilepsy susceptibility gene ‘EJM1’

Ann. Neurol.

(1995)

LiuA.W. et al.

Juvenile myoclonic epilepsy locus in chromosome 6p21.2-pll: linkage to convulsions and electroencephalography trait

Am. J. Hum. Genet.

(1995)

WhitehouseW.P. et al.

Linkage analysis of idiopathic generalised epilepsy (IGE) and marker loci on chromosome by in families of patients with juvenile myoclonic epilepsy no evidence of an epilepsy locus in the HLA region

Am. J. Hum. Genet.

(1993)

PlouinP.

Benign familial neonatal convulsions

LeppertM. et al.

Benign familial neonatal convulsions linked to genetic markers on chromosome 20

Nature

(1989)

MalafosseA. et al.

Confirmation of linkage of benign familial neonatal convulsions to D20S19 and D20S20

Hum. Genet.

(1992)

LeppertM. et al.

Searching for human epilepsy genes: a progress report

Brain Pathol.

(1993)

RonenG.M. et al.

Seizure characteristics in chromosome 20 benign familial neonatal convulsions

Neurology

(1993)

BerkovicS.F. et al.

Phenotypic expression of benign familial neonatal convulsions linked to chromosome 20

Arch. Neurol.

(1994)

LewisT.B. et al.

Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q

Am. J. Hum. Genet.

(1993)

SteinleinO. et al.

Benign familial neonatal convulsions: confirmation of genetic heterogeneity and further evidence for a second locus on chromosome 8q

Hum. Genet.

(1995)

FukuyamaY.

Borderland of epilepsy, with special references to febrile convulsions and so-called infantile convulsions (in Japanese)

Seishin Igaku (Tokyo)

(1963)

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Genetic abnormalities underlying familial epilepsy syndromes
2002, Brain and Development
Genetic defects have been recently identified in certain inherited epilepsy syndromes in which the phenotypes are similar to common idiopathic epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor α4 and β2 subunit genes have been detected in families with autosomal dominant nocturnal frontal lobe epilepsy. Both receptors are components of neuronal acetylcholine receptor, a ligand-gated ion channel in the brain. Furthermore, mutations of two K⁺-channel genes were also identified as the underlying genetic abnormalities of benign familial neonatal convulsions. Mutations in the voltage-gated Na⁺-channel α1, 2 and β1 and the gamma aminobutyric acid (GABA_A) receptor γ2 subunit genes were found as a cause of generalized epilepsy with febrile seizures plus, a clinical subset of febrile convulsions. Na⁺-channels, GABA_A receptor and their auxiliaries may be involved in the pathogenesis of this subtype and even in simple febrile convulsions. Mutation of a voltage-gated K⁺-channel gene can cause partial seizures associated with periodic ataxia type 1 and some forms of juvenile myoclonic epilepsy and idiopathic generalized epilepsy can result from mutations of a Ca²⁺-channel. This line of evidence suggests the involvement of channels expressed in the brain in the pathogenesis of certain types of epilepsy. Our working hypothesis is to view certain idiopathic epilepsies as disorders of ion channels, i.e. ‘channelopathies’. Such hypothesis should provide a new insight to our understanding of the genetic background of epilepsy.
GABA and epileptogenesis: Comparing gabrb3 gene-deficient mice with Angelman syndrome in man
1999, Epilepsy Research
The GABAergic system has long been implicated in epilepsy with defects in GABA neurotransmission being linked to epilepsy in both experimental animal models and human syndromes (Olsen and Avoli, 1997). However, to date no human epileptic syndrome has been directly attributed to an altered GABAergic system. The observed defects in GABA neurotransmission in human epileptic syndromes may be the indirect result of a brain besieged by seizures. The use of animal models of epilepsy has sought to address these matters. The advent of gene targeting methodologies in mice now allows for a more direct assessment of GABA’s involvement in epileptogenesis. To date several genes associated with the GABAergic system have been disrupted. These include the genes for glutamic acid decarboxylase, both the 65- and 67-kDa isoforms (GAD65 and GAD67), the tissue non-specific alkaline phosphatase gene (TNAP) and genes for the GABA_A receptor subunits α₆, β₃, γ₂, and δ (gabra6, gabrb3, gabrg2, and gabrd respectively). Gene disruptions of either GAD67 or gabrg2 result in neonatal lethality, while others, GAD65, TNAP, and gabrb3 exhibit increased mortality and spontaneous seizures. GABA receptor expression has been found to be both regionally and developmentally regulated. Thus in addition to their obvious role in controlling excitability in adult brain, a deficit in GABAergic function during development could be expected to elicit pleiotropic neurodevelopmental abnormalities perhaps including epilepsy. The GABA_A receptor β₃ subunit gene, gabrb3/GABRB3 (mouse/human), is of particular interest because of its expression early in development and its possible role in the neurodevelopmental disorder Angelman syndrome. Individuals with this syndrome exhibit severe mental retardation and epilepsy. Mice with the gabrb3 gene disrupted likewise exhibit electroencephalograph (EEG) abnormalities, seizures, and behavioral characteristics typically associated with Angelman syndrome. These gabrb3 gene knockout mice provide direct evidence that a reduction of a specific subunit of the GABA_A receptor system can result in epilepsy and support a GABAergic role in the pathophysiology of Angelman syndrome.
Chapter 6 Progress in Understanding the Genetics of Epilepsy
1999, Advances in Cell Aging and Gerontology
The progress made in the past decade in targeting human epilepsy genes has been phenomenal. Although these advances shed some light on the understanding of human epilepsies, they probably raise more questions than answers at present. Many gene defects and mechanisms can result in a single phenotype, while many differing phenotypes may result from a single gene defect. Some gene defects may alter specific neurotransmitter function and postsynaptic function; however, many appear to produce alterations at multiple points—the presynaptic level, early development of synaptic connections, intracellular signaling mechanisms with resulting cerebral developmental malformations, failure of cytoprotective mechanisms, and altered cellular metabolism with resultant degeneration of neurons. The chromosomal aberrations highlight the association of seizure phenotypes with certain chromosomes and regions within the human genome. Developing constructs for region-specific gene expression and linking genotype to the phenotype are the challenges for molecular biologists. Such advances will provide a neurobiological basis for understanding the mechanisms underlying development of human epilepsies. The challenge to clinicians and molecular neurobiologists is to unravel this tangled web and translate these advances into practical applications with implications for early diagnosis, genetic counseling and therapy for patients with seizures.
Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12
1999, American Journal of Human Genetics
We identified two large French-Canadian families segregating a familial partial epilepsy syndrome with variable foci (FPEVF) characterized by mostly nocturnal seizures arising from frontal, temporal, and occasionally occipital epileptic foci. There is no evidence for structural brain damage or permanent neurological dysfunction. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance. We mapped the disease locus to a 3.8-cM interval on chromosome 22q11-q12, between markers D22S1144 and D22S685. Using the most conservative diagnostic scheme, the maximum cumulative LOD score was 6.53 at recombination fraction (θ) 0 with D22S689. The LOD score in the larger family was 5.34 at θ=0 with the same marker. The two families share an identical linked haplotype for ≥10 cM, including the candidate interval, indicating a recent founder effect. A severe phenotype in one of the probands may be caused by homozygosity for the causative mutation, as suggested by extensive homozygosity for the linked haplotype and a bilineal family history of epilepsy. An Australian family with a similar phenotype was not found to link to chromosome 22, indicating genetic heterogeneity of FPEVF.
Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy
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Idiopathic epilepsy and genetics
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View full text

