Epilepsy

Genetic Testing for Epilepsy

A Guide for Clinicians

KNOWING WHAT TO LOOK FOR KNOWING WHERE TO LOOK AND KNOWING WHAT IT MEANS
 Figure 1.

Introduction
Epilepsy is a common neurological disorder that affects at least 0.8% of the population. It is
defined by the occurrence of at least two unprovoked seizures occurring more than 24 hours
apart. Seizures are the manifestation of abnormal hypersynchronous discharges of cortical
neurons lasting for several seconds, minutes, or longer. The clinical presentation of seizures
depends upon both the location of the epileptic discharges in the cortex and the extent and
pattern of propagation of the electrical discharges in the brain.

In many cases, seizures result in convulsions and loss of consciousness. Seizures may also
manifest in other ways that affect personality, mood, memory, sensation, and/or movement. Blank
stares, lip smacking, intermittent eye movements, and jerking movements of the extremities are
all examples of possible manifestations of seizures. In some cases these may not be recognized
as a seizure by patients, their family members, or even health care professionals. Seizures can
be classified into various categories (Figure 1).
PLEASE REDRAW to make it look similarly to the one in the guide.
FIGURE 1: Types of seizures. Generalized Tonic-Clonic 12-24%

Complex Partial 8-31%

Absence 5-22%

Infantile Spasms 1-9% Simple Partial 2-12%

Myoclonic 1-11%
Other Partial 7-29%
Other Generalized <1-3%

Unclassified/Mixed 4-43%

Reference: Cowan, LD. The epidemiology of the epilepsies in children. Ment Retard Develop
Disab (2002) 8:171-181.

Etiology
Epilepsy may be an isolated neurological symptom, or it may occur as part of a more complex
syndrome. There are many different causes of epilepsy, including genetic disorders, metabolic
diseases, and structural brain abnormalities. However, in some cases, the cause of epilepsy
is not known. The International League against Epilepsy (ILAE) has described the underlying
causes of epilepsy as the following.3

Genetic: The concept of genetic epilepsy is that the epilepsy is, as best as understood, the
direct result of a known or presumed genetic defect(s) in which seizures are the core symptom

GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS 1

of the disorder.3 The genetic contribution must be evident by extensive and replicable molecular
studies or familial studies, e.g., SCN1A gene has been demonstrated to be associated with GEFS+.9

Structural/metabolic: If there is a specific structural or metabolic disorder that has been proven
in various studies to be associated with increased risk of epilepsy, the cause of epilepsy can
be defined as structural or metabolic. The cause for such a disorder can be acquired (e.g.,
trauma, stroke, infection), genetic (e.g., malformations of cortical development) or both (e.g.,
West syndrome).

Unknown cause: This means that the underlying cause is yet unknown. Epilepsy might be
presenting because of either some genetic defect or as a result of disorder that is not yet
recognized.

Diagnosis of Epilepsy
Clinical and family history
The detailed clinical history may help confirm that the seizure events are in fact epileptic seizures,
rather than non-epileptic events such as fainting, breath-holding, transient ischemic attacks,
strokes, arrhythmias, or hypoglycemia, all of which can manifest similarly to epileptic seizures.
A detailed clinical history also may help clarify potential triggers and diurnal patterns related to
seizure events. The medical history will help to determine if the seizures are isolated or part of a
larger syndrome. In addition to clinical history for the affected individual, a family medical history
should be obtained, including any history of seizures and other neurodevelopmental disorders
in any relatives. This information may help clarify the type of epilepsy in a family, including the
mode of inheritance and the prognosis.

Electroencephalogram (EEG)
Children with a known or suspected diagnosis of epilepsy based on clinical and family history
should undergo an EEG to help confirm the seizure type, and to evaluate recurrence risk for
future seizures. An EEG may also provide important information for making treatment decisions
(Figure 2).

Physical examination
In some cases, an individual with epilepsy may have other related neurological abnormalities,
medical problems, or dysmorphic features that can be identified by physical examination. For
example, many genetic syndromes involving epilepsy also cause developmental delay, hypotonia,
birth defects, ataxia, dystonia, microcephaly or macrocephaly, dysmorphic facial features, or
other features that can be noted in a physical examination.

