Two Cases of Unverricht‐Lundborg Disease Diagnosed Using Genetic Studies
Authors: Wachi Manabu , Sasagawa Mutsuo , Hasegawa Seiichi , Kanazawa Osamu , Endo Kotaro , Naito Haruhiko , Ohnuma Teiichi , Nagamine Kentaro , Kudoh Jun , Shimizu Nobuyoshi 
Published: August 2009

Purpose: Progressive myoclonus epilepsy type 1 (EPMl), also known as Unverricht‐Lundborg disease, is an autosomal recessive disorder characterized by stimulus‐sensitive myoclonus, tonic‐clonic seizures, and slowly progressing cerebellar signs and dementia, with onset between age 6 and 15 years. Recently a few point mutations were identified in the gene encoding cystatin B on chromosome 21q22 of patients with EPMl in Europe. We examined the gene encoding cystatin B of two unrelated Japanese patients suspected to have EPMI.

Case Report: Case I, a 28‐year‐old man, was the third child of healthy nonconsanguineous parents. At age 8 years, he began to have action myoclonus. At the age of 13, he had his first episode of generalized tonic‐clonic seizures. At the age of 16, he developed dementia and cerebellar symptoms including dysarthria and ataxia. The rate of progression of the dementia and cerebellar symptoms was slow. At the age of 28, he was admitted to the hospital. Neurologic examination revealed slurred speech, ataxia, and tremors of his fingers. Electroencephalography (EEG) revealed paroxysmal discharges (33 Hz generalized spike and wave bursts) and photosensitivity. Somatosensory evoked potential (SEP) recording revealed giant SEP. Case 2, a 36–year‐old woman, was the second child of consanguineous parents. At age 10 years, she had her first episode of generalized tonic‐clonic seizures. At the age of 11, she began to have myoclonus in her face and upper extremities, ataxic gait, intention tremors, dysarthria, and dementia. The rate of progression of the dementia and cerebellar symptoms was slow. At age 36 years, she was admitted to the hospital. The abnormal neurologic findings were slurred speech, ataxia, and intention tremors in her fingers. Myoclonus was detected in her eyelids. The EEG showed the typical findings for progressive myoclonus epilepsy (3–4 Hz generalized spike‐and‐wave paroxysms and photosensitivity). SEP recording revealed giant SEP.

Methods: Southern blot analysis of the gene encoding cystatin B was performed by using DNA prepared from the two patients with EPMI. We found enlargement (750–900 bp) of the 5′‐flanking region of the cystatin B gene in both patients. To determine the sequence of this 5′‐flanking region of the cystatin B gene of the patient with EPM1, we attempted to clone the enlarged Eco RI fragments from case 1. The 5′‐flanking region of the cystatin B gene was sequenced by using phage DNA and sequencing primer CST12R. The 12‐mer sequence (5′‐CCCCGCCCCGCG‐3′) is normally repeated 2 or 3 times, but this sequence was markedly increased to 14 copies in the patient's DNA.

Conclusions: The two cases in our report and patients with EPMl reported in Europe exhibited similar clinical and neurophysiological features: recessive inheritance, onset between age 6 and 15 years, stimulus‐sensitive myoclonus, slowly progressive cerebellar signs and dementia, giant SEP, and characteristic EEG patterns (3–5 Hz generalized spike and wave, and photosensitivity). We, therefore, suggest that the identification of the mutant genes encoding cystatin B in patients suspected to have EPMl not only contributes to the diagnosis of Japanese patients suspected to have EPM1, but might also contribute to the development of genetic studies of EPM1.