Elsevier

Neuromuscular Disorders

Volume 29, Issue 9, September 2019, Pages 716-724
Neuromuscular Disorders

Workshop report
241st ENMC international workshop: Towards a European unifying lab for Kennedy's disease. 15–17th February, 2019 Hoofddorp, The Netherlands

https://doi.org/10.1016/j.nmd.2019.07.008Get rights and content

Introduction

The 241st ENMC meeting took place in the Netherlands on the weekend of 15–17th February, 2019, and was focused on Kennedy's Disease (KD), also known as Spinal and Bulbar Muscular Atrophy (SBMA). The meeting involved twenty-four scientists working in academia, hospitals and industry from 8 different countries (Denmark, France, Germany, Israel, Italy, Spain, United Kingdom, USA) along with three patients’ representatives, including one who was also a representative of the USA patient group, The Kennedy's Disease Association (KDA). The goal of this workshop was to bring together leading clinical and basic scientists working in the field of KD to discuss the current understanding of basic disease mechanisms and to share and update the most recent developments in clinical evaluation of patients, with the objective of increasing the prospects of developing and testing new treatments that could effectively slow down disease progression in KD patients. The participants discussed recent developments in KD research and shared the most recent clinical observations. In this report, we summarize the presentations and discussions that took place during the workshop, which range from disease mechanisms, biomarker discovery, plans for an EU Registry for KD as well as an update on ongoing clinical trials. In addition, a dedicated session on the patient's perspective was presented.

Kenneth Fischbeck opened the meeting with an overview of the disease. Kennedy's Disease (KD) also referred to as SBMA is a progressive X-linked neuromuscular disease characterized by bulbar and extremity muscle weakness, atrophy, and fasciculations. Affected males may show signs of androgen insensitivity, such as breast enlargement and reduced fertility. SBMA is caused by expansions of a CAG repeat in the androgen receptor (AR) gene. The disease typically presents in adult males with slowly progressive, relatively symmetrical, lower motor neuron weakness, perioral fasciculations, elevated creatine kinase, and decreased sensory potential amplitudes [1]. Common, but not invariable, manifestations are gynecomastia and a family history consistent with X-linked inheritance. Other non-neuromuscular features include Brugada syndrome [2], urinary retention [3], non-alcoholic fatty liver [4], and fatigue. Primary degeneration of both motor neurons and muscle occurs in SBMA; there are clinical features of denervation and loss of motor neurons in the spinal cord and brainstem, and also increased creatine kinase and histological evidence of muscle fiber degeneration. The disease phenotype can be partially rescued in mouse models with molecular correction in either muscle or the central nervous system [5], [6], [7].

The expanded CAG repeat in the AR gene encodes a polyglutamine tract in the transactivation domain of the AR protein (polyQ-AR), a part of the protein that is separate from the DNA- and hormone binding-domains [8]. The polyglutamine expansion is known to cause a loss of normal AR function and also a gain of function that is toxic to motor neurons and muscle. The mutant proteins have been shown to be toxic in cell culture and animal models, where they form neuronal inclusions and have a tendency to aggregate with increasing repeat length. The toxicity is greater with localization to the nucleus, where the mutant protein has aberrant interactions with other nuclear factors, leading to altered histone acetylation and transcriptional dysregulation, with adverse effects on axonal transport, signal transduction, and mitochondrial function, resulting in neuronal dysfunction and death [9], [10]. There is evidence for many paths to toxicity in animal models, and the challenge is to discern which paths are most important to the disease mechanism in patients.

Section snippets

Disease mechanisms: from AR structure to function in SBMA

Xavier Salvatella described the structural properties of the polyQ-AR associated with SBMA. Contrary to expectations the tract is not disordered but instead forms quite stable helices stabilized by an unusual type of hydrogen bond involving the glutamine side chain [11]. The size and the stability of these helices directly correlates with tract length, suggesting that changes in secondary structure upon polyQ tract elongation may contribute to onset of SBMA, possibly by altering that affinity

Disease mechanisms: peripheral polyQ-expanded AR mechanisms of mutant AR toxicity

Although traditionally considered to be a motor neuron disease, recent findings strongly suggest that in addition to motor neurons, other tissues are also affected in SBMA. Indeed, SBMA is now considered a neuromuscular disorder rather than a pure motor neuron disease, since skeletal muscle may be a primary and early site of pathology. In this session, scientists presented findings that indicate that skeletal muscle represents a good target for therapeutic intervention as not only is it

Preclinical approaches to reduce polyQ-expanded AR toxicity

The discussion on potential novel preclinical approaches for SBMA focused on three main strategies to modulate AR activity by (i) employing AR pharmacological antagonists; (ii) silencing AR coactivators; and (iii) enhancing AR degradation via induction of lysophagy, a lysosome specific form of autophagy.

The first strategy was presented by Aria Baniahmad, who showed that new AR antagonists based on single benzene rings reduce polyglutamine-expanded AR aggregation. These novel AR antagonists

Towards a European registry for SBMA

The next presentation and discussion centered around the necessity to put in place an EU registry of SBMA patients, similar to that which has been implemented in the US for SBMA or for other rare diseases such as Huntington's Disease in Europe.

