This document provides information on genetic epilepsy and juvenile myoclonic epilepsy. It defines epilepsy and describes its various classifications including idiopathic, symptomatic and cryptogenic epilepsy. Juvenile myoclonic epilepsy is discussed in detail, including its genetics, clinical manifestations such as myoclonic jerks and absence seizures, diagnosis through EEG findings, and treatment options involving anti-seizure medications. Circumstances for genetic testing in epilepsy cases are outlined.

1. GENETIC EPILEPSY
DR.SWARUPA SHAMRAO BANSODE
SR DNB NEUROLOGY ,Choithram hospital Indore

2. 
The WHO dictionary defines epilepsy
 as a recurring disorder of the central nervous system (CNS) of different
etiologies which has a typical feature of recurrent seizures
(the clinical manifestation of an abnormal
and immoderate synchronization of a population of cortical neurons leading to
electrical activities in the brain)
due to unconscionable discharge of cerebral neurons.

3.  Epilepsy can be defined with any of the following conditions:
 1. A minimum of two unjustifiable seizures happening more than twenty-
four hours apart.
 2. One reflex seizure with a chance of more seizures similar to the
general recurrence risk of at least 60% after two unprovoked seizures,
occurring over a span of 10 years .
 3. Presence of epilepsy syndrome
 Ref:Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, et al. (2005) Epileptic seizures and epilepsy: Definitions
proposed by the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy(IBE). Epilepsia 46:
470-472

4. (a) Idiopathic epilepsy: epilepsy of predominately
genetic or presumed genetic origin.
(b) Symptomatic epilepsy: epilepsy of an acquired or
genetic cause, associated with gross anatomical or
pathological abnormalities, and/or clinical features,
indicative of underlying disease or condition.
(c) Provoked epilepsy: epilepsy in which a specific
systemic or environmental factor is the predominant
cause of the seizures and in which there are no gross
causative neuroanatomical or neuropathological
changes.
(d) Cryptogenic epilepsy: epilepsy of presumed
symptomatic nature in which the cause has not been
identified.

6.  ROLE OF GENETICS IN EPILEPSY.
 If a parent has idiopathic epilepsy, there is about a 9% to 12% chance that the child will
also have epilepsy.
 if a child has epilepsy, his siblings do have a higher risk of having epilepsy.
 If one twin has idiopathic epilepsy, the identical twin is very likely to have it as well.
 For some reason, children of women with epilepsy have a higher chance of having
epilepsy than children of men with epilepsy.
 Family studies have shown that some epilepsy syndromes are completely determined by
genetics, and genes are a major factor in other syndromes.
 Some inherited metabolic conditions also raise the likelihood of having seizures, as do
some chromosomal disorders.

7. A genetic contribution to etiology has been estimated to
be present in about 40% of patients with epilepsy.
The genetic control of neuronal synchrony may be direct
or indirect, and the various approaches to the
classification of genetic epilepsies reflect this.
-Mendelian disorders
-Non-Mendelian or “complex” diseases
-Chromosomal disorders

10. Only the right dose differentiates between a
poison and a remedy.
—Paracelsus, 1493–1541

14. Circumstances that would indicate the need for genetic testing
1. When the clinical features (age of onset, seizure semiology, and EEG features) are
with a distinct electroclinical syndrome .
• Epileptic encephalopathies
(Includes conditions such as Ohtahara syndrome, early onset myoclonic encephalopathy,
syndrome, malignant migrating partial seizures, etc.)
• Seizures associated with a fever as major trigger (excluding patients meeting clinical criteria
for simple febrile seizures).
- Dravet syndrome o Generalized epilepsy with febrile seizures plus
• Idiopathic (genetic) generalized epilepsy (IGE) refractory to treatment:
-Early onset absence epilepsy ,Myoclonic epilepsy where progressive, associated with
neurocognitive regression, and/or is medically refractory

