Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 17
Genetic Diseases Associated with Epilepsy
Joshua L. Bonkowsky
Martha A. Nance
W. Allen Hauser
V. Elving Anderson
Introduction
Genetics has become increasingly important for understanding epilepsy. Since the advent of molecular genetic technology in the 1980s, it has been possible to categorize and diagnose many neurologic diseases that were previously poorly defined. A number of specific “epilepsy genes” have been identified and are discussed in Chapter 18. However, there are also many genetic disorders that feature epilepsy as a common or prominent symptom. In this chapter we review genetic disorders associated with an increased risk for epilepsy.
Patients having genetic or chromosomal syndromes associated with epilepsy account for 2% to 3% of all cases of epilepsy; in fact, these patients are more likely to be seen first by a pediatrician, family practitioner, or geneticist for diagnosis and treatment of the genetic syndrome. What, then, is the benefit of approaching the epilepsies using a framework of genetic classification of disease?
First, for the clinician, knowing which genetic disorders have a high risk for epilepsy can aid in differential diagnosis. The background population rate of epilepsy is 2% to 4%, whereas in some disorders, epilepsy can be present in almost 100% of patients, and the type of epilepsy can be characteristic of the disorder.
Second, investigation of the disorders that are associated with epilepsy is providing insight into the causes of epilepsy. Understanding that epilepsy is not a general consequence of all chromosomal aberrations but is present in specific chromosomal disorders, for example, has led to a search for epilepsy-related genes at specific chromosomal sites.
Third, by studying the effects of specific gene mutations on intracellular and cell membrane function, by creating animal models of human epilepsy disorders, and by studying in detail the cellular effects of human mutations, the mechanisms of epileptogenesis will be better understood. For most of the conditions described below, the actual mechanism of epileptogenesis is at present poorly understood.
Finally, for the patients and their families, diagnosis of their disorder provides the opportunity for treatment, for genetic counseling, and for tailored treatment of their seizures as well as for health maintenance issues that may arise later in the course of their disease.
Basic Genetic Concepts
Most of the conditions in this chapter involve mendelian (single gene locus) inheritance.71 Because of the rapidly changing knowledge about these disorders, we commonly use two searchable Web-based sites to help with our diagnosis and testing: GeneTests (www.genetests.org) and OMIM (Online Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov/entrez/query.fcgi?db = OMIM). These sites are funded by the National Institutes of Health (NIH), and include clinical and molecular information about genetic disorders, references, and clinical laboratories that test for the different disorders.
Testing (and thus the diagnosis) of genetic disorders associated with epilepsy continues to provide challenges to the clinician. Further, the technology and means of testing is in constant flux. Again, GeneTests is an invaluable resource for finding laboratories that provide clinical testing. Unfortunately, in many instances our knowledge of the diseases has outstripped the ability of laboratories to provide clinical testing. In many diseases any one test is not 100% sensitive, so if the clinical suspicion is high enough, further testing may be warranted.
All testing should be preceded by adequate counseling about the purpose and possible outcomes of the testing and potential choices that might arise (see Chapter 19). The clinical complexity and overlap in phenotypes of these disorders, the implications for genetic testing of other family members, and ramifications on insurance coverage mandate responsible clinical judgment.
A basic grasp of genetic concepts is important for understanding the disorders in this chapter. We have grouped these topics into four areas: Genetic transmission, gene expression, genomic integrity, and genetic heterogeneity.
Genetic Transmission
Four major modes of inheritance have been characterized in detail: Autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial.
Autosomal dominant traits can be expressed when only one of the paired alleles (genes) at a given locus is of a mutant form. However, apparent “skips” in a pedigree may occur as the result of incomplete penetrance. Incomplete penetrance is the presence in an individual of a dominant disease gene without full expression of the mutant phenotype. Sometimes, however, careful examination of individuals carrying a dominant disease gene reveals minimal signs of the condition, indicating variable expression of disease symptoms.
For an autosomal recessive trait to be expressed, both alleles must be of a mutant form (although not necessarily with the same mutation). Both parents of an affected individual are heterozygous disease gene carriers, and careful examination or laboratory evaluation may sometimes reveal heterozygous effects. Ordinarily, however, carriers of a single recessive disease gene are clinically asymptomatic. Because autosomal recessive alleles are generally rare, a detailed family history should be taken to search for any consanguinity.
The hallmark of X-linked diseases is the absence of male-to-male transmission of the genetic trait, since males pass on a Y chromosome, not an X chromosome, to their sons. Thus, the condition usually is found only in male subjects who are in turn related through female carriers. Some X-linked disorders (such as incontinentia pigmenti) are lethal in affected males,
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so that only female carriers of the abnormal gene survive fetal life.
Mitochondrial mutations follow a maternal inheritance pattern. In this situation, the frequency of a trait is the same in male and female subjects, but the condition is always transmitted from an affected mother to most of her children, never from an affected father. A human egg contains several hundred thousand copies of mitochondrial DNA (mtDNA), compared with only a few in sperm. Theoretically, all children of an affected mother should be affected. The expression of a mitochondrial mutation, however, depends on the relative proportion of mutant and wild-type mtDNAs in a given cell (termed heteroplasmy), and this proportion can shift during cell division. Because of a “threshold effect,” tissues with a low proportion of mutant mtDNAs may not show an effect, whereas tissues that have reached the threshold begin to show effects of mitochondrial dysfunction. Organs that have a high rate of energy consumption, such as brain, heart, and muscle, are most often affected by mitochondrial disorders. It must also be noted that some mitochondrial disorders result from mutations in nuclear genes; these defects are inherited in a regular mendelian pattern.
Anticipation is the tendency for affected individuals in successive generations to present with earlier and/or more severe symptoms. This occurs in some genetic disorders, especially those associated with trinucleotide repeat expansions. Certain disorders have a predilection for repeat instability when passed on via either the paternal or maternal germ-line.
Mosaicism, or the presence of more than one genotype in the body, must also be considered in situations when multiple siblings have a disorder despite the absence of any family history of the disorder. In this situation, the parent is phenotypically normal because most of the somatic cells of the body carry the wild-type allele, but the germ cells carry the mutant allele, which is thus passed on to all the offspring.
