Study supports mandatory newborn screening in Japan

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by Steve Bryson PhD |

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This illustration shows a strand of DNA.

A pilot study describes how researchers successfully implemented a newborn genetic screening in Osaka, Japan, to identify infants with spinal muscular atrophy (SMA) as early as possible.

No false-positive results occurred in about 23,000 samples screened in the study; after implementation, newborn screening detected one presymptomatic SMA infant who was treated immediately.

The researchers hope these findings support the development of mandatory SMA screening programs in Japan.

The pilot study, “Newborn screening for spinal muscular atrophy in Osaka -challenges in a Japanese pilot study,” was published in the journal Brain and Development.

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Study sheds light on how SMN protein deficiency can cause SMA

The SMN1 gene carries instructions to make SMN, a protein that is vital for the function of motor neurons, which are specialized nerve cells that transmit signals to control voluntary body movements.

About 95% of people with SMA carry mutations in both copies of their SMN1 gene, one inherited from each parent. As a result, little or no SMN protein is made, triggering the onset of symptoms, such as progressive muscle weakness and atrophy (wasting).

In these patients, age of onset and disease severity is largely dictated by the number of copies of a second SMN2 gene, which can produce some SMN and partially compensate for SMN1 defects.

Currently approved SMA therapies appear to work best in those diagnosed early via genetic analysis, even before symptom onset. Thus, newborn screening programs for SMA (SMA-NBS) are now strongly recommended.

Yet, while SMA-NBS programs have been launched in various parts of Japan, only about 20% of newborns are currently screened for SMA at birth, which “is still insufficient,” the researchers wrote.

Pilot analysis

To improve newborn screening for SMA in Japan, the researchers based at Osaka Women’s and Children’s Hospital (OWCH) established an SMA-NBS program locally and conducted a pilot analysis of their program.

Their SMA-NBS workflow began by collecting dried blood spots (DBS) from newborn infants, 4–6 days after birth, with screening tests performed on days 6–13. With a positive result (SMN1 defects found), a pediatric neurologist is notified, who contacts parents on the same day. SMA diagnosis is confirmed with a second positive test between days 10–28.

The protocol was validated using DBS samples from seven diagnosed SMA patients, all of whom tested positive.

Among the 23,799 newborns eligible for SMA-NBS, 22,951 (97.6%) were screened from February to September 2021. Of the 23,216 collected DBS, 265 were deemed invalid due to insufficient blood volume or other reasons. Samples arrived to the testing facility 4–15 days after birth, with 97.8% of the samples arriving by day 9.

All of the collected DBS samples tested negative for SMN1 defects, with no signs of false-positive tests — a positive test in a newborn without SMA.

“Based on these results, an SMA-NBS program was established in Osaka,” the team wrote. As such, it was added to the optional NBS programs at OWCH beginning in October 2021.

Since then, 40,247 DBS samples have been obtained, with one newborn testing positive 12 days after birth. Further tests confirmed SMN1 defects alongside three copies of the SMN2 gene.

Neurological and muscle tests were all within the normal range, and the infant was diagnosed with presymptomatic SMA on day 20. Although the parents initially were confused by this diagnosis in their otherwise healthy newborn, the team noted, treatment began with support from the clinical team.

The child first received Spinraza (nusinersen) on day 21, an approved therapy designed to increase SMN2-derived SMN protein. On day 29, he was treated with Zolgensma (onasemnogene abeparvovec-xioi), an approved gene therapy that delivers a working copy of SMN1 to cells.

According to researchers, the infant has developed normally so far, without adverse effects from gene therapy.


However, the team noted that although this baby, “who possessed 3 copies of the SMN2 gene, is expected to have a markedly better prognosis than his natural course, performing treatment on day 21 would not be early enough for babies with severe SMA.”

“We should try to reduce the time to treatment for babies with severe SMA by further improving the SMA-NBS system in Osaka,” they said, adding that “initiating treatment within 2 weeks of birth may be a realistic goal.”

The team hopes that “describing the results of our optional SMA-NBS program will lead to the development of mandatory SMA-NBS programs in Japan.”

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