15. 2. When the prognosis based on clinical and EEG findings is poor or
the likelihood of lethal outcome is high.
• Increased frequency and/or severity of seizures, risk for sudden
unexpected death of epilepsy (SUDEP)
• Myoclonic epilepsy where progressive, associated with
neurocognitive regression, and/or is medically refractory
• Epileptic encephalopathies (poorly characterized on clinical and
semiological grounds and a lack of distinctive features on the EEG)

16. 3. When epileptic seizures are refractory to medical treatment as
defined by the ILAE.
• Any other form of IGE refractory to treatment (especially important
when the differential includes IGE or a frontal lobe epilepsy with rapid,
secondarily generalization)
• Sporadic focal onset pharmacoresistant epilepsy

17. 4.When epilepsy is associated with features suggestive of treatable inborn errors of metabolism.
• Clinical features strongly suggestive of an inborn error of metabolism,
for example:
o Family history of known condition o Parental consanguinity
o Newborn or metabolic screening identifies a biochemical marker associated with “metabolic” epilepsy
Examples of important treatable conditions include
o Pyridoxine dependent epilepsy o Pyridoxal phosphate dependent epilepsy
o Creatine deficiency syndromes
o Glucose transporter (GLUT1) deficiency
o Cerebral Folate deficiency

18. 5. When epilepsy is associated with distinctive patterns of malformations of cortical development
identified on neuroimaging studies.
For example:
• Hemimegalencephaly
• Lissencephaly
• Schizencephaly
• Sub cortical band heterotopia (double cortex)
• Cortical dysplasia with focal epilepsy
• Opercular dysplasia/asymmetric, unilateral or bilateral
• Holoprosencephaly
• Agenesis of corpus callosum
• Polymicrogyria
• Periventricular heterotopia
• Tuberous Sclerosis

19. 6.When epilepsy is associated with clinical signs of neurodegeneration.
Neurodegeneration may manifest as:
• Developmental regression in children
• Variable but progressive neurological symptoms of cognitive impairment,
motor disability and/or other neurological signs and symptoms
• Examples include:
o Acquired Epileptic Aphasia (Landau Kleffner syndrome)
o Epileptic encephalopathy with continuous spike wave activity in sleep
o MECP2 duplication syndrome and Rett syndrome
o Atypical Rolandic epilepsy with language deficits+/‐ cognitive disability
o Progressive myoclonic epilepsies ((Unverricht‐Lundborg, NCL, Lafora body, sialidosis)

20. 7. When epilepsy is associated with paroxysmal neurological features.
• Paroxysmal dyskinesias
• Episodic ataxias
• Hemiplegic migraine
8. When epilepsy is associated with additional syndromic features such as
developmental delay/ intellectual disability, multiple congenital anomalies,
dysmorphic features.
• Angelman /Rett syndrome and Angelman‐like syndromes
• X‐linked Epilepsy with Mental Retardation
• Syndromic Mental Retardation associated with epilepsy
• Tuberous sclerosis
9. When familial epilepsy is present, defined as at least 2 first‐degree family
members with related epilepsy syndromes,

21. 7. Conditions that do NOT indicate a need for genetic testing
-Recognizable seizure syndrome with benign course
• Benign childhood epilepsy with central temporal spikes
• Mesial temporal lobe epilepsy with hippocampal sclerosis
• Typical Childhood Absence epilepsy (although if early onset or medically refractory should
consider and test for GLUT1 deficiency)
• Juvenile myoclonic epilepsy well controlled on medications and without intellectual
disability or any signs of neurodegeneration
• Acquired Epilepsy

22. Old term
‘Idiopathic Generalized Epilepsies’
Idiopathic Generalized
Epilepsies
Childhood
Absence
Epilepsy
Generalized
Tonic-Clonic
Seizures
Alone
Juvenile
Absence
Epilepsy
Juvenile
Myoclonic
Epilepsy

23. Age of onset for IGEs
• Onset in adult life considered rare
• Adult patients with an electro-clinical picture compatible
with IGE often represent relapse of childhood epilepsy
• No cut off limit for age defined by international classification
• De novo IGE in adult life reported:
• C Marini et al (2003)- 28 % of IGE began at or > 20 yrs
• Gastaut’s report (1981)- 35% of IGE cases began > age 18