Polygenic disorders remain a major frontier in our understanding of genetic mechanisms of disease. These disorders are common (e.g., idiopathic epilepsy) and show complex inheritance, involving multiple (possibly interacting) genes, with or without additional environmental influences. Identifying the causative genes is challenging.51
Gene Expression
The pathways from genes (the genotype) to physical or clinical traits (the phenotype) are extraordinarily complex. The molecular and developmental events that control phenotypic expression are numerous. They include DNA regulatory elements that control location, levels, rate, and timing of gene expression73; alternative splicing of the primary mRNA transcript to produce different mRNAs; imprinting, or the differential expression of a gene depending on which parent contributed the gene; regulation of mRNA expression by small RNA molecules107; and combinatorial protein and enzymatic complexes.
Genomic Integrity
Deletion or duplication of DNA segments on a chromosome can produce significant clinical effects. Larger deletions, duplications, or translocations can disrupt many genes and produce severe symptoms, including mental retardation and growth failure. Microdeletions, which may not be detectable by standard cytogenetic analysis, can produce contiguous gene syndromes that involve the loss of several neighboring genes and can lead to unique phenotypes depending upon the specific genes deleted.
Recently, a series of inherited disorders has been shown to involve the expansion of DNA trinucleotide repeat sequences. These include myotonic dystrophy, fragile X syndrome, Huntington disease, and some of the spinocerebellar ataxias. Normal individuals show variation in the number of repeats, but above a certain threshold the repeat length becomes unstable, with a tendency for further increase in number of repeats in later generations. Higher repeat numbers are associated with an earlier onset of the condition, greater severity of symptoms, or both—a phenomenon known as anticipation. The mechanisms by which trinucleotide repeat expansions cause disease remain unknown.
Genetic Heterogeneity
Genetic heterogeneity (or locus heterogeneity) is the phenomenon whereby a single clinical phenotype can result from mutations in different genes. This possibility must be considered in the genetic study of any disorder, as it may affect both diagnosis and treatment and also causes problems in gene mapping studies. Thus, the epilepsies are a limited group of phenotypes that may be caused by a number of different genes. For example, seizures can occur from changes in neuronal excitability, neuronal inhibition, or control of the spread of a seizure state, each of which is regulated by many different genes.
From a diagnostic perspective, it is not sufficient to classify epilepsy simply on the basis of the clinical or electrographic appearance of the seizures; some consideration of the underlying cause must be included. To say that a patient has mental retardation and epilepsy could miss the point that both conditions are manifestations of an underlying cause, for example, Angelman syndrome. On the other hand, a purely genetic classification is not satisfactory either, and lacks the clinical and treatment paradigms. Godfrey28 emphasized the continuing interdependence between clinicians and molecular scientists in resolving this problem:
“Do we begin to classify disorders on the basis of molecular lesions or on the basis of clinical criteria? Neither alone seems satisfactory any more. Therefore, we will use both, singly and in combination, but heterogeneity will continue to pose dilemmas in our practices and laboratories.”
Table 1 Risk for Epilepsy, and Other Seizure Associations, in Genetic Disorders
Risk for epilepsy Seizure associations
>75%
Angelman syndrome
Fukuyama congenital muscular dystrophy
Hemimegalencephaly
Lissencephaly
MELAS syndrome
Periventricular nodular heterotopia
Sturge-Weber syndrome
Tuberous sclerosis
Zellweger spectrum disorders
50%–75%
Biotinidase deficiency
Christian syndrome
Landau-Kleffner syndrome
Linear nevus sebaceous syndrome
Rett syndrome
Wolf-Hirschhorn syndrome
30%–50%
Congenital disorders of glycosylation
Glycogen storage disease I and III
Hypomelanosis of Ito
McLeod neuroacanthocytosis syndrome
Metachromatic leukodystrophy
Niemann-Pick disease, type C
Saethre-Chotzen syndrome
Schizencephaly		 <30%
Acute intermittent porphyria
Adrenoleukodystrophy Alzheimer disease
Autism
Börjeson-Forssman-Lehmann syndrome
Brachmann-de Lange syndrome
Cardiofaciocutaneous syndrome
Cohen syndrome
Crouzon syndrome
Fragile X syndrome
Huntington disease
Homocystinuria
Leigh syndrome
Neurofibromatosis types 1 and 2
Parry-Romberg syndrome
Prader-Willi syndrome
Trisomy 13
Trisomy 21
Velocardiofacial syndrome
Wilson disease
No increased risk
Cri-du-chat syndrome
Sex chromosome aneuploidies
Subtelomeric deletions
Williams syndrome
Smith-Magenis syndrome
Lesch-Nyhan syndrome
Mucopolysaccharidoses		 Burst-suppression
Nonketotic hyperglycinemia
Hypsarrhythmia
Menkes disease Nonketotic hyperglycinemia
Infantile spasms
Hypomelanosis of Ito
Lissencephaly
Tuberous sclerosis
Wolf-Hirschhorn syndrome
Other nonepileptic events
Alzheimer disease (myoclonus)
Angelman syndrome (myoclonus)
Coffin-Lowry syndrome (stimulus-induced drop attacks)
Niemann-Pick disease, type C (gelastic cataplexy)
Trisomy 13 (apneic spells)
MELAS, mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes; WAGR, Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.
Genetic Disorders Associated with Epilepsy
Table 1 summarizes the genetic disorders discussed in this chapter. It lists the disease name, its associated gene (if known), and seizure frequency. We have organized the genetic disorders in the following broad categories:
  • Chromosome disorders
  • Contiguous gene disorders
  • Metabolic disorders
  • Genetic syndromes; which are further subdivided as follows:
    • Short stature
    • Early overgrowth
    • Skeletal dysplasias
    • Facial defects
    • Connective tissue
    • Neurocutaneous
    • Ectodermal and mesodermal dysplasias
  • Disorders of brain development
  • Neurodegenerative disorders
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Chromosome Disorders
The chromosome disorders represent a wide array of possible disorders caused by additions, deletions, or rearrangements of chromosomal material (see Chapter 261). Classical cytogenetic methods are now complemented by more sensitive methods such as high-resolution chromosome banding, fluorescent in situ hybridization (FISH), and the polymerase chain reaction (PCR). Small deletions or duplications are now detectable, and the contribution of an individual gene to the overall phenotype of a chromosome disorder can often be determined.
Six percent of patients with epilepsy and intellectual impairment have chromosomal abnormalities, while 50% of patients with epilepsy and multiple congenital abnormalities have chromosomal abnormalities, as noted by Singh et al.105 in their review of the frequency and types of epilepsies resulting from disorders of each of the chromosomes (see also the review by Battaglia and Guerrini4).
