Taiwan is one of only a small group of countries and territories around the world that routinely screens most newborns for Duchenne muscular dystrophy (DMD), a serious genetic disease that primarily affects boys. Amid ongoing advances in the scientific understanding and treatment of DMD, however, more countries are likely to consider adding the condition to their newborn screening (NBS) panels in the near future.

DMD is a challenging disease that causes progressive loss of muscle function and early death. Most boys with DMD are apparently healthy at birth and will only start showing signs of the condition, notably muscle weakness and difficulty with motor skills, in early childhood. Given the typically slow and subtle onset, the journey to diagnosis can be long, costly and emotionally difficult for caregivers.

In adding DMD to NBS panels, some hope that early detection of the condition will avoid an extended diagnostic journey, enable proactive treatment, and provide more time for complex life planning decisions that can improve patient and caregiver outcomes. A recent study from the EveryLife Foundation for Rare Diseases, a US-based research and advocacy group, indicates that early diagnosis could also result in substantial cost savings to healthcare systems as well [1].

To better understand the practical considerations and potential benefits of NBS for DMD, Lab Insights spoke with Dr Yin-Hsiu Chien, a paediatrician and medical geneticist who currently directs the Newborn Screening Centre at National Taiwan University Hospital (NTUH). In addition to leading the pilot of NBS for DMD at NTUH, she was also the lead author in a journal article that describes its methods and results [2].

Launching the DMD screening pilot

NBS for DMD was first piloted in February 2021 at NTUH, which operates one of the three main public sector NBS centres in Taiwan. Dr Chien and colleagues at NTUH were therefore the first in Taiwan—and among the first in the world—to recognise the potential benefits of DMD screening.

“We saw DMD screening as important for several reasons,” says Dr Chien. “It affects around 1 in 5,000 live male births, so the prevalence is relatively high compared to other rare genetic diseases. It is also an X-linked disease, and given the risk of recurrence, early detection can also help parents with reproductive planning. Finally and most importantly, many promising treatments are in development, and we know that early intervention has potential to lead to a better prognosis.”

Dr Chien also notes that an FDA-approved IVD kit for DMD screening was available at the time NTUH launched its pilot, allowing them to get started more quickly than in previous studies in other countries and territories. Results from that pilot, which covered the first 50,572 newborns and identified 3 confirmed DMD cases, were published in May 2022. Since then, the other two NBS screening centres in Taiwan adopted DMD screening as well.

Today, DMD screening is provided to newborns in Taiwan as part of an ‘extended panel’ that sits on top of the standard, government-funded panel and requires an out-of-pocket payment from parents. More than 90% of parents in Taiwan opt for the extended panel, so the vast majority of Taiwanese newborns now receive DMD screening at birth (see this earlier Q&A with Dr Chien on Lab Insights for more information about how Taiwan’s NBS system is structured).

How DMD screening works in Taiwan

Biochemical screening for DMD measures creatine kinase (CK-MM), a muscle damage marker that is typically elevated at birth in patients with the condition. The initial samples are taken from the same dried blood spot (DBS) samples that are used for other NBS tests; subsequent samples will require an additional blood draw.

In the NTUH pilot, Dr Chien and colleagues decided on a multi-step protocol that started by measuring CK-MM within a few days of birth. Babies in the top 1% of the CK-MM range, which amounted to 750 ng/mL or more for full term newborns and 650 ng/mL for premature babies, were flagged for retesting. This cutoff range, which was determined in reference to a previous study in China, was designed to limit false positives but without losing any true positives.

Babies in the top 1% were then retested at two weeks, and those with a CK-MM value of at least 300 ng/mL or more were retested a third time. They also had their family history taken to assess additional risk factors and received further testing via a next-generation sequencing (NGS) panel that covered DMD and other neuromuscular conditions (the NGS test was performed on the same dried blood spot sample that was collected at birth).

Exploring alternate protocols

One challenge with CK-MM is that it is not a highly specific marker for DMD. Elevated CK-MM can also be caused by birth trauma or other situations, so initial screens in the neonatal context will often yield a high false positive rate. Alternate protocols have thus been considered across various studies in an effort to improve test accuracy.

Some studies have chosen different cut-off thresholds for CK-MM retesting. “Previous studies suggest that CK-MM in DMD is typically over 1,000 ng/mL in newborns, whereas transient elevation was more likely to be in the 400-500 ng/mL range,” observed Dr Chien. “But despite good separation, we stuck with rescreening the top 1% because we wanted to limit the risk of false negatives.”

It is also technically possible to use NGS as a 2nd or even 1st-tier test, including via a neuromuscular panel or even whole exome or genome testing. This would be particularly beneficial for parents who are not able to come back for the second CK-MM screen, but it would also increase the total cost of screening. Dr Chien also believes it would still be necessary to do biochemical testing via CK-MM in parallel, as “we still don’t understand all the genetic variants.”

Explaining results to parents

Another challenging aspect of DMD screening for newborns involves explaining results to parents. For parents whose newborns have CK-MM values in the top 1%, it is important to ensure they understand the importance and purpose of rescreening without causing undue alarm.

“Our nursery unit tends to have the strongest bond with the parents and so they usually manage most of the communication,” says Dr Chien. “We encourage all families to come back for rescreening, but for families whose CK-MM values are particularly high and which are not explained by other clinical factors, we might provide especially strong encouragement.”

For parents whose children ultimately receive genetic confirmation of DMD, clinicians and genetic counsellors face the deeper challenge of delivering a devastating, life-altering diagnosis that often elicits feelings of grief, pain, fear and other negative emotions. However, Dr Chien is hopeful that new treatments will provide a more optimistic outlook.

“DMD screening for newborns is here to stay in Taiwan,” she says. “The value of this approach and the next steps for those who test positive will be much clearer when we have better treatment options available here.”

This article was written by Will Greene, Healthcare Engagement Lead at Roche Diagnostics Asia Pacific and co-lead on Project Strongbow, an initiative to drive best practices in newborn screening and rare disease diagnostics through educational content and community building. Visit our Newborn Screening page to see more of our articles and videos on this topic. 

References:

[1] The Cost of Delayed Diagnosis in Rare Disease: A Health Economic Study (2023) EveryLife Foundation. Available at: https://everylifefoundation.org/wp-content/uploads/2023/09/EveryLife-Cost-of-Delayed-Diagnosis-in-Rare-Disease_Final-Full-Study-Report_0914223.pdf

[2] Chien, Y.-H. et al. (2022) ‘Duchenne muscular dystrophy newborn screening: The first 50,000 newborns screened in Taiwan’, Neurological Sciences, 43(7), pp. 4563–4566. doi:10.1007/s10072-022-06128-2.