Familial Juvenile Myoclonic Epilepsy

Maria Elisa Alonso^*

Marco T. Medina^†

Iris E. Martínez-Juárez^†,‡

Reyna M. Durón^†

Julia N. Bailey^‡

Minerva López-Ruiz^§

Ricardo Ramos-Ramirez^§

Adriana Ochoa-Morales^*

Aurelio Jara-Prado^||

Astrid Rasmussen-Almarez^||

Lourdes León^¶

Gregorio Pineda^¶

Ignacio Pascual Castroviejo^**

Sonia Khan^††

Rene Silva^‡‡

Lizardo Mija^§§

Lucio Portilla^¶

Dongsheng Bai^‡

Katerina Tanya Perez-Gosiengfiao^‡

Jesús Machado-Salas^‡

A.V. Delgado-Escueta^‡

^*Instituto Nacional de Neurología y Neurocirugía, Tlalpan, Mexico

^†National Autonomous University of Honduras, Tegucigalpa, Honduras

^‡Comprehensive Epilepsy Program, David Geffen School of Medicine at UCLA, Los Angeles, California

^§Unidad de Neurología y Neurocirugía, Hospital General de Mexico, Mexico City, Mexico

^||Neurogenetics and Molecular Biology, Instituto Nacional de Neurología y Neurocirugía, Tlalpan, Mexico

^**Pediatric Neurology Department, University Hospital La Paz, Madrid, Spain

^††Neurosciences Department, Riyadh Armed Forces Hospital, Saudi Arabia

^‡‡Nuestra Señora de La Paz Hospital, San Miguel, El Salvador

^§§Neurological Sciences Institute, Lima, Peru

^¶Department of Epilepsy, Institute of Neurological Sciences, Lima, Peru

^‡Comprehensive Epilepsy Program, David Geffen School of Medicine at UCLA, Los Angeles, California

Introduction

Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome responsible for 4% to 11% of all epilepsies (1,2,3,4,5,6,7,8) based on hospital records and 0.00045 based on an estimate of the prevalence of JME in hospital-based studies (9). Based on population studies, the prevalence of JME is 0.003 (10). JME is genetically heterogeneous and six chromosome loci have been defined in different racial ethnic groups: 6p12-11, 6p21.3, 15q14, 6q24, 2q22-2q23, 5q34 and 3q26 (11,12,13,14,15,16,17,18,19,20,21,22) (Table 17-1). Different modes of inheritance have been described: autosomal recessive by Panayiotopoulos and Obeid in 1989 (23) autosomal dominant by Serratosa, Delgado-Escueta, Medina et al. in 1996 (12), and Cossette et al. in 2002 (20), as well as polygenic by Janz, Tsuboi and Christian in 1973 (24,25). The complexity of JME is revealed in segregation analyses using small nuclear pedigrees (26). In 1988, Greenberg et al. (26) suggested a two-locus model in which one locus was inherited recessively and the other was either dominantly or recessive inherited based on segregation analysis. In 2001, Durner et al. (27) proposed an oligogenic model where a locus in chromosome 8, common to most idiopathic generalized epilepsies, is influenced by a locus on chromosome 6 to produce the JME phenotype and by a locus on chromosome 5 to produce absence seizures.

TABLE 17-1. Chromosomal loci for myoclonic epilepsies of adolescence

Locus	Country/ethnic group	Number of families	Mode of inheritance	Phenotype	References
6p12-11	Los Angeles, California	22	AD	Classic JME and pCAE evolving to JME	11
	Belize	1	AD	Classic JME	12
	Mexico	31	AD	Classic JME (pyknoleptic absences excluded)	13
6p12-11	Netherlands	18	AD	JME	22
6p21.3	Los Angeles, California	24	AD	Classic JME	14
	New York	85	AD	Classic JME mixed with CAE evolving to JME	15
6p21.3	Germany	29	AD	JME	16
15q14	United Kingdom and Sweden	25	AR	JME	17
6q24	Saudi Arabia	34	AR	JME, some nonproband members with mild gait ataxia and tremors	18
2q22-2q23	Germany	1	?	Classic JME with absences Family member 3-Hz sW	19
5q34GABR1	French-Canadian	1	AD	4/8 affected family members had pCAE One epilepsy onset at 5 years	20
3q26	Germany	1	AD	Classic JME	21