Epilepsy occurs in 1% to 10% of patients with trisomy 21 syndrome (Down syndrome), and electroencephalographic (EEG) abnormalities are present in more than 20%.21,104,118 EEG abnormalities ranged from slowing, asymmetry, and asynchrony to diffuse or focal epileptiform activity.21 Seizures most often begin early in childhood, and can be of different types; infantile spasms occur occasionally (0.5% to 2% of patients), while myoclonic seizures are distinctly uncommon.89,104,123
Trisomy 13 syndrome is commonly accompanied by severe developmental retardation, microcephaly, and severe craniofacial dysgenesis, including holoprosencephaly. Seizures occur in 25% of patients and apneic spells in 58%.33
Trisomy 18 syndrome, the third common autosomal trisomy, is characterized by poor somatic growth and hypoplasia and dysplasia of many internal organs, including the brain. Gross malformations of the brain range from heterotopias to holoprosencephaly, which may be associated with apneic episodes and seizures.33 Others report a much lower incidence of seizures in trisomy 18 patients than in trisomy 13.125
More than 50% of patients with Wolf-Hirschhorn syndrome (del4p16) have seizures, which can be difficult to control. Characteristic EEG and seizure patterns (including infantile spasms) are associated with this syndrome.3 The incidence of seizures may depend on the exact site of the deletion, as the “critical region” is still being delineated. In contrast, patients with cri-du-chat syndrome (del[5p]) are microcephalic but generally do not have severe seizures.
The fragile X syndrome is included here as a chromosome disorder for historical reasons. The first diagnostic test for this disorder was cytogenetic, based on the presence of a visible disruption in the X chromosome (the “fragile X”) when cells of affected individuals were grown in a culture medium low in folate. Fragile X syndrome is now known to be a trinucleotide repeat disease caused by the expansion within the FMR-1 gene of a trinucleotide that is repeated in tandem only a few times in normal individuals. Fragile X syndrome is responsible for about 2% to 5% of all cases of mental retardation in male individuals, and also has been associated with mental retardation in females, although usually less severe than in their
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male relatives. In large series, about 20% of males and 5% of females with fragile X syndrome have clinically apparent seizures, and about 50% have abnormal EEGs.6,121 No patient had infantile spasms. EEG abnormalities included nonspecific slowing as well as epileptiform or paroxysmal discharges; other authors have reported a high incidence of centrotemporal (rolandic) spike discharges in FMR-1 mutation carriers in the second half of the first decade of life, both with and without clinical seizures. Seizures and EEG abnormalities in individuals with fragile X syndrome tend to improve with age.
Other less common chromosome deletion and translocation syndromes are associated with the presence of epilepsy. Seizures were present in a series of over 400 different chromosome imbalances105; eight disorders were highly associated with epilepsy: Wolf-Hirschhorn (4p-) syndrome, Miller-Dieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p, and ring chromosomes 14 and 20. Notably, epilepsy is not a prominent feature of the sex chromosome aneuploidies, such as Turner syndrome or Klinefelter syndrome. Subtelomeric deletions at the ends of chromosomes have been reported to be a significant cause of mental retardation,61 but seizures appear to only be an occasional association.
Contiguous Gene Disorders
Three contiguous gene disorders associated with seizures are discussed below: Angelman syndrome, Prader-Willi syndrome, and Velocardiofacial syndrome (Miller-Dieker syndrome is discussed later in this chapter). Other contiguous gene disorders not associated with an increased risk of seizures include Williams syndrome, WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Potocki-Shaffer syndrome, and Smith-Magenis syndrome.
Angelman syndrome was first identified cytogenetically as involving loss of the maternal chromosome region 15q11-13. Affected patients have severe mental retardation, epilepsy, ataxic jerky movements, inappropriate laughter, and absence of speech. UBE3A, a ubiquitin-protein ligase, is the minimal gene mutation responsible for the core phenotype, but the phenotypic presentation depends on the type of mutation and which associated genes are involved.60,70
Seizures with onset at <3 years of age and EEG abnormalities are findings in more than 80% of patients, and are part of the diagnostic criteria for Angelman syndrome.120 Abnormal EEGs are commonly present in infancy and may be the first diagnostic sign.8,24 EEG abnormalities in infants often include irregular, generalized, high-voltage sharp-wave and spike-wave activity. Although only 30% of patients have seizures in the first 2 years of life, by 3 years of age 85% will have developed seizures, most often of the absence, myoclonic, or generalized tonic–clonic types. However, some of the abnormal movements in Angelman syndrome are cortically based myoclonus, responsive to GABAergic (γ-aminobutyric acid) drugs.
Prader-Willi syndrome also involves chromosome region 15q11-13, but in contrast to Angelman syndrome, results from loss of the paternally derived chromosome. Patients with Prader-Willi syndrome have infantile hypotonia, short stature, small hands and feet, hypogonadism, and mental retardation, and as children develop hyperphagia and obesity.37 Seizures are present in 15% to 20% of patients, but in contrast to Angelman syndrome, the seizures are not severe, chronic, or therapeutically challenging.9 Molecular diagnosis is based on abnormal methylation studies, which detect 99% of cases.13
Velocardiofacial syndrome, a contiguous gene deletion involving chromosome region 22q11.2, is characterized by congenital heart disease, palatal abnormalities, characteristic facial features, learning difficulties, and immune deficiency. Former names for velocardiofacial syndrome are DiGeorge syndrome and Shprintzen syndrome. Seven percent of patients with velocardiofacial syndrome develop seizures.57 In addition, infants with velocardiofacial syndrome sometimes present with seizures secondary to hypocalcemia because of parathyroid deficiency.
Metabolic Disorders
There are several general mechanisms by which metabolic disorders can result in seizures (see also Chapters 261 and 262). First, any disorder that alters the cellular metabolic environment (such as hyperammonemia) can provoke seizures. Second, some metabolic disorders can lead to secondary structural abnormalities in the brain. For instance, cortical infarctions can develop in patients with MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes) that can act as epileptogenic foci even in the absence of acute systemic metabolic disturbance. Finally, a tendency to epilepsy may be intrinsic to the metabolic disturbance or disease itself, if the metabolic pathway is necessary for the function of neurons and/or glia. The treatment of seizures in patients with metabolic disorders must include treatment of the metabolic derangement; seizures are likely to persist despite anticonvulsant therapy if an untreated metabolic abnormality is present, and anticonvulsant therapy may not be necessary if the metabolic derangement is brought under control.