Epilepsies with single gene inheritance

Abstract

Genetics of epilepsy

Multifactorial inheritance of generalized and focal epilepsy

Online Mendelian Inheritance in Man, OMIM (TM)

Identification and characterization of the tuberous sclerosis gene on chromosome 16

Cell

Refined localization of TSC1 by combined analysis of 9834 and 16p13 data in 14 tuberous sclerosis families

Hum. Genet.

A locus for cerebral cavernous malformations maps to chromosome 7q in two families

Genomics

Unstable expansion of CAG repeat in hereditary dentaeorubral-pallidoluysian atrophy (DRPLA)

Nat. Genet.

Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p

Nat. Genet.

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes

Cell

Causal heterogeneity in isolated lissencephaly

Neurology

Isolation of a Miller-Dieker lissencephaly gene conttining G protein β-subunit-like repeats

Nature

Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly

Nat. Genet.

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

The fragile X genotype is characterized by an unstable region of DNA

Science

Periventricular heterotopias: an X-linked dominant epilepsy locus causing aberrant cortical development

Neuron

Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene

J. Neurol. Neurosurg. Psychiatry

Progressive myoclonus epilepsies: clinical and genetic aspects

Epilepsia

Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPMI)

Science

Juvenile myoclonic epilepsy may be linked to the Bf and HLA loci on human chromosome 6

Am. J. Med. Genet.

The phenotypic spectrum related to the human epilepsy susceptibility gene ‘EJM1’

Ann. Neurol.

Juvenile myoclonic epilepsy locus in chromosome 6p21.2-pll: linkage to convulsions and electroencephalography trait

Am. J. Hum. Genet.

Linkage analysis of idiopathic generalised epilepsy (IGE) and marker loci on chromosome by in families of patients with juvenile myoclonic epilepsy no evidence of an epilepsy locus in the HLA region

Am. J. Hum. Genet.

Benign familial neonatal convulsions

Benign familial neonatal convulsions linked to genetic markers on chromosome 20

Nature

Confirmation of linkage of benign familial neonatal convulsions to D20S19 and D20S20

Hum. Genet.

Searching for human epilepsy genes: a progress report

Brain Pathol.

Seizure characteristics in chromosome 20 benign familial neonatal convulsions

Neurology

Phenotypic expression of benign familial neonatal convulsions linked to chromosome 20

Arch. Neurol.

Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q

Am. J. Hum. Genet.

Benign familial neonatal convulsions: confirmation of genetic heterogeneity and further evidence for a second locus on chromosome 8q

Hum. Genet.

Borderland of epilepsy, with special references to febrile convulsions and so-called infantile convulsions (in Japanese)

Seishin Igaku (Tokyo)