In this chapter, we describe 258 families ascertained through a proband with JME from the United States, Mexico, Honduras, Belize, El Salvador, Peru, Saudi Arabia, and Spain. We provide evidence for their subdivision into four subsyndromes based on their seizure phenotypes. We compare the seizure phenotypes in these four subsyndromes with seizure phenotypes of probands with JME in published studies that identified chromosome loci for JME. We then calculate the risks of having seizures or epilepsy in relatives from families of the two most common subsyndromes, namely classic JME and childhood absence epilepsy (CAE) that evolves to JME. We discuss the implications of varying relative risks in parents, siblings, offspring, and distant relatives. We hypothesize whether one or more genes influence the heritability and expression of JME and absence.

Methods

Patient and Family Database (Table 17-2)

TABLE 17-2. Characteristics of 258 probands and families with JME subsyndromes

	Classic JME n (%)	CAE evolving to JME n (%)	JME with adolescent pyknoleptic absences n (%)	JME with myoclonic astatic seizures n (%)
No. of families	186	45	18	9
No. of relatives in multiplex/multigenerational families	1756	541	201	48
No. of relatives affected	136	91	28	5
Family structure
Simplex	94 (51%)	13 (29%)	7 (39%)	5 (56%)
Multiplex	24 (13%)	7 (16%)	1 (5%)	—
Multigenerational	30 (16%)	12 (27%)	5 (28%)	—
Multiplex	38 (20%)	13 (29%)	5 (28%)	4 (44%)
Multigenerational
Mode of transmission
Maternal	42 (46%)	18 (57%)	4 (36%)	2 (50%)
Paternal	29 (31%)	10 (31%)	5 (45%)	2 (50%)
Bilineal	8 (9%)	1 (3%)	2 (19%)	—
Not defined (multiplex families)	13 (14%)	3 (9%)	—	—
Sex in probands
Female	103 (55%)	29 (65%)	13 (72%)	5 (56%)
Male	83 (45%)	16 (35%)	5 (28%)	4 (44%)
Ratio of affectedness F:M	1.3:1	1.8:1	2.6:1	1.25:1
Mean age + SD (years)
At recruitment	25.9 (14–58)	27.2 (11–62)	27.4 (17–38)	24.3 (17–36)
Onset of absences	16.8 (11–30)	6.9 (1–11)	15.8 (11–32)	15
Onset of myoclonias	15.1 (7–28)	14 (8–47)	14.3 (8–30)	16.1 (11–30)
Onset of GTCS	15.9 (8–33)	12 (2–37)	14.3 (11–20)	16.8 (8–25)
Years of follow-up	12.4 (1–41)	19.4 (5–52)	13.8 (5–26)	11.1 (3–18)

During family recruitment, we encountered 293 individuals who had been diagnosed with JME by field study sites of the international consortium of GENESS (Genetic Epilepsy Studies). Of these, 258 families were ascertained through a proband with adolescent-onset myoclonias and grand-mal seizures. An extended pedigree was constructed for each family. All available affected relatives were interviewed and examined to determine their state of affectedness, clinical diagnoses, and EEGs. The number of relatives affected in nuclear and extended families and seizure types were registered. EEGs were also performed on asymptomatic relatives who volunteered for the procedure. Clinical diagnoses of seizure types and electroencephalographic diagnoses of affected and family members were independently verified by at least two epileptologists. Seizure types, age at onset, and evolution of seizures from infancy through adolescence and adulthood were determined. The diagnosis of seizure types and epileptic syndromes was based on the International League Against Epilepsy classification of 1981, 1985, 1989, and 1993 (28,29,30,31). Families were grouped as multiplex, multigenerational, or multiplex/multigenerational. Maternal, paternal, or bilineal transmission were determined by pedigree findings. To determine the long-term outcome, 222 patients (86%) have been followed from 1978 to 2003 in epilepsy clinics from Los Angeles (California), Mexico City (Mexico), Tegucigalpa (Honduras), Bakersfield (California), Saudi Arabia, El Salvador, Belize, Peru, and Spain. Eleven families are presently residing in the United States and were evaluated in Los Angeles, but were originally from Australia, Iran, and China.