Wolf et al.124 reviewed the main characteristics of the epilepsies that are found in the inborn errors of metabolism and outlined a general approach to diagnosis and treatment. For more detailed information see also The Molecular and Metabolic Basis of Inherited Disease,103 Diagnostic Recognition of Genetic Disease,81 and Atlas of Metabolic Diseases.80
In patients with disorders of carbohydrate metabolism and glycogen storage diseases, seizures occur in association with hypoglycemia or during times of metabolic stress. Accordingly, seizures occur in 25% to 40% of patients with glycogen storage disease types I and III and rarely in other types, in which systemic hypoglycemia is uncommon. Patients with d-glyceric acidemia and galactosemia have myoclonic seizures, and abnormal waking EEGs are seen in more than 50% of children with galactosemia.
Niemann-Pick disease, type C (NPC) is a lipid storage disease with a variable age of onset, typically presenting with ataxia, vertical supranuclear gaze palsy, dementia, and, in infants, hypotonia and organomegaly.85 Inheritance is autosomal recessive; most cases are caused by mutations in NPC1, and diagnosis is based on impaired cholesterol esterification in cultured fibroblasts that show positive filipin staining. About one third of patients with NPC have seizures, which are often resistant to treatment. Ironically, seizures tend to decrease with prolonged survival, possibly due to continued neuron loss. Gelastic cataplexy, the sudden loss of muscle tone from humorous stimuli, is present in about 20% of children with NPC.56,88
A number of the disorders of amino acid metabolism (including the urea cycle disorders) feature seizures or epilepsy. The urea cycle defects are especially marked by significantly elevated levels of ammonia; about 50% of neonates with elevated ammonia will have seizures, along with cerebral edema.110 The use of valproic acid is contraindicated in these disorders because it can raise ammonia levels. Seizures are also prominent in HHH (hyperammonemia, hyperornithinemia, hypercitrullinemia) syndrome, nonketotic hyperglycinemia, and homocystinuria.
HHH syndrome, like other disorders of the urea cycle, may present at any time from infancy to adulthood with lethargy, episodes of vomiting or neurologic dysfunction, seizures, and
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coma. It is somewhat more likely to appear later in life than other disorders of the urea cycle, which usually develop in infancy or childhood.
Nonketotic hyperglycinemia (NKH) presents in infancy with intractable generalized or myoclonic seizures, hypotonia, apnea, and high levels of glycine in the blood and cerebrospinal fluid (CSF). NKH has autosomal recessive inheritance, and is caused by mutations in the glycine cleavage system. The EEG most commonly shows a burst-suppression pattern, but hypsarrhythmia can also be seen. NKH should be considered in the differential diagnosis of a patient with infantile spasms. Most patients die before 1 year of age, although affected males have a longer survival rate and better neurologic function.48 Diagnosis can be made by detecting elevated levels of glycine in the serum, but in some cases CSF amino acid analysis is necessary, as glycine levels may only be elevated in the CSF and not in the serum. Brain magnetic resonance imaging (MRI) can be useful for diagnosis as well, as reported abnormalities include ventriculomegaly, absent corpus callosum, posterior fossa cysts, delayed myelination, areas of diffusion-restriction, and an elevated glycine peak on magnetic resonance spectroscopy (MRS).59 Treatment with standard anticonvulsants may not be successful, and treatments directed toward lowering glycine levels have met with only mild success.
Homocystinuria is a relatively common metabolic disorder. The frequency of epilepsy in homocystinuria has been estimated at 21%, with the most common seizure type being generalized tonic–clonic seizures.74 These seizures are not associated with any identifiable metabolic “crisis,” and epileptiform EEG findings are common both in patients with seizures and in patients who are clinically asymptomatic.17
Pyridoxine-dependent seizures (PDS) occur within the first hours or days of life and respond dramatically to treatment with vitamin B6. PDS has autosomal recessive inheritance, and several different gene loci have been implicated.5 Any infant presenting with idiopathic seizures in the first week of life warrants a trial of pyridoxine, as appropriate treatment can lead to a seizure-free, neurologically normal outcome.115
Seizures commonly accompany the metabolic crises of not only the urea cycle disorders, but also of the organic acidurias, such as propionic acidemia, isovaleric acidemia, biotinidase deficiency, and glutaric aciduria, type I. The most common seizure types are generalized myoclonic or infantile spasms. In general, seizures are more likely to be a presenting feature in infants or young children with these disorders than in children with variants of later onset. Biotinidase deficiency can present with ataxia, developmental delay, seizures, and an eczematous rash. Seizures were the presenting feature in 38% of patients, and 55% of patients had seizures.100 Glutaric aciduria, type I, is an autosomal recessive disorder presenting with macrocephaly, a progressive movement disorder that can be misdiagnosed as cerebral palsy, and progressive neurologic symptoms that may acutely worsen during periods of illness.47 MRI may show frontotemporal atrophy and enlarged CSF spaces in the sylvian fissures (“bat-wing” appearance)80 (see also Chapter 262). Seizures more commonly accompany the acute decompensatory episodes.
Mitochondrial disorders typically can be diagnosed by elevated blood and/or CSF lactate levels (see also Chapter 263). Leigh syndrome (subacute necrotizing encephalomyelopathy) is a group of disorders that manifests in infancy with lethargy, failed neurologic development, seizures, and progressive respiratory dysfunction. Leigh syndrome can be caused by mutations in mitochondrial or nuclear DNA. Seizures are present in roughly 30% of patients.90 Older children or adolescents may have symptoms of the mitochondrial deletion disorders MERRF (mitochondrial encephalomyopathy with ragged red fibers) and MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes). (MERRF is discussed in Chapter 262 as one of the primary genetic epilepsy syndromes.) Seizures in MELAS occur initially at times of metabolic disarray and lactic acidosis, but they may become self-perpetuating as structural lesions accumulate in the brain. During the strokelike episodes, the EEG can show characteristic focal high-voltage delta waves with polyspikes.25 Seizures are a presenting sign in 28% of patients with MELAS and are present at some point in 96% of patients.45
The peroxisome biogenesis disorders (the Zellweger spectrum disorders, including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease) have autosomal recessive inheritance. Seizures are very common, and are a significant management problem in neonatal adrenoleukodystrophy.111 The EEG shows diffuse or multifocally abnormal patterns or hypsarrhythmia. In severely affected patients, aberrant cortical structure can sometimes be seen with central nervous system (CNS) imaging. Most severely affected patients die within the first 1 to 2 years of life.