Genetic testing
The information obtained from clinical and family histories, physical examination, and EEG can
help a clinician determine whether genetic testing should be offered to a patient with epilepsy
and which specific genetic test(s) may be appropriate.2

2
Genetics of Epilepsy
The last decade has witnessed the discovery FIGURE 2: Typical EEG abnormalities for
of many genes involved in epilepsy. Most different types of seizures.
of these genes are expressed in the brain
and encode subunits of ion channels that
play vital roles in stabilizing or propagating
neuronal activity. Disruption of these genes
in general induces neuronal hyperexcitability,
thus causing seizures. As described above,
there are many forms of epilepsies. A single
gene may be associated with different
forms of epilepsy, but one type of epilepsy
may also result from defects in any one
of a variety of genes.5 Inherited channels
caused by mutations in ion channel or
Normal EEG (9yr-old child)
neuroreceptor genes (e.g., SCN1A-related
disorders and KCNQ2, KCNQ3 mutations
in benign familial neonatal seizures) can
present with seizures.9 Rarely epilepsy
syndromes can be the result of severe
mutations in single genes whereas more
commonly epilepsy is likely to be caused
by the combined effect of variants in a
number of genes that cannot be currently
defined. Examples of monogenic causes of
epilepsy are pyridoxine-dependent epilepsy
and neuronal ceroid lipofuscinoses (NCL). Modified hypsarrhythmia during sleep in patient
In some cases, copy number variations with infantile spasms (8mo-old infant)
associated with neuropsychiatric disorders
can be involved in epilepsy too. It is well
known that the 1p36 microdeletion, Wolf-
Hirshhorn, Miller-Dieker, Pallister-Killian, and
Angelman syndromes include epilepsy as
a major feature, but these disorders also
involve various other clinical features as
well.2 Table 1 shows the common genetic
disorders that have been associated
with epilepsy. Some rare mitochondrial
disorders, such as MERRF and MELAS
can also present with epilepsy as one of Generalized spike wave in
the symptoms.1 patient with absence epilepsy (3yr-old child)

GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS 3

Table 1: Genetic disorders associated with Epilepsy

Syndrome Clinical Presentation Inheritance Genes

Adenylosuccinate Psychomotor delay, intellectual disability, AR ADSLI,C,A
lyase deficiency intractable seizures autism
Angelman/Angelman- Developmental delay, onset AD CNTNAP2I,C,A
like syndromes at >6 months of age, ataxia, SLC9A6I,C,A
tremulousness, happy appear- NRXN1I,C,A
ance, microcephaly, seizures TCF4I,C,A
UBE3AI,C,A
Autosomal dominant Seizures arising from sleep, AD CHRNA2C,A
nocturnal frontal prominent motor manifestations CHRNA4C,A
lobe epilepsy CHRNB2C,A
Autosomal dominant Ictal auditory symptoms and AD LGI1C,A
partial epilepsy with receptive aphasia, secondary
auditory features generalization, benign course
Baltic myoclonus Individuals in late childhood or AR CSTBC,A,P
(Unverricht-Lundbord adolescence with photosensitive
disease) myoclonus, seizures, ataxia
Benign familial Seizures from 2 days of age to AD SCN2A,I,C
neonatal-infantile 6 months, normal development
seizures (BFNIS)
Benign familial neonatal Neonatal seizures at approximately 3 AD KCNQ2I, KCNQ3I
seizures (BFNS) days of age, resolution at <1 month of
age, generalized or focal tonic-clonic
seizures, normal development
Creatine deficiency Developmental delay, seizures, Various GAMTI,C, GATMC
syndromes positive magnetic resonance SLC6A8C
spectroscopy, autism
Early-onset epileptic Early onset, multiform and Various ALDH7A1I, ARXI
encephalopathy and/ intractable seizures, cognitive, ATP6AP2I
or infantile spasms behavioral, and neurological CDKL5I,C
PCDH19I,C
POLGI,C,A
PNPOI, SCN1AI,C
SLC2A1I,C,A
SLC25A22I
SPTAN1I
STXBP1I
Epilepsy with variable Variable clinical presentations with com- XL SYN1C,A
learning and behavioral binations of epilepsy, learning difficulties,
disorders macrocephaly, and aggressive behavior
Generalized epilepsy Onset of febrile seizures at <1 year of AD GABRG2I,C
with febrile seizures age, persistence beyond age 6 years, SCN1AI,C
plus (GEFS+) evolution to mixed seizure types SCN1BI,C
SCN2AI,C

Superscript indicates the panels on which the genes are present. I = infantile epilepsy panel; C = Childhood-
onset epilepsy panel; A= Adolescent onset epilepsy panel; P = Progressive myolconic epilepsy panel

