Abstracts

Rationale: Unverricht-Lundborg disease (ULD) (EPM1) is a progressive myoclonus epilepsy with variable severity and course, and variable degrees of cognitive deterioration. The onset is usually between 6 and 15 years of age with myoclonus and generalized tonic-clonic seizures. 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.Methods: We present a 30-year-old female patient with a distant family history of Unverricht-Lundborg disease on the maternal side. She had seizure onset at 11 and carries a diagnosis of juvenile myoclonic epilepsy (JME). The patient and her partner presented for preconceptional genetic counseling. CGH array employing approximately 180 000 oligonucleotides was carried out in the patient. Carrier screening for the CSTB gene was carried out for both the patient and her partner, employing PCR for the dodecamer repeat, and sequencing of the CSTB gene to rule out point mutations.Results: A 30-year-old female patient 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 are well-controlled with valproic acid. She carries a clinical diagnosis of JME. The patient was born prematurely at 25 weeks gestation weighing 750 grams. Her developmental milestones were normal, and she was on the honor roll at school in grade 10. She works as a highschool teacher for behaviourally challenged children. The parents were of Irish and French-Canadian origin from the Gasp peninsula of Quebec. Four siblings of the maternal grandmother were diagnosed clinically with ULD and were known to us; three sisters died in their 20 s and 30 s, and one 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 progressive myoclonic epilepsy. CGH array in the patient was normal. CSTB testing in the patient surprisingly revealed that she 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 a normal number of dodecamer repeats and no potential EPM1-causing sequence alterations. Conclusions: 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.