Among the lysosomal storage disorders, epilepsy is a prominent or early feature of Krabbe disease and some forms of Gaucher disease. Generalized or myoclonic seizures become prominent during the course of Tay-Sachs disease and Sandhoff disease, and they can also be seen in patients with sialidosis and Farber disease. Seizures occur as a later phenomenon in about 20% of patients with adrenoleukodystrophy and in up to 46% in patients with metachromatic leukodystrophy.1 The EEG features of these diseases have been reviewed.76
Acute intermittent porphyria, caused by deficiency of the enzyme porphobilinogen deaminase, leads to recurrent seizures in about 10% to 20% of affected patients. The treatment of seizures is difficult because many of the standard anticonvulsants (phenytoin, valproic acid, and in particular the barbiturates) can trigger metabolic crises in individuals with porphyria and are therefore considered unsafe to use. Reynolds and Miska94 have recommended diazepam, paraldehyde, or bromides for treatment of seizures during acute metabolic crises. A recent report documents the successful treatment of seizures with gabapentin.112 Gabapentin and other nonhepatically metabolized drugs such as levetiracetam are appealing drugs to consider in patients with porphyria.
Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the adenosine triphosphatase (ATPase) copper-transporting gene ATP7A. Symptoms, which appear within the first 3 months of life, include failure to thrive, developmental regression, hypotonia, coarse short hair, and seizures. EEGs obtained early in the course show multifocal spikes, but hypsarrhythmia develops as the neurologic disorder progresses. Seizures may be generalized or partial, and they are variable in severity. Copper therapy does not affect the EEG, but seizures may respond to standard anticonvulsant therapy.23
In general, seizures are not a primary feature of disorders of purine metabolism (e.g., Lesch-Nyhan syndrome), endocrine and exocrine disorders, and the immune deficiency disorders. In addition, the mucopolysaccharidoses, some of which produce profound declines in mental function, are not associated with seizures or epilepsy.
An exciting advance in the past decade has been the recognition of two novel types of metabolic disorders: congenital disorders of glycosylation and CSF neurotransmitter disorders.
Congenital disorders of glycosylation, also known as carbohydrate-deficient glycoprotein syndromes, are a heterogeneous group of disorders with multiorgan effects caused by defects in glycoprotein biosynthesis.53 Patients may have developmental delay, ataxia, neuropathy, and characteristic physical findings including inverted nipples and facial dysmorphism. Diagnosis is made by serum transferrin isoelectric focusing. Seizures have been reported in up to 50% of patients.86
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CSF neurotransmitter disorders are a group of metabolic diseases that affect the production of neurotransmitters; diagnosis relies upon CSF fluid collection and measurements of neurotransmitters, their metabolites, and their intermediates. Symptoms include seizures, dystonia and other extrapyramidal disorders, ocular movement abnormalities, autonomic instability, and ataxia.46,49 Timely diagnosis is difficult but important because of the effective treatments available for many of these disorders. Because of limited data regarding the prevalence and symptoms, seizure frequencies are not known for the different CSF neurotransmitter disorders.
Genetic Syndromes
Many disorders seen by the neurologist or geneticist are not easily classifiable; often, they have been grouped according to a prominent physical finding or abnormality. It is important to realize, however, that disorders lumped into a certain category may share nothing except the presence of a single cardinal feature and yet differ widely in regard to their tendency to cause epilepsy.
In genetics, use of the term syndrome implies that a common etiology underlies all symptoms and signs included as part of the syndrome, whereas in the epilepsy literature, syndrome is used to describe a collection of signs or symptoms that commonly occur together; a specific or constant etiology is not implied. (For instance, the Lennox-Gastaut epilepsy syndrome may be present in patients with a number of different genetic disorders or syndromes!) In the discussion below, the terms disease, disorder, and syndrome are used interchangeably to refer to genetically defined entities.
The outline of this section follows the format of Smith’s Recognizable Patterns of Human Malformation.54
Disorders with Short Stature
Seizures are noted particularly in some of the syndromes associated with short stature, including Brachmann-de Lange syndrome (14% to 20%),2,43 Marinesco-Sjögren syndrome, Smith-Magenis syndrome, and the DeSanctis-Cacchione variant of xeroderma pigmentosa (but not in other variants of xeroderma pigmentosa or in other “premature aging” disorders, such as progeria, Seckel syndrome, or Cockayne syndrome).
Disorders of Early Overgrowth
Seizures have been described in up to 25% of patients with Börjeson-Forssman-Lehmann syndrome, caused by mutations in the X-linked PHF6 gene.68 Further, EEG abnormalities, consisting mostly of low-voltage fast activity or nonspecific slowing, were present in at least 50% of patients, as well as in otherwise asymptomatic female carriers.96 Neonates with Beckwith-Wiedemann syndrome may present with seizures secondary to hypoglycemia, and occasional patients have an ongoing seizure disorder. Finally, seizures with or without severe brain malformation may be seen in patients with hemihypertrophy (which is in itself not a diagnosis, but rather a physical sign of diverse etiologies); patients with significant somatic asymmetry should always be evaluated for CNS structural abnormalities.
The incidence of epilepsy has not been reported to be significantly elevated in the syndromes of Bannayan-Riley-Ruvalcaba, Cohen (6% incidence of seizures), Marshall-Smith, Simpson-Golabi-Behmel, Sotos, and Weaver.
Skeletal Dysplasias
Many of the skeletal dysplasias cause abnormal skull or facial shape. However, deformation of the cranial contents alone does not necessarily result in seizures. Thus, patients with achondroplasia, metaphyseal dysplasias, or the osteopetrosis syndromes do not have a high risk for epilepsy or seizures. However, seizures do occur in patients with bony diseases related to systemic hypocalcemia, such as Albright osteodystrophy and hypophosphatasia (2% to 24%, greater frequency with earlier age of onset); the seizures are presumably related to the metabolic disruption and are not a primary feature of the bony disease. Patients with osteogenesis imperfecta do not have increased seizure risk, although a single study demonstrated EEG abnormalities in half of 56 patients.93 Finally, cortical dysplasias (and thus an increased risk for seizures) have been reported in thanatophoric dysplasia.
