Around half of treated SMA type 1 children show cognitive dysfunction

Lindsey Shapiro PhD avatar

by Lindsey Shapiro PhD |

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More than half of the children with spinal muscular atrophy (SMA) type 1 who received disease-modifying therapies (DMTs) in their first year of life showed cognitive deficits in a recent study.

Cognitive problems were more likely in boys and in those who required assisted ventilation or feeding.

“Given the high rate of children with cognitive impairment in our cohort, this important aspect should be considered and cognitive testing should be routinely performed in the follow-up to allow early intervention and to evaluate the effect of each therapeutic intervention,” the researchers wrote in “Cognitive function in SMA patients with 2 or 3 SMN2 copies treated with SMN-modifying or gene addition therapy during the first year of life,” which was published in the European Journal of Paediatric Neurology.

Within the last decade, three DMTs have become available for SMA in several countries — Spinraza (nusinersen), Evrysdi (risdiplam), and the one-time gene therapy Zolgensma (onasemnogene abeparvovec). Such treatments, combined with an early diagnosis through newborn screening, have changed the landscape in SMA. Patients are living longer and achieving motor milestones they wouldn’t have otherwise reached.

The effects are especially profound for those with SMA type 1, the most common and most severe form of the condition where muscle weakness and wasting, feeding issues, and respiratory failure lead to death within the first couple years of life, if left untreated.

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Cognitive development in boys, girls with SMA type 1

Because these severely affected children hadn’t historically survived to school age, there’s not as much known about their cognitive development, which is relevant now that DMTs have resulted in them living longer. Studies that have investigated this have seen variable results, according to the researchers here, who performed cognitive testing in 20 SMA patients (eight boys, 12 girls) seen at clinics in Germany who’d started treatment within the first year of life. Nineteen started treatment after their symptoms emerged, while one was diagnosed and treated presymptomatically.

All the children had two or three copies of SMN2, the “backup” gene that produces the SMN protein patients lack due to mutations in SMN1.

Treatment was started from 40 days to nearly a year after the onset of symptoms in the symptomatic patients. The presymptomatic child started showing symptoms about 2.5 years after treatment started.

Fourteen children were treated with Spinraza, followed by Zolgensma. Four children received Zolgensma alone, one child Spinraza alone, and one Evrysdi, followed by Zolgensma.

Cognitive testing was performed at a median age of 3. For 12 children between the ages of 2-3, the Bayley Scales of Infant Development (BSID-III) was used, while the Wechsler Preschool and Primary Scale of Intelligence was used for the remaining eight children at age 5.

Eleven children showed below-normal cognitive development, with cognitive impairments considered moderate or severe in nine. Three children had above average cognitive performance.

The boys had significantly lower cognitive performance than the girls. All eight boys had abnormal results, while three girls did.

The boys in the study seemed “more severely affected by the disease” and had a greater need for ventilation and feeding support and generally lower motor function, which could have affected the findings, the researchers said.

The children who needed assisted ventilation were at a 12.5-times higher risk of cognitive deficits than those who didn’t and those who required feeding support were at a nine times higher risk.

On the other hand, achieving more motor milestones was linked to better cognitive outcomes. All the children who could walk had a normal cognitive score, whereas all those whose highest-achieved motor milestone was head control showed impairments. Higher cognitive scores were also associated with an older age at starting treatment, which researchers said could be related to an overall milder disease in those patients.

While the findings indicate a “substantial number” of children had cognitive dysfunction, larger and longer-term studies would help understand how cognitive function evolves in this group, said the researchers, who also indicated the mechanisms underlying cognitive dysfunction in SMA remain to be unraveled.

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