Abstract

Introduction BMD is regarded as spectrum and needs finer classification. Objectives Wide clinical and molecular data on BMD are available but no correlation. Aims To correlate malfunction of circadian oscillators with different clinicopathologic presentations of BMD spectrum. Methods Based on 73 patients, we have differentiated 5 disease activity patterns. A divergent model of one master (CLOCK/BAML1 heterodimer)+4 slave circadian oscillators (neuronal PAS domain protein 2, Rora, Rev-erb, and CSNK1E) and downstream effector genes ( PER1, PER2, PER3, CRY1, CRY2, Teneurin 4, NCAN (Neurocan), GSK3-b, casein kinase I epsilon ) were designed to highlight heterogeneity in regard to genetics and presentation. Results Five patterns of activity curves with the appropriate molecular explanations can be drawn: – one attack, rare exacerbations, near normal inter-interval mental functioning; pathogenesis lies in master mutation. Lifetime events are the cause of deregulation; – frequent attacks with inter-interval derangements due to major mutation of the master oscillator and ambiguity between master and slave. No time for circadian re-establishment, wide range of downstream genes activity, and a full-blown clinical picture; – one major attack and no apparent remission, wide range of signs. Hyperactive mutant of slave and suppression of the master; – rapid cycling due to master mutation and complete change of the innate frequency; – a diagnostic dilemma of mild continuous signs and symptoms with no prominent attacks and overlap with borderline or schizotypal PD due to mutation in some downstream genes (i.e. GSK3-b or Per, CRY, NCAN ). Conclusions Finding molecular correlation with disease subtypes and activities is possible.

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