Craniosynostosis can arise from diverse syndromic, chromosomal, metabolic, hematologic, and environmental causes. Thus, the presence of seizures in a patient with craniosynostosis should prompt an evaluation of the etiology of the craniosynostosis, as well as CNS imaging. Seizures occur frequently (percentage in parentheses) in patients with Christian syndrome (60%),33 Crouzon syndrome (12%),64 and Saethre-Chotzen syndrome (36%),20 but not in Apert syndrome.
Disorders with Facial Defects
A large number of genetic syndromes affect facial morphogenesis, or cranial nerve formation, but the majority do not have associated seizures (see Gorlin et al.).33 Teratogens such as anticonvulsants can also result in facial defects, but these are not discussed here. A significant risk for seizures in patients with oral-facial syndromes is the presence of CNS structural abnormalities. For example, FG syndrome is characterized by hypotonia, characteristic facial appearance, and agenesis of the corpus callosum.34 EEG abnormalities have been described in FG syndrome patients,82 and seizures have been reported in 0% to 60% of patients.98
Cardiofaciocutaneous syndrome (CFC syndrome), characterized by distinctive facial appearance; unusually sparse, brittle, curly hair; skin abnormalities; heart malformations; growth delays; and/or varying degrees of mental retardation, has been reported to have fairly common seizures (5 of 22 cases).26 Recent molecular evidence shows that CFC syndrome and Noonan syndrome (which also has unusual facies and congenital heart defects) are distinct entities.52
Patients with Coffin-Lowry syndrome may have paroxysmal drop attacks (stimulus-induced drop episodes [SIDES]) that in the past were believed to be seizures. However, detailed characterization of these events has revealed that they are nonepileptic events with features of both cataplexy and hyperekplexia.77
Eleven percent of patients with Parry-Romberg syndrome develop seizures.108 Affected patients have progressive hemifacial atrophy, often with trigeminal neuralgia and ophthalmologic abnormalities; the etiology is unclear, and there is some discussion as to whether the disease is a form of autoimmune scleroderma.
Facial disorders not associated with an increased risk of seizures include branchial arch syndromes, facial clefting syndromes, Langer-Giedion syndrome, Moebius syndrome, Treacher Collins syndrome, and Smith-Lemli-Opitz syndrome.58
Connective Tissue Disorders
Seizures do not occur with increased frequency in any of the connective tissue disorders (Marfan syndrome, Ehlers-Danlos syndromes, osteogenesis imperfecta), with the exception of homocystinuria (discussed above).
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Neurocutaneous Disorders
The diagnosis of a neurocutaneous disorder should prompt surveillance for seizures, as epilepsy is a common feature in these disorders.63
Neurofibromatosis type 1 (NF1) is the most common of the neurocutaneous disorders. The incidence of epilepsy in NF1 is reported to be 5% to 11%.119 NF1, also known as von Recklinghausen disease, is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris Lisch nodules. NF1 has autosomal dominant inheritance and its associated gene (neurofibromin) has been identified, but because of the large size of the gene, diagnosis is based on clinical criteria.38 New-onset seizures in a patient with a personal or family history of NF1 should prompt a search for intracranial neoplasm, as patients have a lifelong increased risk for a variety of CNS tumors, especially optic nerve and brainstem gliomas.
Neurofibromatosis type 2 (NF2), an autosomal dominant mutation in neurofibromin-2 (merlin), is genetically and clinically distinct from NF1. NF2 is associated with bilateral vestibular schwannomas, multiple meningiomas, and other CNS tumors. NF2 has an approximately 8% seizure risk.22
Tuberous sclerosis complex (TSC) is characterized by hypomelanotic macules, facial angiofibromas, shagreen patches, ungula fibromas, brain tubers and/or subependymal nodules, seizures, mental retardation, kidney angiomyolipomas, and cardiac rhabdomyomas. Inheritance is autosomal dominant, caused by mutations in either TSC1 (hamartin) or TSC2 (tuberin).
Seizures affect up to 80% of TSC patients,31,64 and infantile spasms occur in up to one third of patients.113 The most common cause of infantile spasms is TSC; 25% of patients with infantile spasms have TSC. Because of this association, an infant presenting with infantile spasms should have a careful skin examination, and if indicated, an examination with a Wood lamp to look for hypomelanotic macules. Further, significant evidence suggests that first-line treatment for infantile spasms in TSC patients is vigabatrin (not adrenocorticotropic hormone [ACTH], which is used for non-TSC infants with infantile spasms).40
Overall, 60% of TSC patients are mentally retarded, and of these 98% have seizures; only 59% of those TSC patients without retardation had seizures.101 Sixty-four percent of patients with TSC who have infantile spasms will develop mental retardation.30
Subependymal glial nodules occur in 90% of individuals with TSC, and cortical or subcortical tubers in 70%.19 Patients with more than four cortical lesions visible on MRI were more likely to have intractable seizures.95 Progressive intracranial calcification (of uncertain relevance to the seizure disorder) develops in children with this disease, and they are at risk for brain tumors, in particular giant-cell astrocytomas.
