SMA newborn screening: zebrafish tests help prevent overtreatment

Newborn screening aims to detect spinal muscular atrophy (SMA) early, as delayed treatment can lead to severe disability or death in infancy. A collaborative team from the University of Cologne and Griffith University reports that, in rare cases, a positive screening result may reflect an undetected SMN1 gene variant rather than a true absence of the gene.

The studies examined two newborns, a girl from Germany and a boy from Australia, whose routine screening initially failed to detect the SMN1 gene, a key genetic factor in SMA. Under typical protocols, this would prompt rapid treatment because the child may be considered at high risk.

However, follow-up genetic analysis identified rare SMN1 variants that the screening assay did not detect. Whether these variants were disease-causing remained uncertain, raising a critical question for clinicians, including neonatologists and neurologists, as well as for families facing time-sensitive decisions.

"For parents, such a diagnosis is extremely distressing. Within days, they are confronted with the prospect of a potentially fatal disease and the necessity of immediate, irreversible treatment," says Wirth. "Our data show that in rare cases it is crucial to take a step back and clarify the functional significance of a variant."

To clarify the clinical relevance of the variants, the research team used an established zebrafish model. Zebrafish embryos without a functional SMN1 homolog develop severe movement disorders within days and die prematurely. When a functional gene variant is introduced, the animals remain healthy.

Both SMN1 variants found in the infants proved to be functional, and typical SMA symptoms did not appear in the model.

"For the first time, we showed that every single, patient-specific gene variant can be functionally tested – and quickly enough to influence clinical decision," says Dr Jean Giacomotto from Griffith University in Australia, who led the study in EMBO Molecular Medicine.

Additional functional analyses and epidemiological data supported the zebrafish results.

After careful interdisciplinary review and consultation with the parents, the treating medical teams decided not to initiate SMA therapy. Both children are now over two years old, show normal motor development, and have no signs of neuromuscular disease.

MEDICA-tradefair.com; Source: University of Cologne