Genetic treatments in paediatric neuromuscular disorders

The significant advances brought by genetic treatments for paediatric neuromuscular disorders were the focus of a talk at the 24th Annual Neurology Update Meeting in Dublin.

The 2025 meeting – which was directed by Dr Petya Bogdanova-Mihaylova, Consultant Neurologist, Tallaght University Hospital (TUH), Dublin – took place in O’Reilly Hall, University College Dublin, on 10 October.

This year’s meeting featured a diverse programme on a broad spectrum of topics ranging from common neurological problems to rare neurological disorders, from conditions presenting in childhood to adult-onset conditions.

During the morning session, Dr Declan O’Rourke, Consultant in Paediatric Neurology, Children’s Health Ireland, Temple Street, began his presentation by describing the natural history of spinal muscular atrophy (SMA) in children before the advent of gene replacement therapy.

More than 90 per cent of patients with SMA type 1 would not survive or would need permanent ventilatory support by two years of age, according to Dr O’Rourke.

Prior to the availability of current therapies, the management for SMA type 1 focused on nutritional support through nasogastric feeding, non-invasive ventilation, and palliative care approaches.

Dr O’Rourke then outlined the genetic therapeutic advances that have transformed the management of SMA in recent years.

These therapies alter the genetic barriers to normal muscle and nerve development that occur in a child with SMA.

Nusinersen (Spinraza) became commercially available in Ireland in August 2019 for patients with SMA types 1, 2, or 3 who are under 18 years of age.

Onasemnogene abeparvovec (Zolgensma) is approved for presymptomatic SMA in patients with up to three copies of the SMN2 gene, or for those with a clinical diagnosis of SMA type 1. It became available in Ireland in October 2021.

In addition, Risdiplam (Evrysdi) became commercially available in Ireland in October 2023 for patients with SMA types 1, 2, or 3 and one to four copies of SMN2 who are under two months of age.

Dr O’Rourke told the meeting that disease state at presentation is the most important factor in determining outcome.

“The earlier the drug is given, the better the outcome,” he said, noting that treatment is most effective when started before symptoms develop.

He added that this makes the planned expansion of the national newborn bloodspot screening (NNBS) programme to include SMA particularly welcome. “Through newborn screening, and then starting treatment as soon as we can, we will be able to offset nearly all of the disease burden.”

The recommendation to include SMA in the programme was put forward in 2023, but has not yet occurred.

However, speaking to the Medical Independent after his presentation, Dr O’Rourke said he expects screening to commence in the coming months.

“Before [genetic therapy], we had nothing, just supportive treatment. Children developed very severe, very progressive, life-limiting symptoms. But now we have treatments that have completely altered the natural history of that condition.”

Dr O’Rourke noted that guidelines are now in place to guide therapy selection, but emphasised that initiating treatment as early as possible is the critical factor in achieving optimal outcomes.

In his presentation, he also discussed recent progress in the area of Duchenne muscular dystrophy (DMD).

Earlier this year, the European Commission granted conditional marketing authorisation for givinostat (Duvyzat) for the treatment of DMD in ambulant patients aged six years and older who are receiving concomitant corticosteroid therapy.

In addition, Dr O’Rourke spoke about other DMD therapies which are being examined, such as the DELIVER trial. This commenced in August 2022 to assess the next generation molecular therapy DYNE-251 at sites around the world. The therapy targets male children with the specific type of DMD amenable to exon 51 skipping.

CHI, in partnership with St James’s Hospital, Dublin, successfully opened Ireland’s participation in the trial at the end of last year.

“There’s a lot going on in this area too, which hopefully can give some hope and promises for families of patients with DMD,” Dr O’Rourke said.

Speaking earlier in the same session, Prof Sinéad Murphy, Consultant Neurologist, TUH, and Clinical Associate Professor at Trinity College Dublin, discussed the hospital’s role as Ireland’s designated site within the European Reference Network for Rare Neurological Diseases (ERN-RND).

Prof Murphy highlighted that TUH serves as the Irish ERN expert centre for cerebellar ataxia, hereditary spastic paraplegia, atypical parkinsonian syndromes (APS), and genetic Parkinson’s disease. TUH’s involvement ensures Irish patients have access to a European framework of expertise, registries, and collaborative clinical research.