SMN-related neurodevelopmental disorder: type 1 Spinal Muscular Atrophy and the brain

285^th ENMC International Workshop:

Location: Hoofddorp, The Netherlands

Title: SMN-related neurodevelopmental disorder: type 1 Spinal Muscular Atrophy and the brain

Date: 31st January - 2nd February 2025

Organisers: Prof. S. Quijano-Roy (France), Prof. G. Baranello (United Kingdom), Prof. M. Farrar (Australia), Dr. D. Gómez Andrés (Spain).

Early Career Researchers (ECR): Dr. R. Garcia-Uzquiano (France), Dr. C. Brusa (United Kingdom), Dr. M. Alvarez Molinero (Spain).

Translations of this report by:

French by Dr R. Garcia Uzquiano
Spanish by Dr. M. Alvarez Molinero
Italian by Dr. C. Brusa
German by Prof. U. Schara-Schmidt
Portuguese by Dr. J. Ribeiro
Turkish by Dr. D. Ardıçlı
Dutch by Dr. R. Wadman
Polish by Dr. M. Mroczek

Participants: Prof. S. Quijano-Roy (France), Prof. G. Baranello (United Kigdom), Prof. M. Farrar (Australia), Prof. D. Gómez Andrés (Spain), Dr. R. Garcia-Uzquiano (France), Dr. C. Brusa (United Kingdom), Dr. M. Alvarez Molinero (Spain), Prof. T. Crawford (USA), Dr. M. Catteruccia (Italy), Dr. J. Ribeiro (Portugal), Prof. U. Schara-Schmidt (Germany), Dr. D. Ardıçlı (Turkey), Dr. C. Castiglioni (Chile), Prof. D. Germanaud (France), Dr. M. Scoto (United Kingdom), Prof. L. Ouss (France), Prof. T. Gillingwater (United Kingdom), Dr. N. Molitierno (Italy), Prof. P. Claus (Germany), Prof. B. T.  Darras (USA), Prof. I. Desguerre (France), Prof. N. Deconinck (Belgium), Dr. D. Kariyawasam (Australia), Dr. F. Cumbo (Italy), Dr. R. Wadman (Netherlands), Dr. M. Mroczek (Polish SMA association researcher, Switzerland), Dr. Y. Erbas (patient representative, Netherlands, Belgium), Ms. P. Thorman  (patient representative, United Kingdom).

Background information:

Due to significant improvements in medical care and remarkable therapeutic innovations achieved in SMA during these recent years, survival and motor outcomes in this degenerative disease have drastically changed. This is especially apparent in those who inherit the most severe SMA genotypes, for whom the new treatments may be lifesaving or allow progress or stabilisation in their motor, breathing and/or feeding outcomes. In fact, most infants treated at a presymptomatic stage, either by newborn screening or due to family history of SMA, show little or no delay in their motor development, what indicates that the most optimal efficacy of these therapies is obtained before symptoms of motor neuron degeneration are observed.

However, doctors, scientists and researchers have noticed that a proportion of treated children with favourable motor response show, unexpectedly, impaired cognitive or social skills in the first years of life, or a delay in their communication abilities compared to their peers, or behavioural particularities. At the moment, it is not fully understood how common these differences are, which areas of development are most affected, what causes these differences, or whether new SMA treatments may impact in their occurrence.

To provide the best care and support for children with SMA, it is important to have a better picture of these developmental changes and study their frequency and trajectories. Identifying their causes and long-term outcomes will help improve diagnosis, treatment, care and guidance for families. Therefore, further research is needed to ensure children with SMA receive the better support possible to thrive in all aspects of their development.

Workshop aims:

• Bringing Experts Together: Clinicians, scientists, researchers, and advocacy group representatives from around the world shared their experiences and research on brain development in children with SMA. This includes those with SMA type 1 (SMA1) and those diagnosed through newborn screening or prenatal testing.
• Addressing Parents’ Concerns & Understanding Development: The group reviewed current practices and investigated the best ways to assess neurodevelopment in children with SMA This will help to answer parents’ and caregivers’ concerns to improve early detection of developmental differences.
• Improving Early Support & Care: There is an urgent need for recommendations on early interventions to support children’s cognitive, communication, and behavioural development.
• Planning Future Research & Collaboration: The meeting identified key gaps in knowledge and set plans for future research. This includes large studies on development in SMA to improve epidemiology and diagnostic tools, provide care guidelines, and facilitate the research of potential treatments.

Workshop outcomes/deliverables:

Experts confirmed that a substantial proportion of the children followed by them with SMA1, who would not have survived infancy without the new treatments, now manifest features of impaired neurodevelopment. These present in a range of ways that may affect speech, social interaction, behaviour and/or cognitive abilities. This is supported by recent basic and preclinical studies suggesting that low SMN protein levels may affect the developing brain in utero and eventually in early postnatal life.

Children with 1 or 2 copies of the SMN2 gene, those who have early symptoms of weakness, or those who experience treatment delays, seem to be at higher risk. The impact of current treatments on neurodevelopment is still unclear and requires further research.

Early identification of potential difficulties and timely referrals to clinical specialists and therapists seem important. Supporting child and family wellbeing may also be central to improve outcomes for affected children. As such, developmental outcomes for children with SMA may be able to be modified..

While a core screening strategy to monitor development in the clinic was agreed, further research and international collaboration were considered necessary in order to develop specific diagnostic and intervention guidelines. Experts emphasized in particular the need to include standardized multimodal neurodevelopmental assessments in national registries as a way to improve data collection and research collaboration.

Impact for the patients and their families:

• Early Monitoring & Intervention: Like other children at increased risk of neurodevelopmental impariment or with chronic neurological conditions, children with SMA may benefit from close follow-up, preventive strategies, and early interventions, in particular speech therapy. Clinicians should actively look for neurodevelopmental concerns by listening to parents and using appropriate screening or assessment tools.
• Careful Interpretation of Assessment tools: Standard neurodevelopmental tests may not always be accurate in children with severe motor, respiratory, or swallowing difficulties. Instead of reporting test results in one moment in time, clinicians should consider longitudinal monitoring to track development over time.
• Supporting Families & Advocacy: Advocacy groups stressed the importance of educating parents about early signs of developmental challenge and providing guidance that focuses on strengths. Families need information, psychosocial support, peer connections, and access to effective interventions.
• Global Impact & Research Collaboration: There is an international consensus among SMA experts that collaboration across different centres is urgent to define epidemiology of the neurodevelopmental differences and facilitate basic and clinical research necessary to better understand the causes of brain dysfunction in SMA. Including families’ perspectives in research and care strategies will be key to ensuring better support for children with SMA.

Next steps:

To further understand how SMA affects brain development, experts plan to:

• Share Workshop Findings – Disseminate key conclusions to raise awareness.
• Launch an Online Survey – Assess the prevalence of neurodevelopmental challenges and study their characteristics and trajectories to identify specific SMA subgroups.
• Develop diagnostic and care guidelines for neurodevelopmental disorders in SMA.
• Form Research Working Groups – Establish a research alliance to study both clinical and preclinical aspects of SMA, including deep phenotyping, diagnostic tools, brain anatomy & neuroimaging, molecular biology, and biomarkers.

These initiatives will help improve the care of individuals with SMA and also advocate for additional scientific research to understand the reasons for why development may be different in children with SMA and how.

A full report will be published in Neuromuscular Disorders (PDF).