Multi-system involvement in Spinal Muscular Atrophy

Location: Hoofddorp, The Netherlands

Title:  264th ENMC workshop on Multi-system involvement in Spinal Muscular Atrophy

Date:  19-21 November 2021

Organisers: Dr Giovanni Baranello (UK), Prof. Tom Gillingwater (UK), Prof. Kathryn Swoboda (USA), Dr Rashmi Kothary (CAN)
Co-Organisers: Dr Nora Detering (GER), Dr Niko Hensel (CAN), Dr Alberto Zambon (ITA)

Translations of this lay report:
Danish by Prof. John Vissing
Italian by Dr Alberto Zambon

Participants: Prof. Simon Parson (UK), Dr Mariacristina Scoto (UK), Prof. John Vissing (DK), Dr Melissa Bowerman, Prof. Brunhilde Wirth (GER), Prof. Peter Claus (GER), Prof. Janbernd Kirschner (GER), Prof. Enrico Bertini (ITA), Dr Stefania Corti (ITA), Dr Lorenzo Maggi (ITA), Prof. Ludo van der Pol (NL), Dr Ewout Groen (NL), Dr Charlotte Sumner (USA), Dr Eduardo Tizzano (SPA), Prof. Susana Quinajo Roy (FRA), Dr Isabelle Desguerre (FRA), Prof. Alexander Van Nuijs (BL), Mencia De Lemus (SPA), Rivka Smit (patient), Prof. Mary Schroth (Cure SMA), Dr Deepa Chand, Dr Ben Tichler, Dr Ksenja Gorni

Spinal Muscular Atrophy (SMA) has classically been viewed as a motoneuron disease caused by loss of the Survival Motor Neuron 1 (SMN1) gene and low SMN protein levels. SMN is expressed in all cells and tissues and ubiquitously reduced in SMA patients. Not surprisingly, there is growing evidence of multi-system involvement in SMA. Recently approved SMN-enhancing therapies impressively ameliorate the neuromuscular presentation resulting in an increased survival of severely affected patients. However, limited peripheral drug availability in some of the treated patients may set the focus on previously overseen peripheral organ phenotypes. Moreover, there is the concern that now longer living patients will develop signs of systemic non-neuronal manifestations over time, which is one of the most important questions to address. Finally, patients receiving treatment after the onset of symptoms may have accumulated peripheral organ defects which cannot be rescued by SMN restoration. With the evolving landscape of therapeutics in SMA and the ever-changing natural history of the disease, there is the need for broader systemic monitoring of SMA progression. This is a challenging endeavour since SMN-enhancing treatments introduce a substantial variability to the patient population. Therefore, a coordinated effort by clinical and basic researchers with the involvement and support of patients is needed to provide a framework for the detection and treatment of the multi-system phenotypes in SMA.

Workshop aims:

1. To critically review the scientific evidence supporting the presence of multi-systemic involvement in SMA across different tissues, organs and systems in relation to the underlying molecular and pathophysiologic mechanisms
2. To identify still under-investigated “non-neuronal” manifestations of SMA and explore the potential impact of SMN-modulating treatments on the systemic manifestations of the disease in preclinical models
3. To provide a comprehensive evaluation of the different aspects characterizing the multi-system involvement in SMA patients
4. To establish a framework for an integrated and collaborative approach across a variety of stakeholders to identify and monitor possible multi-system manifestations in SMA with potential implications for the therapeutic strategies

Workshop outcomes

SMN levels, functions, and the need of animal models

The SMN protein is ubiquitously expressed in all cells and tissues of the body. However, SMN levels largely differ between organs and cells and the workshop participants agreed that it is crucial to carefully measure the SMN amounts in different organs. Cells and organs with a high SMN expression in non-affected subjects and/or a strong reduction in SMA conditions may be susceptible in SMA and monitoring the SMN levels may contribute to the identification of peripheral organ defects. Studies evaluating SMN levels in patients treated with SMN-enhancing drugs are highly relevant – organs without sufficient SMN restoration may develop pathological changes over time. The careful characterization of SMN-levels in patients should contribute to the development of a second generation of animal models which better represent the current clinical landscape of treated SMA. Large animal models as well as ‘treated’ animals are important pre-clinical tools for the predication of possible peripheral phenotypes in SMA and may guide clinicians in their studies. The participants agreed on the importance of cross-species observations and a careful characterization of their models. Moreover, animal models can be used to modulate SMN levels in an organ specific manner to decipher to which extent organ intrinsic versus extrinsic SMN contributes to a peripheral phenotype. Finally, the underlying molecular mechanisms need to be characterized – are there organ-specific or more homogenous disease-specific pathways? Answers to this question may contribute to future combinatorial treatment regimens.

Detection of peripheral organ pathologies in patients

Clinical studies represent a valuable source to explore the multisystem effect of SMN depletion in humans. However, high individual heterogeneity further increased by the administration of new therapies poses significant challenges. During the workshop, it was agreed that there is an urgent need to join forces to establish well-designed clinical protocols aimed at investigating specific research questions, in particular in those phenotypes “emerging” as a consequence of treatments. A well-characterized population is essential, and information regarding genotype (e.g., SMN2 copies, polymorphisms), baseline clinical severity (e.g., SMA type 1 subtype), subclinical findings (e.g., significant reduction of compound motor action potential – CMAP – in “pre-symptomatic” patients), and timing of SMN enhancing drug application related to disease onset, should be always collected. Specific sub-populations of SMA patients (e.g., SMA patients with 2 SMN2 copies, adults, etc.) could serve as cohorts to answer different questions. Lastly, efforts should be directed to the identification of reliable outcome measures. For instance, the use of standardized assessment tools is fundamental to clarify the prevalence and nuances of brain-associated comorbidities including cognitive impairment and/or autistic spectrum disorders in patients affected by SMA, and those patients with 2 SMN2 copies could be an ideal cohort to be studied. Furthermore, pre-symptomatically CNS only treated patients may be an informative cohort to dissect the true prevalence of systemic involvement in SMA.

Importance of the patient perspective to direct scientific efforts

To set a focus on patient-relevant investigations within the workshop consortium, inclusion of the patients’ perspective reveals additional important insights. Once the neuromuscular phenotype is under treatment, SMA patients will require a need for individual medications depending on their individual status of peripheral symptoms. An update for care is crucial since current care aspects relate to most severe SMA types neglecting everyday life of treated SMA patients. However, the implementation of multi-disciplinary medical care shall consider the prioritized independence of a patient avoiding the medical visits being a putative burden to the patient’s life. In addition to clinical monitoring, the data collection by international and national patient registries and patient organizations may be beneficial for a better understanding of the patients’ needs. However, the development and implementation of a global international data repository may be limited by diverse local regulations, support, and restrictions of centers.

Next Steps

These initial discussions have highlighted several important ‘unknowns’, the importance to share data and to bridge researchers, clinicians and patients to prioritize research questions. All participants agreed to be part of a working group that might bring forward and work on the research questions and knowledge gaps highlighted during the workshop, and to have regular remote follow up meetings and possibly a new face-to-face meeting in 2023.

A full report is published in Neuromuscular Disorders (PDF)