Objective: To report for the first time on a detailed description of the phenotype, natural history and quality of life (QoL) in a relatively large cohort of patients with North Sea Progressive Myoclonus Epilepsy (PME)/ Progressive Myoclonus Ataxia (North Sea PME/PMA).

Background: In 2011, Corbett et al. reported for the first time homozygous mutations in GOSR2 (c.430G>T; p. Gly144Trp) as a novel cause of childhood-onset PME. Interestingly, the ancestors of patients apparently originate from countries bound to the North Sea. Until now, only 20 patients have been described.

Method: We collected data on clinical- and neurophysiological features of 14 patients (5-46 years) with North-Sea PME/PMA. We assessed QoL using the SF-36 or PedsQL questionnaire.

Results: The clinical phenotype is quite homogeneous, very young children have frequent falls and are clumsy. Ataxia and areflexia become evident from the age of two years, followed by myoclonus starting around six years. Myoclonus was generalized, stimulus sensitive and worse at action, suggestive of cortical myoclonus. Factors such as heat, fever and light(-flashes) in particular appeared to exacerbate myoclonus. Most patients developed seizures (n=10), often before their second decade. On perceived QoL, physical functioning was severely affected in most patients (adults mean 12; children mean 52; maximal score is 100, lower scores indicate worse QoL) whereas interestingly emotional functioning did not appear to be affected at all (adults mean 83; children mean 83). Nerve conduction studies (NCS) were performed in 8 patients, in 4 patients (50%) findings were most compatible with a sensory neuronopathy. A consistent finding was an absent H-reflex in all patients tested for it. EMG was performed in 5 patients, in 4 patients (80%) findings were most compatible with a motor neuronopathy.

Conclusion: North Sea PME/PMA is characterized by a rather homogeneous clinical phenotype associated with a progressive early-onset ataxia, progressive myoclonus and epilepsy. Physical functioning in patients with North Sea PME/PMA is severely affected, but apparently does not lead to poor scores on emotional domains of health-related QoL. In order to gain more insight into the pathogenesis and optimize treatment of North Sea PME/PMA we generated a Drosophila fly model.

References: Corbett MA, Schwake M, Bahlo M, et al. A mutation in the Golgi Qb-SNARE Gene GOSR2 Causes Progressive Myoclonus Epilepsy with Early Ataxia. Am J Human Genet 2011; 88: 657-663. Egmond ME, Verschuuren-Bemelmans CC, Nibbeling EA, et al. Ramsay Hunt Syndrome: Clinical Characterization of Progressive Myoclonus Ataxia caused by GOSR2 mutation. Mov. Disord 2014;29:139-143. Boissé Lomax L, Bayly MA, Hjlagrim H, et al. ‘North Sea’ progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation. Brain 2013: 136; 1146-1154. Anderson DG, Németh AH, Fawcett KA, Sims D, Miller J, Krause A. (2016). Deep Brain Stimulation in Three Related Cases of North Sea Progressive Myoclonic Epilepsy from South Africa. Movement Disorders Clinical Practice, 4(2), 249-253.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-detailed-delineation-of-the-clinical-phenotype-natural-history-and-quality-of-life-in-patients-with-north-sea-progressive-myoclonus-epilepsy/