Abstract
Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two‐point parametric linkage analyses were performed with 5185 single‐nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2–q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage (Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3–q31.2 (Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease‐causing genes, favoring the concept of JME as several distinct diseases. Whole‐exome sequencing will likely identify a CAE/JME gene in 2q21.2–2q31.1, a JME/pA gene in 13q13.3–q31.2, and a cJME gene in 17q12.
Highlights
According to the World Health Organization (2014), “Epilepsy is the most common serious brain disorder worldwide with no age, racial, social class, national nor geographic boundaries”
The probands and their families were collected by neurologists at the local study sites of the international consortium of Genetic Epilepsy Studies (GENESS)
The proband of pedigree 1 with CAE/Juvenile myoclonic epilepsy (JME) presented at 10 years of age with pyknoleptic absences with 3-4 Hz spike and wave complexes
Summary
According to the World Health Organization (2014), “Epilepsy is the most common serious brain disorder worldwide with no age, racial, social class, national nor geographic boundaries”. The epilepsies afflict approximately 65 million persons globally, and almost 3 million in the USA (Hauser and Hesdorffer 1990; England et al 2012). Juvenile myoclonic epilepsy (JME) is the most common of these genetic generalized epilepsies and accounts for 18% of the genetic epilepsies and 11.9% of all epilepsies (Goosses 1984; Camfield et al 2013), afflicting approximately 8.5 million persons worldwide and about 360,000 persons in the USA. In 1854, Delasiauve proposed the term “motor petit mal” to describe myoclonic jerks. Rabot (1899) introduced the term “myoclonic” in his description of a patient with “myoclonic shocks”, in which the clinical description was equivalent to Herpin’s shocks and Delasiauve’s “motor petit mal” In 1854, Delasiauve proposed the term “motor petit mal” to describe myoclonic jerks. Herpin (1867), gave the first reliable description of JME when he wrote about “impulsions” or “commotions” or “secousses” or “shocks that shake the whole body like an electric commotion” . . . shocks which were violent enough to cause a patient to involuntarily throw an object from their hands. Rabot (1899) introduced the term “myoclonic” in his description of a patient with “myoclonic shocks”, in which the clinical description was equivalent to Herpin’s shocks and Delasiauve’s “motor petit mal”
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