Infantile-onset seizures, often severe, are a presenting feature of encephalocraniocutaneous lipomatosis. This disorder involves skin, eye, adipose tissue, and brain. Neurologic manifestations include seizures, ventricular enlargement, calcifications, mental retardation, and cerebellopontine angle tumors.67
Proteus syndrome is a complex disorder with uncertain etiology; clinical features include disproportionate, asymmetric overgrowth of body parts; connective tissue nevi; epidermal nevi; vascular malformations of the capillary, venous, and lymphatic types; and dysregulated adipose tissue.15 Seizures have been reported in association with Proteus syndrome, although the incidence is not known. Hemimegalencephaly refers to hamartomatous malformation of the brain with diffuse migrational abnormalities of an entire cerebral hemisphere; there are both “isolated” and syndromic (including some of the neurocutaneous syndromes such as Proteus syndrome) causes. Seizures tend to have onset in infancy and may be difficult to control medically. A recent study listed seizures in 100% of patients, with 26% requiring hemispherectomy to achieve seizure control.102
Epidermal nevus syndrome is characterized by nevi following the lines of Blaschko, along with noncutaneous involvement of the brain, eye, and skeletal systems; but it is most likely a collection of several separate entities with similar clinical features (including linear nevus sebaceous syndrome). Linear nevus sebaceous syndrome is characterized by midline nevus sebaceous, seizures (in 67% of patients), mental retardation, and associated CNS abnormalities including hemiatrophy and ventricular dilatation.116
Sturge-Weber syndrome is a sporadically occurring disorder of the vasculature of the face and head. Intracranially, unilateral leptomeningeal angiomas and calcifications develop, which commonly follow the course of the angiomatous vessels.87 Seizures occur in 80% of patients with Sturge-Weber syndrome.109 Unilateral or bilateral epileptiform discharges can be present, with or without unilateral or bilateral background slowing.10,97
Incontinentia pigmenti is an X-linked disorder of the skin, hair, nails, teeth, eyes, and CNS, caused by mutations in the NEMO gene (NF-kappaB essential modulator).106 CNS malformations and seizures have been reported in this disorder, although the prevalence is uncertain. Patients with hypomelanosis of Ito have skin depigmentation along the lines of Blaschko and neurologic symptoms including language disabilities, seizures, hypotonia, mental retardation, and autistic behavior, with underlying abnormalities in the CNS white matter.99 The disorder is probably an etiologically diverse group of conditions with genetic mosaicism as a common feature.65 Seizures are reported in up to 49% of patients, and infantile spasms in 8% of patients.84
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease), characterized by the presence of multiple arteriovenous malformations (AVMs), does not have an increased risk of seizures. However, brain MRI with vascular imaging is indicated early in life to look for cerebral AVMs, and antibiotic prophylaxis is indicated for patients with a pulmonary AVM, as they can develop a cerebral abscess and seizures. Lipoid proteinosis (Urbach-Wiethe syndrome), nevus basal cell carcinoma syndrome (Gorlin-Goltz syndrome), pseudoxanthoma elasticum, and Sjögren-Larsson syndrome are not associated with seizures.
Ectodermal and Mesodermal Dysplasias
Seizures are not a feature of the ectodermal dysplasias. Diseases that disrupt the development of primarily mesodermal structures, such as the multiple intestinal polyposis syndromes and the multiple endocrine neoplasias, also are not associated with epilepsy.
Genetic Disorders of Brain Development
The past 10 years have seen an explosion in information about the genetics of CNS developmental abnormalities. In part, this has been facilitated by the advances in CNS imaging made possible by high-resolution MRIs, which have revealed underlying brain abnormalities in many patients with seizures (see Chapters 14, 79, and 260). Guerrini and Filippi36 reviewed the frequency of seizures and EEG findings in each disorder and also outlined procedures for genetic testing and genetic counseling (see also the review by Mochida72).
Holoprosencephaly is characterized by failure of the forebrain to divide into separate hemispheres and ventricles; there is a continuum of clinical features and severity, often with other
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malformations of the CNS and neuronal migrational abnormalities. Causes include teratogens, gross chromosome abnormalities in structure or number (25% to 50% of cases), syndromes, and single gene mutations in 18% to 25% of cases.75 If genetic testing is indicated, high-resolution chromosome karyotypes should be obtained, and if necessary, FISH analysis of the known genes. About 80% of patients with holoprosencephaly also will have a craniofacial abnormality.14 Seizures are common, but incidence depends on the etiology of the holoprosencephaly and the extent of malformations. In addition, hypersynchronous activity on EEG was seen in patients with holoprosencephaly without seizures.39
Schizencephaly is a structural brain abnormality, in which a CSF-filled cleft, lined by gray matter, extends from the pial surface of the brain to the ventricle. A variety of etiologies are hypothesized, and there are syndromic and familial cases, although no causative genes have yet been identified. Seizures are present in about 50% of patients.35
Septo-optic dysplasia (de Morsier syndrome) is a midline CNS disorder characterized by hypoplastic or absent optic discs and nerves, absent septum pellucidum, and pituitary deficiencies; seizures occasionally accompany this disorder. Mutations in the homeobox gene HESX1 have been found in some patients with septo-optic dysplasia.16
Seizures are not a typical feature of the developmental disorders of the posterior fossa, such as Arnold-Chiari malformation, Dandy-Walker malformation, or Joubert syndrome. Seizures have been reported in patients with Arnold-Chiari I malformation (in which the cerebellar tonsils are displaced downward through the foramen magnum), although it is not clear if the incidence is increased.11 The unusual respiratory pattern and eye movements in infants with Joubert syndrome, however, can mimic seizures.
Lissencephaly, or smooth brain, is a pathologic or MRI finding of abnormal neuronal migration, resulting in absent (agyria) or reduced number (pachygyria) of gyri. Ninety percent of patients with lissencephaly have seizures, with onset before age 6 months in 75%. Almost 80% have infantile spasms. Different types of lissencephaly have been described including LIS-1–associated lissencephaly (Miller-Dieker syndrome), X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia (caused by mutations in ARX), and DCX-associated lissencephaly. Miller-Dieker syndrome is a microdeletion (contiguous gene deletion) of chromosome region 17p13.3, characterized by lissencephaly (with four rather than six nerve cell layers in the cortex) and a specific facial phenotype. The lissencephaly is caused by mutations in LIS-1,92 while the facial features are due to the contiguous genes deleted in the syndrome.
Polymicrogyria is characterized by multiple small gyri with abnormal cortical lamination, frequently accompanied by seizures. Types include bilateral frontoparietal polymicrogyria, bilateral frontal polymicrogyria, and bilateral perisylvian polymicrogyria. Heterotopias are abnormal collections of gray matter, typically either in the deep white matter of the cerebral hemispheres or in the periventricular regions. X-linked periventricular nodular heterotopia has been associated with mutations in the FLN1 and ARGEF2 genes. Approximately 90% of patients with periventricular nodular heterotopia have epilepsy.
Three disorders have been described with the combination of brain abnormalities and congenital muscular dystrophy: Muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD).32 All three are characterized by infantile hypotonia and a “cobblestone” appearance of lissencephaly in their brain MRIs. There is significant clinical overlap in their symptoms; MEB and WWS also may have eye abnormalities, hydrocephalus, and leukoencephalopathy.117 MEB and WWS are caused by mutations in genes (POMGnT1 and POMT1, respectively, although there are several other gene loci also identified) involved in the glycosylation of a-dystroglycan, a structural protein.117 FCMD is caused by mutations in the fukutin protein; seizures are present in 80% of patients with an average onset age of 3 years.126 In MEB and WWS, seizures have been reported, although the incidence has not been established.
