1. Benign form of Unverricht–Lundborg disease (ULD) mimicking juvenile myoclonic epilepsy (JME) in adulthood

Abstract

Unverricht–Lundborg disease (ULD) (EPM1) is an autosomal recessive neurodegenerative disease with progressive myoclonus epilepsy (PME). The onset is usually between 6 and 15 years of age with myoclonus and generalized tonic-clonic seizures, variable severity and course, and variable degrees of cognitive deterioration. With good antiepileptic management, the patients can now survive into their 50’s and 60’s. The gene for this disorder was identified in 1996 as cystatin B ( CSTB ), a cysteine protease inhibitor. The most common mutation is a dodecamer repeat, although rare point mutations have also been described. To present an extended phenotype of ULD (EPM1). The proband who carried a diagnosis of juvenile myoclonus epilepsy (JME) presented with her partner for preconceptional genetic counseling. Since she had a distant family history of Unverricht–Lundborg disease on the maternal side, carrier screening for the CSTB gene was carried out for both, employing detection of the dodecamer repeat expansion and sequencing of the CSTB gene to rule out point mutations. This 30-year-old female had a single generalized tonic-clonic seizure during sleep at the age of 11 years, and onset of myoclonic jerks on awakening at around the same time, which were well-controlled by valproic acid. She carries a clinical diagnosis of JME. She was born prematurely after 25 weeks’ gestation weighing 750 grams. Developmental milestones were normal, and she was on the honor roll at school in grade X. She works as a high school teacher for behaviourally challenged children. Both paternal grandparents were of Irish origin; both maternal grandparents were French–Canadian, from the Gaspé peninsula of Quebec. Four siblings of the maternal grandmother were diagnosed clinically with ULD and were known to us; the three affected sisters died in their 20’s and 30’s, and the affected brother died at age 65. A third degree cousin of the mother had epilepsy and died at 18 years of age. A paternal uncle had a single generalized tonic-clonic seizure at the age of 7 years. A distant cousin of the paternal great grandmother was also said to have PME. CSTB testing revealed that our patient was a compound heterozygote for two mutations: an expansion of the dodecamer repeat and a splice site c.67–1G > C mutation in intron 1, predicting a deletion of the downstream exon 2 with in-frame deletion of 34 aminoacids (p.delV23_K56). This is the second most common mutation underlying EPM1, and the most common point mutation. The husband has no potential EPM1-causing sequence alterations. Although ULD is often confused with JME in the early stages of the disease, it is rare to find patients with ULD at age 30 who are as well controlled and high-functioning as this patient. Furthermore, other compound heterozygotes with the same combination of mutations have had more severe phenotypes with progressive deterioration. The reason for the milder phenotype in this individual remains unexplained, and may be due to modifying genes and/or gene–environment interactions.