We excluded 35 patients and their families: (a) 5 with progressive myoclonic epilepsies (PME), (b) 9 with myoclonic absences (MA), (c) 4 with typical childhood absence epilepsy (CAE) that remits or persists in adolescence with or without grand-mal seizures, (d) 7 with grand-mal epilepsy only, (e) 2 with photogenic epilepsy with female preponderance, (f) 4 with early childhood myoclonic epilepsy, (g) 2 with familial adult myoclonic epilepsy, and (h) 2 whose family members had partial epilepsies that were mistaken for ME.

For genetic analysis, each class of degree relative was examined separately for history of epilepsy. First-degree relatives were parents, siblings (brothers and sisters), and offspring; second-degree relatives were uncles, aunts, nieces, and nephews, and third-degree relatives included cousins. For analysis purposes, offspring were analyzed separately from the other first-degree relatives. For risk calculations, we used the cumulative or lifetime prevalence of having epilepsy reported from the Rochester study considering a frequency of familial history of epilepsy of 3% (32,33). An estimated prevalence of 0.00045 for JME and 0.00066 for childhood absences was used for the risk calculations (9).

Results

We subdivided the 258 families into four groups according to the combination of seizure types afflicting the proband, the age of probands at onset of seizures, the results of physical, neurologic, brain-imaging examinations, and the long-term outcome after treatment with valproate (VPA) and/or the new generation of antiepileptic drugs (AEDs) (Fig. 17-1; Tables 17-2 and 17-3).

TABLE 17-3. Phenotypes of JME subsyndromes

	Classic JME (n = 186)	CAE evolving JME (n = 45)	JME with pyknoleptic absences adolescence (n = 18)	JME myoclonicastatic (n = 9)
Age at onset of main seizure	15.1 years (7–28 years)	5 years (1–10 years)	16 years (11–32 years)	14.2 years (8–19 years)
Gender ratio	1.25 F:1 M	1.8 F:1 M	2.6 F:1 M	1.2 F:1 M
Seizure type in probands	Adolescent myoclonias, grand-mal and rare absences	Childhood pyknoleptic absences, followed by myoclonias and grand mal; 30% eyelid myoclonia + absences	Adolescent pyknoleptic absences, myoclonias and grand mal	Myoclonias, grand-mal, rare absences, and infrequent astatic seizures
EEG	4- to 6-Hz polyspike-and-slow wave complexes Photoparoxysmal response in 13%	3-Hz spike-and-slow wave complexes (1/3 mixed with 4- to 6-Hz polyspike-and- slow wave complexes) Low amplitude 15- to 25-Hz fast rhythms Photoparoxysmal response in 22%	4- to 6-Hz polyspike-and-slow wave complexes Photoparoxysmal response in 15%	4- to 6-Hz polyspike-and-slow wave complexes Photoparoxysmal response in 1/4
Family history	49%	71%	61%	5/9 probands
Main seizure type in family members	JME and tonic–clonic	Absence seizures and tonic–clonic	JME and tonic–clonic	JME and tonic–clonic
Transmission	Maternal > paternal	Maternal > paternal	Maternal = paternal	Maternal = paternal
Response to treatment	58% Seizure-free; 85% without grand mal on VPA mono- or polytherapy	7% Seizure-free; 72% without grand mal with VPA mono- or polytherapy	56% Seizure-free, on VPA mono- or polytherapy	6/8 Seizure-free
Prognosis
Seizure breakthroughs	56% have rare to infrequent myoclonia and grand-mal breakthroughs	93% Very frequent breakthroughs	39% Rare to infrequent breakthroughs	3/8 Rare to infrequent breakthroughs
Persistent seizures	Myoclonic and tonic–clonic seizures	Absences	Absences with or without myoclonic seizures	Astatic (1/8)