24. Juvenile absence epilepsy
• JAE may be linked to chromosome 8, 21,18, probably 5
• JAE is an IGE syndrome mainly manifesting with severe Typical
absence seizures .
• 80% also suffer from GTCSs
• 1/5 have sporadic myoclonic jerks

25. Demography
• Peak age at onset – 9 to 13 years (70% of patients)
• Range: 5 to 20 years
• Myoclonic jerks and GTCSs usually begin 1–10 years after the onset of
absences.
• GTCSs may precede
• Both sexes are equally affected.
• In pts > 20 years, prevalence of JAE :- around 2-3%

26. Clinical features
 Frequent and severe typical absences are the characteristic and defining seizures of
JAE
 hallmark of the absence is abrupt, brief and severe impairment of consciousness with
total or partial unresponsiveness.
 ongoing voluntary activity usually stops at onset but may be partly restored during the
ictus.
 Automatisms are frequent, usually occurring 6–10 s after onset of EEG discharge
 Duration of absences : 4 to 30 s but it is usually long (about 16 s).
 GTCSs occur in 80% of patients, mainly after awakening, may be nocturnal or
diurnal
 Myoclonic jerks : s/i 15–25% , are infrequent, mild and of random distribution.

27. Seizure-precipitating factors
• Mental and psychological arousal
• sleep deprivation
• fatigue
• alcohol
• excitement
• lights
• However, clinical photosensitivity, which is a consistent
provocation of seizures (absences, GTCSs or jerks), may
be incompatible with JAE.

28. Diagnosis= EEG findings
• The ictal EEG shows 3–4 Hz GPSWD.
• frequency at initial phase of the discharge is usually fast (3–5 Hz).
• There is a gradual, smooth decline in freq. from initial to terminal phase.
• The discharge is regular, with well-formed spikes and polyspikes, which retain a
constant relation with the slow waves

29. Prognosis
• Life-long disorder
• Seizures can be controlled in 70–80%
• With age, after 4thdecade, absences become less severe in terms of
impairment of cognition, Duration and frequency
• GTCSs are usually infrequent, often brought onby
precipitating factors

30. Treatment
• Valproate- controls all seizure types in 70–80%
• Lamotrigine- controls absence and GTCSs in 50–60%
• good monotherapy option in women, where valproate is
unsuitable.
• If monotherapy with valproate is partially effective,
• small doses of lamotrigine (particularly if GTCS is the problem)
• Ethosuximide (particularly if absencespersist)
• Levetiracetam: All Sz types
• Rx is lifelong, as withdrawl attempts may precipitate Sz despite
years of Sz free interval

31. Juvenile Myoclonic Epilepsy
• Is genetically determined.
• Incidence: 1 per 1000-2000 people internationally.
• represents approximately 5-10% of all epilepsies; 20 to 30% of all
IGEs
• Both sexes are equally affected
• mean age of onset is 15 years, range of 5 to 34 years
• majority diagnosed between 12 and 18 years.

32. • Genetics
• Around 50–60% of families of probands with JME report seizures in first- or
second-degree relatives.
• 2 proposed models of inheritance
• polygenic with a lower manifestation threshold for
females Autosomal dominant with variable penetrance.
• two-locus model: dominant gene on chromosome 6p, and yet-unknown
recessive gene.
• Fifteen chromosomal loci are suspected of central role, only 3 are considered
as putative JME causing genes:
• EFHC1, GABRA1, and
CLCN2
• Possible susceptibility locus in chromosome 6p11–12 (EJM1) or 15q14
(EJM2)
• A gene, C6orf33, in the EJM1 region has been identified.