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Syndrome Clinical Presentation Inheritance Genes
Glucose transporter Early-onset refractory seizures, AD SLC2A1I,C,A
Type I deficiency movement disorders, ataxia, pro-
syndrome gressive encephalopathy, acquired
microcephaly, and spasticity
Juvenile Myoclonic Typically seizures begin between AD CACNB4C,A
Epilepsy (JME) late childhood and early adulthood, EFHC1C,A
characterized by quick jerks of the arms, GABRA1C,A
shoulder, or occasionally the legs
Lafora disease Progressive myoclonus, myoclonic AR EPM2AC,A,P
epilepsy, absences, and dementia EPM2BC,A,P
Microcephaly with Infantile-onset seizures accompanied AR PNKPI
early-onset intractable by microcephaly developmental
seizures and develop- delay and various behavioral
mental delay (MCSZ) problems (typically hyperactivity)
Mowat-Wilson Distinctive facial features, Hirschsprung Various ZEB2I,C
syndrome Disease, intellectual disabilities, genital
abnormalities, congenital heart disease,
agenesis of the corpus callosum, seizures,
eye defects and severe speech impairment.
Neuronal Ceroid Intellectual and motor deterioration, AR CLN3I,C,A,P
Lipofuscinoses (NCL) seizures, visual loss, and early mortality CLN5I,C,A,P
CLN6I,C,A,P
CLN8I,C,A,P
CTSDI,C,A,P
MFSD8I,C,A,P
PPT1I,C,A,P
TPPI,C,A,P
Ohtahara syndrome Suppression burst on electroen- Various STXBP1I, ARXI
cephalogram, tonic seizures
Progressive Myoclonic Myoclonic seizures, cognitive AR PRICKLE1C,A,P
Epilepsy (PME) impairment, ataxia, and dementia
Pyridoxine depen- Vitamin B6-responsive seizures AR ALDH7A1I
dent seizures
Rett/Atypical Rett Rett Syndrome: Regression then Various CDKL5I,C
syndrome stagnation, onset at <18 months of FOXG1I,C
age, loss of purposeful hand move- MECP2I,C
ments, acquired microcephaly
Atypical Rett Syndrome:
Early-onset seizure variant of Rett
syndrome, Infantile spasms
West Syndrome Infantile spasms, hypsar- Various TSC1I, TSC2I
rhythmia, encephalopathy CDKL5I,C, ARXI
STXBP1

There are 4 subpanels and a comprehensive panel available to order. ATP1A2 and SRPX2 are not part of any subpanel,
but are included in the comprehensive panel along with all the other genes listed in this table.
Superscript indicates the panels on which the genes are present. I = infantile epilepsy panel; C = Childhood-
onset epilepsy panel; A= Adolescent onset epilepsy panel; P = Progressive myolconic epilepsy panel

GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS 5

Clinical Utility of Genetic Testing
Genetic testing for epilepsies is often complex because mutations in so many different genes
can cause seizures. Nevertheless, genetic testing can be useful in certain clinical scenarios
when it can help in clarifying the prognosis, assist in treatment and management of the patient,
and predict the risk of a disease in family members. Genetic testing is termed diagnostic if
the patient is symptomatic and predictive if the patient is asymptomatic, but at risk for having
a disorder in the future.1

TABLE 2: Clinical utility of genetic testing

1. Diagnostic testing in an individual with epilepsy

Confirm a clinical diagnosis of a specific genetic syndrome or type of epilepsy
Distinguish between syndromic and non-syndromic forms of epilepsy
Establish the genetic cause of idiopathic epilepsy
Provide information about prognosis
2. Assistance with selection of optimal treatment options
3. Predictive testing for asymptomatic family members of a proband with a
known disease-causing mutation associated with a genetic form of epilepsy
Enable clinical monitoring, follow-up, and optimal treatment when symptoms
develop in an individual with a positive result
Reduce anxiety and forego clinical monitoring if result is negative
4. Prenatal diagnosis in at-risk pregnancies for known, pathogenic mutations
5. Genetic counseling, recurrence risk determination, and family planning

Utility of genetic testing in treatment:

The treatment of epilepsy depends upon the type of seizure, age of the patient, and other factors.
Knowledge of the genetic etiology of epilepsy may guide selection of the most appropriate
treatment options in some cases. A number of antiepileptic medications are used in the treatment
of epilepsy. The specific type and etiology of seizures may influence the selection of antiepileptic

6
medication for each patient. For example, certain medications may be more effective for infantile
spasms and are therefore first choices for patients with spasms. Likewise, certain medications
may be contraindicated for patients with a specific electroclinical or genetic diagnosis (Table
3). Dietary modifications including the ketogenic diet are useful in certain conditions1 such as
for patients with glucose transporter type 1 deficiency syndrome (SLC2A1 gene).

TABLE 3: Genetic test results applied to therapeutic decision-making

Disorder Genes Treatment Implications

Alpers-Huttenlocher and other POLG Avoid valproic acid, which can
POLG-related disorders induce or accelerate liver disease

Creatine deficiency syndromes SLC6A8, Oral creatine (GAMT, AGAT)

GAMT, GATM

GEFS+, and other SCN1A- SCN1A Valproate, clobazam, stiripentol, leveti-

related disorders racetam, topiramate. Avoid phenytoin,
carbamazepine, and lamotrigine.

