Evrysdi benefited baby despite her having 1 copy of SMN2 gene

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by Andrea Lobo |

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An 8-month-old girl with a clinical and genetic diagnosis of spinal muscular atrophy (SMA) type 1 saw her condition improve after starting treatment with Evrysdi (risdiplam), according to a recent case reported in China.

Specifically, the treatment improved the girl’s muscle tone and head control as well as her leg and hand strength, allowing her to sit alone and play with toys for two minutes after seven months of therapy.

According to the researchers, the patient’s clinical improvements were unexpected, considering she had only one copy of the SMN2 gene, commonly associated with a higher disease severity.

The case was reported in “Real-world evidence: Risdiplam in a patient with spinal muscular atrophy type I with a novel splicing mutation and one SMN2 copy,” published in Human Molecular Genetics.

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How an interruption in SMA treatment affected my quality of life

SMA is caused by mutations in the SMN1 gene, resulting in little or no production of the survival motor neuron (SMN) protein. Everyone inherits two copies of the gene, one from each parent, and the disease only develops if both SMN1 copies have disease-causing mutations.

The most common mutation is a gene deletion in both gene copies, where a large part of the SMN1 gene is completely missing. In a lower proportion of patients, however, one SMN1 gene copy has a deletion while the other has the complete gene but with a disease-causing mutation.

The SMN protein can also be produced by the SMN2 gene, but this “backup” gene only produces about 10% functional SMN. Usually, more SMN2 copies are associated with a lower disease severity.

The case study

Here, scientists in China described the case of a girl with SMA type 1 with mild symptoms, including normal breathing and swallowing. This SMA type is the most common and usually one of the most severe, in which symptoms develop within the first six months of life.

The parents reported limb weakness when she was 3 months old. When she was 5 months old, the parents took her to the researchers’ neurology department, where the girl was found to have hypotonia (low muscle tone); she’d also not yet achieved expected motor milestones, such as head control or the ability to turn over.

Considering the clinical symptoms and neurological examination showing decreased muscle tone and strength and the absence of reflexes in the limbs, she was suspected to have SMA type 1.

A genetic analysis revealed the patient had one deleted SMN1 gene copy, while the other copy had a novel mutation (c.628-3T>G), and she had only one SMN2 gene copy. The newly identified mutation led to an alternative splicing of SMN1‘s messenger RNA (mRNA) — a molecule used as a template for protein production — but retained partly normal mRNA.

According to the researchers, this finding could explain why the patient with only one copy of SMN2 had a milder clinical condition, relative to most with type 1. Alternative splicing is a natural process that allows for a single gene to produce different proteins by adding or removing exons, which are protein-coding regions.

When the patient was 8 months old and had an established genetic diagnosis of the disease, she started treatment with Evrysdi, which took into consideration the treatment cost, the aim of initiating treatment as soon as possible, and avoiding injection-associated pain.

Evrysdi, one of three currently approved disease-modifying treatments for SMA, is an oral small molecule that works by preventing the alternative splicing that results in the exclusion of exon 7 from SMN2‘s mRNA.

During the treatment, researchers evaluated the patient’s Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score, a reliable standard for assessing motor skills in patients with SMA. The score ranges from 0 to 64, with higher scores indicating better motor function.

After three months of treatment, the patient showed moderate improvement in muscle tone, head control, as well as lower limb and hand strength. She maintained normal breathing and swallowing and could sit unassisted for five seconds.

The patient’s CHOP-INTEND score increased from 8 to 26. According to the researchers, “such a remarkable improvement was beyond our expectations, as the patient had only one copy of SMN2.”

After seven months of treatment, she could sit alone and play with toys for two minutes, and her CHOP-INTEND score increased from 26 to 40.

“Overall … this study is the first report on the treatment of [Evrysdi] in a patient with one SMN2 copy in a real-world setting,” the researchers concluded. Moreover, “our findings expand the mutation spectrum of SMA.”

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