A baby with spinal muscular atrophy (SMA) type 0 treated with both Spinraza (nusinersen) and Zolgensma is showing benefits relative to the natural course of this most severe disease form, but also limits to treatment effectiveness, a case report suggests.
While the child continues to show motor improvements after one year of treatment, compared with how this disease would progress without treatment (its natural history), complications that include difficulties in breathing and swallowing, as well as heart and skin abnormalities, remain and affect her quality of life.
These findings highlight the complexities and potential limitations of treating patients with the most severe form of SMA, the researchers wrote.
The case study, “Clinical Course in a Patient With Spinal Muscular Atrophy Type 0 Treated With Nusinersen and Onasemnogene Abeparvovec,” was published in the Journal of Child Neurology.
SMA is caused by mutations in the SMN1 gene, which impair the production of SMN, a protein produced by virtually every cell in the body and essential for motor neuron and muscle health.
SMN deficiency is known to kill motor neurons (nerve cells), leading to muscle weakness and wasting. Increasing data also suggest that SMA is a multisystem disease, with a lack of SMN protein possibly affecting other tissues and organs.
This can be particularly evident in young patients with more severe forms of the disease, who have greater systemic complications that include heart defects, metabolic abnormalities, and skin and bone problems.
Patients with SMA type 0, the disease’s most severe form, start to show symptoms during fetal development (little fetal movement) and rarely survive beyond their first weeks of life. Breathing and swallowing difficulties, heart abnormalities, and joint and muscle malformations are usually evident at birth.
Type 0 patients typically have only one copy of a second SMN gene, called SMN2, that can partly compensate for the loss of SMN1-produced SMN protein. The more SMN2 copies a patient has, the higher is the likelihood of more SMN being produced and a milder form of the disease being evident.
Currently approved disease-modifying therapies for SMA — Biogen’s Spinraza and Novartis’ gene therapy Zolgensma — are designed to increase SMN protein levels. Spinraza works by boosting SMN2’s production of SMN, while Zolgensma delivers a healthy copy of the SMN1 gene to cells.
Their potential benefits in SMA type 0 patients, who may lack enough motor neurons to allow for significant improvements, remain unknown.
“Given the severity of symptoms at birth in type 0 patients, as well as lack of data on potential response to treatment, the decision on whether to offer treatment to these patients is a complex one,” the investigators wrote.
Researchers at the Children’s Hospital of Philadelphia reported, for a first time, on a baby girl diagnosed with SMA type 0 and treated with both Spinraza and Zolgensma.
During the pregnancy, both parents were identified as carriers of one mutated SMN1 copy, increasing the likelihood that both gene copies would be mutated in their child, and the baby would develop SMA. Additional genetic tests were delayed.
Despite reports of normal fetal movement during pregnancy, prenatal imaging showed potential congenital defects, including in the heart. At birth, the girl had breathing problems (requiring ventilation support), a weak cry and suck, facial weakness, and minimal spontaneous movements.
These findings were suggestive of SMA type 0, which was confirmed through genetic testing when she was 6 days old. After discussing treatment options, the parents decided to start the baby, then 2 weeks old, on Spinraza (the only approved therapy at that time).
Her motor skills improved significantly (as assessed with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, or CHOP-INTEND, score) over the first two months of treatment, again compared with the natural history of type 0 disease.
However, sustained breathing and swallowing difficulties led to permanent ventilation support and a feeding tube. By then, heart defects and skin problems were also detected.
At nearly 4 months old, she received a single dose of Zolgensma through the U.S. Food and Drug Administration’s compassionate use program, which allows access to therapies before their approval in particular cases.
Her maximum CHOP-INTEND motor score (of 44) was reached one month after the gene therapy. Skin problems persisted — including “significant digit necrosis” (tissue death on the digitis of her hands and feet requiring amputation) and rash — and further analyses revealed that she also had problems in blood vessels, blood clots, weak bones, and moderate scoliosis.
Since being treated with Zolgensma, the baby has been given two additional doses of Spinraza. At 13 months old (the last follow-up visit to date), she continued to make small gains in motor function, without signs of regression. However, she remained profoundly weak and dependent on respiratory and nutritional support.
“Although our case demonstrates a clear benefit from treatment in motor function, there remains significant medical morbidity with systemic issues common and uncommon in spinal muscular atrophy,” the researchers wrote.
Her premature birth may have contributed to motor gains observed, they added, as earlier treatment is associated with greater therapy benefits. But tissues in which the need for SMN protein is thought to be high during critical prenatal periods may not have responded to postnatal treatment, the team suggested.
“This case highlights the challenges in treating those with more severe disease … and raises questions of how some systemic complications may respond to current SMN replacement therapies,” the researchers concluded.
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