Glucose transporter type SLC2A1 Seizures typically respond

1 deficiency syndrome to a ketogenic diet

Pyridoxal 5-phosphate- PNPO Seizures respond to treatment with

dependent epilepsy supplemental pyridoxal 5-phosphate (PLP)

Pyridoxine-dependent epilepsy ALDH7A1 Seizures respond to treatment with sup-

Folinic-acid responsive seizures plemental vitamin B6 and/or folinic acid

Lafora disease EPM2A, EPM2B Avoid phenytoin, lamotrigine,

carbamazepine, and oxcarbazepine

Unverricht-Lundborg disease CSTB Avoid sodium channel blockers and

GABAergic drugs, which can increase
myoclonus, dementia, and ataxia

West syndrome TSC1, TSC2, Vigabatrin for infantile spasms with TSC
CDKL5 (STK9),
ARX, STXBP1,
MEF2C

GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS 7

Genetic Test Results and What They Mean
There are three possible outcomes of genetic testing: a positive result, a negative result, or a
variant of unknown significance (VUS).2

Positive:
A positive result indicates that a disease-causing mutation was identified in the tested individual.
This finding confirms the diagnosis of a particular type of epilepsy and provides valuable information
to the physician and family members about treatment, prognosis, and recurrence risk. All
first-degree relatives (e.g., children, siblings, and parents) of a patient with a positive genetic
test result can then be offered predictive genetic testing. If a family member is found to be
positive for the familial mutation, this individual is also at risk to develop the epilepsy syndrome
and should be referred for further evaluation. It is important to note that there is variability in
symptoms, age of onset, severity, and response to therapeutic agents, even among members
of the same family who have the same genetic mutation causing epilepsy.

Negative:
A negative result in an individual with epilepsy does not rule out a genetically inherited epilepsy
syndrome. Possible reasons for a negative result could be (1) the patient has a mutation in
a gene not included in the testing panel, (2) the patient may have a mutation in a part of an
epilepsy gene that was not covered by the test, or (3) the patient does not have a heritable form
of epilepsy. A negative result obtained in a specific genetic test in an individual with epilepsy
indicates that predictive of asymptomatic family members will not be informative for that same
test, and is not warranted. However, family members of a clinically affected individual with
negative test results may still be at risk for epilepsy syndromes and thus should be evaluated
by a neurologist if indicated.

If an asymptomatic individual is negative for a mutation identified in a family member with epilepsy,
the result is considered a true negative. This indicates that the individual is not at increased
genetic risk for the familial epilepsy syndrome and instead has the same risk as a person in
the general population to develop seizures. Specific clinical monitoring for the development of
seizures is not necessary in individuals with a true negative result.

Variant of Unknown Significance:

One of the most difficult results to interpret is the finding of a variant of unknown clinical significance
(VUS). This situation indicates that the pathogenic role of the variant cannot be clearly established.
In some cases, testing of other family members may help clarify the clinical significance of a
VUS. If other relatives with epilepsy are found to have the same variant, it is more likely that
the variant is disease-causing. The greater the number of affected family members who carry
the VUS, the greater is the likelihood that the VUS is pathogenic. Likewise, if an individual has
apparently sporadic epilepsy, the finding that a VUS is de novo (arose new in that individual and
was not inherited from a parent) indicates that the variant is likely disease-causing.

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References:

1. Pong, et al. Developments in molecular genetic diagnostics: An update for the pediatric epilepsy
specialist, Pediatr Neurol (2011) 44:317-327.
2. Pal, et al. Genetic evaluation and counseling for epilepsy. Nat Rev Neurol (2010) 6:445-453.
3. Berg, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the
ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia (2010) 51: 676-685.
4. Deprez, et al. Genetics of epilepsy syndromes starting in the first year of life. Neurology (2009)
72:273-281.
5. Baulac, S and Baulac, M. Advances on the genetics of Mendelian idiopathic epilepsies. Neurol Clin
(2009) 27:1041-1061.
6. Macdonald, et al. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol
(2010) 588:1861-1869.
7. Ottman, et al. Genetic testing in the epilepsies Report of the ILAE Genetics Commission. Epilepsia
(2010) 51:655-670.
8. Ramachandran, et al. The autosomal recessively inherited progressive myoclonus epilepsies and their
genes. Epilepsia (2009) 50:29-36.
9. Steinlein, et al. Genetic mechanisms that underlie epilepsy. Nat Rev Neurosci (2004) 5:401-408.

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