33. Clinical manifestations
• JME is characterised by:
• Myoclonic jerks on awakening
• GTCSs in nearly all
• Typical absences > 1/3
• Characteristic age-related onset.
• Absences - between the ages of 5 and 16years.
• Myoclonic jerks follow 1–9 years later- age of 14 or 15 years.
• GTCS appear few months later than myoclonicjerks,

34. Myoclonic jerks
• occur after awakening
• most prominent and characteristic seizure type.
• shock-like, irregular and arrhythmic clonic movements of proximal
and distal muscles UL
• May be restricted to fingers: Pt. drops things or looks clumsy
• may be violent enough to cause falls.
• 1/5 describe jerks as unilateral, but VEEG shows b/l jerks

35. Typical absence seizures
• 1/3 have typical absences: brief with subtle impairment of consciousness
• Absences appearing < age 10 years may be more severe. They become
less frequent and severe with age.
• 1/10 do not perceive absences, despite Generalised Polyspike Wave
Discharges > 3 s.
• On video-EEG with breath counting during hyperventilation, these
discharges manifest as mildly impaired cognition, eyelid flickering or
both.

36. GTCSs:- clonic–tonic–clonic
• usually follow the onset of myoclonic jerks.
with an accelerating• Myoclonic jerks, usually in clusters and often
frequency and severity may precede a GTCS
so-called clonic–tonic–clonic generalised seizure.

37. Circadian distribution
• Myoclonic jerks
• within 30-60 min ofawakening.
• rarely occur at other times unless the patient istired.
• GTCSs - mainly on awakening, may also be purely nocturnal or random
• Absence seizures rarely show a circadian predilection.

38. Cognition and behavior
demonstrates variable
• Majority have normal global cognitive capacities.
• However, formal neuropsychological testing
degrees of frontal lobe dysfunction
• likely influenced by - antiseizure drugs, seizure frequency, genetic
variability, psychosocial conditions, and educational level
• Advanced neuroimaging studies suggeste underlying structural cause:
• involvement of frontal thalamocorticalcircuits
• Dysfunctionin dopaminergic and serotoninergic neurotransmission
systems
• abnormal attenuation of normal age related decline in cortical volume
compared with healthy controls over 2 years

39. • Psychiatric comorbidity
• increased risk for comorbid psychiatric illness and personality disorder. Up to 50 % meet
formal criteria for a psychiatric disorder (mostly anxiety or mood disorder),
• 20 to 35 percent have cluster B personality traits such asimpulsivity, humor
reactivity, emotional instability, difficulty accepting social rules
• Poorly controlled seizures and antiseizure drugs themselves may also put
patients at risk for psychiatric side effects and mood disorder
• Functional MRI suggest frontal-insular network dysfunction may contribute to
emotional disturbances

40. Seizure-precipitating factors
• Sleep deprivation, fatigue, excessive alcohol intake
• Photosensitivity is confirmed with EEG > 30%.
• < 1/10 have seizures induced by photic stimulation in daily
life
• Others:
• mental stress
• Emotions: excitement
• Concentration

41. Diagnosis = EEG
• MRI may show abnormalities in mesio-frontal cortical structures in some
• EEG in untreated patients is usually abnormal 3–6 HzGPSWD unstable intradischarge
frequency :- 2 to 10 Hz, with a mean of 3–5 Hz.
• 1/3 – show photoparoxysmal responses.
• 1/3- show focal EEG abnormalities of single spikes, spike–wave
complexes or slow waves.
• EEG discharge of myoclonic jerk is a gen. burst of polyspikes of 0.5–2 s

42. Ictal discharges of absences consist of spike/double/treble or polyspikes
preceding or superimposed on slow waves
Polyspikes consist of 8-10 spikes with a characteristic ‘worm-like’ or
compressed capital W appearance
Normal EEG in suspected JME should prompt an EEG during sleep and
awakening

43. Diagnostic dilemma- misdiagnosis of JME is 90%
• Reasons for misdiagnosis
• lack of familiarity withJME
• Improper h/o myoclonic jerks
• Misinterpreting absences as CPS
• misinterpretation of jerks as focal motorseizures
• high prevalence of focal EEG abnormalities.
• Aids in diagmosis
• characteristic clustering of myoclonic / other generalised seizures of
IGEs
• circadian distribution
• precipitating factors
• and EEG manifestations.

