The X-linked neuromuscular disorder Duchenne muscular dystrophy (DMD), which historically has been diagnosed in boys between the ages of 3 and 6 years, has become an important candidate for newborn screening.
"Early diagnosis of DMD is critical," said Stephen Chrzanowski, MD, PhD, of Boston Children's Hospital.
"As a rare disease, families unfortunately often face a tortuous and confusing diagnostic odyssey to identify DMD, long after injury and damage has occurred to muscle, or siblings may have also been born with DMD," Chrzanowski pointed out. "Additionally, mothers who are carriers for DMD may also be affected, requiring their own monitoring and care."
Despite improved screening diagnostic techniques and new treatment options, DMD is rarely screened for at birth, Chrzanowski noted.
The creatine kinase-MM (CK-MM)–specific assay has been approved by the FDA, and DMD should be considered for the Recommended Uniform Screening Panel (RUSP) for newborn screening, he added.
DMD has a prevalence of less than 10 cases per 100,000 males. It is very rare in girls, occurring in less than one case per 1 million females.
DMD is caused by variants of the DMD gene located on the X chromosome; mutations in the gene prevent the production of dystrophin.
"With the concurrence of novel therapies and FDA-approved screening techniques, we are at an opportune time to recommend and implement newborn screening for DMD on a national level," Chrzanowski said.
New DMD Treatments
Since 2016, four exon-skipping antisense oligonucleotides received accelerated FDA approval, based on the surrogate endpoint of increased dystrophin production: eteplirsen (Exondys 51), viltolarsen (Viltepso), golodirsen (Vyondys 53), and casimersen (Amondys 45).
A novel corticosteroid vamorolone (Agamree) was approved in 2023, and the histone deacetylase (HDAC) inhibitor givinostat (Duvyzat) was approved in 2024. The first gene therapy, delandistrogene moxeparvovec (Elevidys), received accelerated approval in 2023, and another gene therapy, fordadistrogene movaparvovec (PF-06939926), is being evaluated in a phase III clinical trial.
The four exon-skipping drugs are "collectively applicable to approximately 30% of the DMD population owing to their variant-specific mechanisms of action," Chrzanowski and co-authors wrote in a JAMA Neurology viewpoint article.
"Intuitively, earlier treatment and diagnosis may lead to improved long-term outcomes, though a paucity of data to support this exists, as we have not had the opportunity to perform newborn screening until recently," Chrzanowski said.
Newborn Screening Panels
The RUSP is a list of disorders that HHS recommends for states to screen as part of their universal newborn screening programs. A condition must be nominated, then reviewed by the advisory committee on Heritable Disorders in Newborns and Children. DMD was nominated for the RUSP in 2023.
The RUSP provides recommendations for implementation but specifics, including cut-offs, may vary by state, Chrzanowski pointed out.
"For example, different states utilize different multi-tiered approaches, using an initial cost-effective and sensitive screening assay for creatine-kinase followed by genetic testing," he said. "To address this, we need more data to provide more quantitative and data-driven recommendations for states to implement their own newborn screening guidelines."
Two recent studies showed the feasibility of newborn screening. In New York, a 2-year pilot study referred newborns with elevated CK-MM for genetic counseling and testing, including deletion or duplication analysis and next-generation sequencing of the DMD gene, followed by next-generation sequencing for a panel of neuromuscular conditions if no pathogenic variants were found. Of 36,781 newborns screened, 42 (including 25 males) were referred for genetic testing. DMD gene deletions or duplications consistent with DMD or Becker muscular dystrophy were found in four males, and one female DMD carrier was identified.
In North Carolina, 2 years of newborn screening began with CK-MM, followed by total creatine kinase and next generation sequencing of an 86-neuromuscular gene panel, including the DMD gene, if indicated. Of 13,354 newborns screened, the program identified two males with DMD. Birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improved the sensitivity and specificity of screening.
Potential Obstacles
One potential problem with the CK-MM test is that creatine kinase at birth may be falsely elevated for reasons unrelated to DMD. "It's likely that newborn screening through a screening-CK assay will identify non-DMD conditions without treatment, such as congenital myopathies or limb girdle muscular dystrophies," Chrzanowski noted.
Clear guidelines are available for how to undergo follow-up confirmatory genetic testing and how and when to inform families of such diagnoses. "Though disease-modifying treatments may not yet be available, providing supportive treatments -- physical and occupational therapy -- and genetic counseling will be valuable to these families," Chrzanowski said.
Another potential challenge is that access to the multidisciplinary care that DMD patients need varies throughout the country. "Newborn screening is the ultimate 'equalizer' to provide equity of care, as DMD is a non-discriminatory disease, affecting all socioeconomic, ethnic, and racial groups," Chrzanowski observed.
Despite potential problems, about 80% of caregivers and 61% of health providers said they see a net benefit to newborn DMD screening in a recent survey.
"We are at a unique juncture with the emergence of adequate screening techniques and novel therapeutics that may be more efficacious with earlier treatment, making this an opportune time to implement newborn screening for DMD," Chrzanowski said. "Newborn screening will identify pre-symptomatic boys with DMD, allowing for more systemic application of therapy with the hope of better longitudinal clinical outcomes."
Disclosures
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