Davide Pareyson reported the experience of the Italian SBMA Registry, which has been developed to (i) collect data useful for epidemiological and natural history studies, (ii) test outcome measures, (iii) facilitate recruitment in clinical trials, (iv)

Biomarkers and outcome measures for SBMA

Apart from functional measures of disease status (e.g. walking distance, swallowing, grip strength), there are currently no reliable biomarkers for SBMA. The Workshop participants recognized the urgent need for more accurate, reproducible biomarkers of disease progression in order to enable patient stratification and for the evaluation of disease progression, both of which are essential for effective clinical trials.

Pierre-Francois Pradat presented results of neuroimaging studies which

Clinical trials for SBMA

Kenneth Fischbeck next presented an overview of recent clinical trials in SBMA. Over the past 16 years a number of treatments have been found to be effective in mouse models of SBMA; the challenge has been to convert these findings into effective treatment in patients. Most promising in this regard are interventions close to the mutant AR protein, including androgen reduction, selective AR modulation, altering AR PTMs, and decreasing AR expression. The toxicity of the mutant AR has been shown

Patients perspective

The patient representatives, Marco Bertolotti and Gianni Fabris discussed the importance of collaboration between patient associations, clinicians and basic scientists for the advancement of SBMA. The role of patient associations in the dissemination of information was highlighted, for example about the importance and need for national registries as a means to update the SBMA patient community in international scientific efforts in SBMA research.

Edward Meyertholen from the USA was present

Next steps

In order to increase scientific and clinical collaborations among groups working in different countries, it was agreed that an International Conference on SBMA should be organized. The Workshop participants highlighted the importance of researchers collaborating with patients’ associations in the organization of the meeting, in order to reinforce the communication of scientific and clinical progress to SBMA patients and families, and to providing the community with the possibility of directly

ENMC workshop participants - KD Consortium

Dr. A. Baniahmad (Germany), Dr M. Basso (Italy), Mr. M. Bertolotti (Italy), Dr A. Caricascole (Italy), Mr. G. Fabris (Italy), Dr K. Fischbeck (U.S.A.), Dr P. Fratta (United Kingdom), Prof. I. Gozes (Israel), Prof. L. Greensmith (United Kingdom), Dr B. Malik (United Kingdom), Dr E. Meyertholen (U.S.A.), Dr D. Pareyson (Italy), Prof. M. Pennuto (Italy), Prof. A. Poletti (Italy), Dr P.F. Pradat (France), Dr G. Querin (France), Dr C. Rinaldi (United Kingdom), Dr G. Ronzitti (France), Dr P. Rusmini

Acknowledgments

This 241st Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Muscular Dystrophy Campaign (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Spierfonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Telethon Foundation (Italy), Spierziekten Nederland (The

References (70)

  • A. Hashizume et al.

    A functional scale for spinal and bulbar muscular atrophy: cross-sectional and longitudinal study

    Neuromuscular Disorders

    (2015)
  • J.M. Morrow et al.

    MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

    Lancet Neurol

    (2016)
  • T.-.H. Lai et al.

    Cerebral involvement in spinal and bulbar muscular atrophy (Kennedy's disease): a pilot study of PET

    J Neurol Sci

    (2013)
  • G. Querin et al.

    The spinal and cerebral profileof adult spinal-muscular atrophy: a multimodal imaging study

    Neuroimage Clin

    (2019)
  • M. Katsuno et al.

    Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

    Lancet Neurol

    (2010)
  • L.E. Fernandez-Rhodes et al.

    Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial

    Lancet Neurol

    (2011)
  • C. Grunseich et al.

    Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

    Lancet Neurol

    (2018)
  • N. Pourshafie et al.

    MiR-298 counteracts mutant androgen receptor toxicity in spinal and bulbar muscular atrophy

    Mol Ther

    (2016)
  • A. Araki et al.

    Brugada syndrome in spinal and bulbar muscular atrophy

    Neurology

    (2014)
  • G. Querin et al.

    Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

    J Neurol Neurosurg Psychiatry

    (2016)
  • R.D. Guber et al.

    Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy

    Neurology

    (2017)
  • K. Sahashi et al.

    Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy

    Hum Mol Genet

    (2015)
  • A. La Spada et al.

    Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

    Nature

    (1991)
  • C. Rinaldi et al.

    Pathological mechanisms of polyglutamine diseases

    Nat Educ

    (2015)
  • A. Escobedo et al.

    Side chain to main chain hydrogen bonds stabilize polyglutamine helices in transcription factors

    Nat Commun

    (2019)
  • E. De Mol et al.

    Regulation of androgen receptor activity by transient interactions of its transactivation domain with general transcription regulators

    Struct

    (2018)
  • Z. Yu et al.

    Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model

    J Clin Invest

    (2006)
  • K. Oki et al.

    Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy

    J Appl Physiol (1985)

    (2015)
  • A. Rocchi et al.

    Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet

    Acta Neuropathol

    (2016)
  • N. Chahin et al.

    Serum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis

    Muscle Nerve

    (2009)
  • A.E. Harding et al.

    X-linked recessive bulbospinal neuronopathy: a report of ten cases

    J Neurol Neurosurg Psychiatry

    (1982)
  • D. Borgia et al.

    Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients

    Hum Mol Genet

    (2017)
  • N. Chahin et al.

    Serum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis

    Muscle Nerve

    (2009)
  • S. Yamada et al.

    Decreased peak expiratory flow associated with muscle fiber-type switching in spinal and bulbar muscular atrophy

    PLoS ONE

    (2016)
  • C. Milioto et al.

    Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes

    Sci Rep

    (2017)

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    Members of the KD Consortium are listed under Participants at the end of this report.

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