44. Prognosis
• All seizures are probably life-long, may improve after 4thdecade of life
• well controlled in upto 90% with approproate medication
• Pts with all 3 types of seizure - more likely to be drug resistant

45. Pharmacological treatment
1. Valproate
Is the most effective AED in the treatment of JME.
Serious adverse reactions in women
However may be considered as first line in men
2. Levetiracetam
In non-control independent studies, 62–67% JME that failed with
valproate, became Sz free with levetiracetam monotherapy or
• polytherapy.
• first & only newer AED licensed for the Rx of myoclonic seizures in
JME
• favourable profile in women and pregnancy.
• good safety profile, and sparse meaningful interactions with other
drugs.

46. • 3. Lamotrigine
• It was promoted as the only alternative to valproate in women
• interactions with hormonal contraception and pregnancy
• ? teratogenic potential- have been reported.
• 4. Clonazepam
• small doses (0.5–2 mg HS) - most effective Rx for myoclonic jerks.
• alone may not suppress GTCSs
• may suppress warning of impending GTCS manifested as myoclonic jerks
• Mild JME with myoclonic jerks only: clonazepam alone may be used

47. Treatment failure
• If valproate is contraindicated or not tolerated, treatment
with levetiracetam, lamotrigine or topiramate : broad
spectrum agents
• Combination therapy be considered after two single
medication failures
• Lamotrigine, levetiracetam, topiramate, zonisamide, and
benzodiazepines are all options for adjunctive therapy
• Lifestyle modification- Avoid Sz precipitants

48. Duration and withdrawal of medication
• Life-long treatment usually considered necessary in JME
• Withdrawal results in relapses, even if seizure free for many years with
appropriate AED.
• In mild forms of JME, reduce medication slowly over months or years,
especially after 4thdecade of life.
• Persistence of myoclonic jerks consider continued medication.

50. Epilepsy with GTCS only
• GTCSs
• occur on awakening (17–53%)
• diffusely whilst awake (23–36%)
• During sleep(27–44%)
• or randomly(13–26%)
• GTCSs are most severe forms of epileptic seizures
• while absences and myoclonic jerks
• may be mild and sometimes inconspicuous to the patient
• imperceptible to theobserver.
• A patient with a first GTCS has often suffered from minor seizures
(absences, myoclonic jerks or both), sometimes many years prior to GTCS

51. Demographic data
 high incidence in families ? EJM1locus
 Age at onset :- 6 to 47 years
 peak at 16 or 17 years
 Men (55%) >women, d/t alcohol exposure and sleep
habits.
 Prevalence - 13–15% among IGEs
 Sz recipitzting factors: same
 Photosensitivity- common

52. Diagnosis= EEG
• GPSWD in half of patients with pure Epilepsy withGTCS
• Normal EEG should prompt a video-EEG on sleep and on awakening.
• Myoclonic jerks / brief absences will often be revealed
• Focal EEG abnormalities in the absence of generalised discharges are
rare.
• Photoparoxysmal responses are reported in 17% of females & 9% of
males

53. Prognosis
• Life-long disease
• High (83%) incidence of relapse on withdrawal of AED
• Intervals between seizures become shorter with time, the
precipitating factors less obvious, and GTCSs more random
(diurnal and nocturnal),
• Occurs due to evolution of disease or drug modifications.

56.  The majority of patients with genetic generalised epilepsy syndromes
will become seizure free on antiseizure monotherapy; those for whom
control proves elusive may benefit from combination regimens.
 Despite treatment, some patients with genetic generalised epilepsies do
not become seizure free or relapse when treatment is discontinued
 Treatment can be lifelong in some individuals, although others may
remain seizure free without medication.
 Choice of antiseizure medication depends on the efficacy for specific
seizure types, as well as tolerability

57. Thank You