The role of brain dystrophin in muscular dystrophy; Implications for clinical care and translational research

Location: Hoofddorp, The Netherlands

Title: 249^th ENMC workshop on The role of brain dystrophin in muscular dystrophy: implications for clinical care and translational research

Date: 29^th November-1^st December 2019

Organisers: Dr J. Hendriksen (the Netherlands), Dr. M. Thangarajh (USA),  Dr H.E. Kan (the Netherlands) and Prof F. Muntoni (UK)

Translations of this report by:

German by Prof U Schara
French by Dr C. Vaillend
Italian by Prof. A. Ferlini
Danish by Prof J. Vissing
Dutch by Dr M. van Putten and Dr N. Doorenweerd

Participants: Dr Y. Aoki (Japan), Dr P. Collin (the Netherlands), Dr M. Colvin (USA), Dr N Doorenweerd (the Netherlands), Prof A. Ferlini (Italy), Dr A. Goyenvalle (France), Dr J. Hendriksen (the Netherlands), Dr J. Hoskin (UK), Dr H.E. Kan (the Netherlands), Mr F. Lamy (France), Dr K. Maresh (UK), Prof F. Muntoni (UK), Dr E.H. Niks (the Netherlands), Prof U. Schara (Germany), Prof D. Skuse (UK), Prof V. Straub (UK), Prof S. Takeda (Japan), Dr M. Thangarajh (USA), Dr N. Truba (USA), Prof S. Tyagarajan (Switzerland), Dr C. Vaillend (France), Dr M. van Putten (the Netherlands), Prof J. Vissing (Denmark), Dr E. Vroom (the Netherlands).

The 249^th ENMC workshop was held from the 29^th of November to the 1^st of December 2019, and brought together 24 representatives of patients, neuromuscular, neuropsychology, and psychiatry experts from Europe, the United States, and Japan. The topic of this workshop was the brain comorbidities in Duchenne and Becker muscular dystrophies (DMD and BMD respectively).

The molecular basis of the brain involvement present in patients with DMD and BMD is increasingly being unravelled. We now appreciate that cognitive, behavioural, and psychiatric symptoms may affect up to approximately 50% of individuals with DMD, and recent evidence indicates a high prevalence of brain comorbidities in patients with BMD, as well. This finding is related to the deficiency of multiple dystrophin variants, also called isoforms, during brain development in different brain locations. These central nervous system (CNS) symptoms have important clinical implication for the affected individuals and their full participation in life; more importantly, these CNS symptoms are often not well recognised and managed adequately in clinical settings. Moreover they are not addressed by the genetic therapies under development, as these treatment approaches mainly aim to improve skeletal and heart muscle function and do not target the brain of the patients.

The topics discussed during the three day workshop encompassed experimental and clinical aspects relevant for dystrophin in the brain. Regarding the experimental and preclinical aspects, we discussed: i.  the genetic regulation of the various forms of dystrophin in the brain, and their distribution in different brain regions, drawing attention to similarities and differences between the human and mouse models; ii) which are proteins that interact with the different forms of dystrophin in different areas of the brain; iii) which are the behavioural and structural correlates in different mouse models with genetic changes that differently disrupt the different forms of dystrophin in the brain and how does this change over time; iv) the effect of restoring different forms of dystrophin after birth using different genetic therapies. Regarding the clinical topics, we discussed: i) what is the frequency and severity of brain related symptoms in DMD/BMD; ii). what can brain imaging telling us about the features of dystrophin deficiency (both in DMD and BMD patients)); iii) what can the human symptoms teach us to direct the deeper assessment of the mdx mouse models deficient in the various forms of dystrophin, and vice-versa, what are emerging features from the studies in the mice that should be explored further in patients; iv). What are the recommended standards of care for the assessment and management of CNS symptoms; v) what are the treatment options to improve the outcome of DMD/BMD patients in whom neuropsychiatric symptoms occur?

The representatives from patient advocacy groups’ elegantly articulated how common and significant the cognitive symptoms are in affected individuals, and highlighted the extra burden for the families that these symptoms cause. Too often the neuromuscular specialists concentrate exclusively on the muscle and heart complications, with little attention to the early diagnosis and intervention for the brain problems. It is encouraging that at least some of the behavioural aspects of DMD can be improved by medication, but these therapies are not systematically utilised; and much more research to investigate the underlying mechanisms for the CNS symptoms is required, in order to find more specific interventions.

The participants’ agreed to collaborate further regarding patient registries, experimental models, and clinical studies on these topics and specific working groups were formed to address specific areas. This collaboration will also be facilitated by the recently awarded European Union H2020 grant to address the Brain Involvement iN Dystrophinopathies (BIND) which will begin in January 2020. A full report of the conference is published in Neuromuscular Disorders.