Neurodegenerative Disorders
Rett syndrome is an X-linked progressive neurologic disease characterized by initial normal development, followed by a plateau and then regression of cognitive and motor skills, deceleration of head growth, and the development of autistic-like features.127 The classic phenotype is only present in girls; however, some few cases of affected males (with much worse clinical characteristics) have also been reported. Rett syndrome is caused by mutations in the MECP2 gene.
EEG abnormalities are an invariable feature of Rett syndrome, and seizures are present in 50% of patients.78,83 The waking EEG usually shows a poorly organized, slow background, which is interrupted by multifocal or bilaterally synchronous spikes or sharp waves that may become constant during sleep. Later in the course, the EEG may show only nonspecific low-voltage activity. The percentage of rapid eye movement (REM) sleep is diminished throughout the course of the disease. It has also been noted that not all “spells” in patients with Rett syndrome are epileptic.27 Nearly 25% of 62 patients had episodes of breath holding, staring, laughing, or jerking that were without EEG correlation.
Autism, autistic-spectrum disorders, Asperger disorder, Landau-Kleffner syndrome (LKS), and pervasive developmental delay represent a spectrum of disorders with diverse etiologies. Thirteen percent of children with autism have epilepsy; another 22% have EEG abnormalities but no seizures.12 Exact diagnostic criteria for LKS (or acquired epileptic aphasia) remain contentious, but patients present with a progressive childhood-onset aphasia associated with EEG abnormalities, most commonly continuous spike-and-wave discharges during sleep (electrical status epilepticus of sleep). Up to 70% of patients have clinical seizures.114
Seizures occur at an increased frequency in Alzheimer disease (10% of autopsy-proven cases,42 16.8% of institutionalized patients7), but they may not recur or require treatment. Myoclonus occurs in up to 10% of patients, and nonspecific EEG slowing is common, particularly as the disease progresses.
Seizures are a prominent feature of the neuronal ceroid lipofuscinoses (NCLs). Patients present with a combination of visual loss, seizures, and progressive cognitive impairment or dementia. The NCLs are autosomal recessive lysosomal storage disorders, characterized pathologically by electron microscopy revealing fingerprint or curvilinear profiles, or granular osmiophilic deposits.29 At least six different genes have been identified; diagnosis relies upon a combination of enzymatic testing for the protein defect and/or electron microscopy studies. The seizure disorder may appear as a progressive myoclonic epilepsy.62 Raininko et al.91 reported abnormal EEGs in 25 of 33 patients with juvenile NCL; 23 of these 25 EEGs showed paroxysmal activity, either focal or generalized. The EEG typically shows posteriorly prominent, light-induced spikes, and as the disease progresses, low-voltage activity with marked slowing predominates. Treatment of the seizures can be difficult; valproic acid tends to be poorly tolerated because of side effects, while lamotrigine appears to be more effective.122
Seizures are reported to occur frequently (30%) in patients with Huntington disease whose symptoms first appear in
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childhood or adolescence, but much less often (2%) in the more typical adult-onset disease.41 Huntington disease is caused by an autosomal dominant trinucleotide repeat expansion in the HD gene. Generalized, akinetic, or myoclonic seizures, rather than partial seizures, are seen. EEG abnormalities are seen in 74% of juvenile-onset Huntington disease patients.66
Epilepsy is not a feature of Parkinson disease and its variants, except that Nygaard et al.79 reported complex partial seizures in 7 of 55 patients with progressive supranuclear palsy.
The spinocerebellar ataxias (SCAs) are a large and heterogeneous group of genetic disorders, characterized chiefly by progressive cerebellar ataxia. Epilepsy is reported in SCA10, SCA17, and dentatorubropallidoluysian atrophy (Haw river syndrome) (DRPLA),69 which are caused by dominantly inherited triplet repeat expansions. Epilepsy is reported in 20% to 100% of SCA10 patients. Myoclonus and epilepsy are a defining feature of the “myoclonus epilepsy” form of DRPLA, but are infrequent or absent in the ataxic or choreic forms of the disease. Epilepsy occurs in all DRPLA patients with onset before age 20.50 This disease appears to be less common in the United States than in Japan, where it may be responsible for 10% to 20% of adolescent- or adult-onset progressive myoclonus epilepsy.
In Wilson disease, an autosomal recessive disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, 6% of patients develop epilepsy with a greater incidence in patients with juvenile onset of symptoms.18 McLeod neuroacanthocytosis syndrome is an X-linked disorder with red blood cell acanthocytosis and basal ganglia degeneration; up to 40% of patients develop seizures.55 Pantothenate kinase–associated neurodegeneration (PKAN) (Hallervorden-Spatz syndrome) is characterized by progressive dystonia, dysarthria, rigidity, and pigmentary retinopathy. No seizures were reported in any patient with classic PKAN.44
Summary and Conclusions
More than half of the references cited here are new since the first edition of Epilepsy. This reflects the impressive strides in diagnosis made possible by advances in molecular and radiologic diagnostics, and the corresponding attention given to the topic both by epileptologists and by geneticists. The material includes comprehensive reviews of the epilepsies in broad genetic categories (such as chromosome abnormalities, inborn errors of metabolism, and neuronal migration disorders) as well as in specific disorders (such as the tuberous sclerosis complex).
In some of the disorders discussed in this chapter, the underlying genetic involvement is obvious, for example, the patient with trisomy 13 and dysmorphic characteristics on examination. In other situations the clinician must associate the findings of history and examination with characteristics of the epilepsy to make a diagnosis, as in patients with Angelman syndrome. A key point is that in many instances, the genetic syndromes with epilepsy now have specific genetic diagnoses.
This discussion of genetic syndromes and epilepsy is not exhaustive, but it provides a summary of the more common disorders a neurologist or geneticist might encounter. Appropriate treatment is dependent upon diagnosis, and diagnosis can be aided by recognizing those genetic syndromes accompanied by epilepsy. Thus, identification of the genetic and molecular bases for these disorders may provide an opportunity for directed pharmacotherapy. It may be noted that this approach complements the study of comorbidities that are observed in patients with primary epilepsies in which seizures are the primary manifestation. With these points in mind, this chapter should be of interest to epileptologists and other neurologists as well as to geneticists.
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