It’s back to the drawing board for Duchenne muscular dystrophy (DMD) testing, paediatric neurologists say after finding evolving genetic technologies and cascade screening have done little to temper disease incidence over the past four decades.
A retrospective, population-based review of all DMD-positive males born in New South Wales and the Australian Capital Territory between 2002 and 2012 saw no statistically significant difference in disease incidence or “theoretically preventable” cases in the first versus second half of the study period.
The findings echo European and US studies, which showed overall DMD incidence “remained essentially unchanged not only within the study period, but when compared over the last forty years [to 1980], with an epidemiological plateau replicated across international jurisdictions”, the authors wrote in the European Journal of Human Genetics.
They “indicate that despite the evolution of novel genetic technologies, coupled with dedicated neurogenetic services that facilitate targeted cascade screening, the impact on DMD incidence from this approach has reached saturation” and highlight the need for innovative strategies that further reduce disease occurrence, the authors suggested.
Led by Dr Didu Kariyawasam, paediatric neurologist at Sydney Children’s Hospital, they found cumulative incidence was 19.7 per 100,000 male live births and 1 in 5,076 live-born males were diagnosed with DMD.
While there were some annual fluctuations in incidence, there was little difference in 2002–2007 and 2008–2012 rates (incidence rate ratio: 1.13, 95% CI: 0.76–1.69, P = 0.52), even with improving access to cascade screening via multiple ligation probe assay and next generation sequencing, genetic counselling and reproductive technologies.
Similarly, “theoretically preventable” cases were relatively stable, with an incidence rate ratio of 2.07 (95%: 0.58–9.21, P = 0.23).
“Our results align with the current global birth prevalence of DMD of 15.1–19.5 per 100,000 live male births seen in the most recent studies from Europe and USA, a fall from a peak global incidence of 22.6 cases per 100,000 live male births spanning 1950–1980,” the authors wrote.
Why haven’t incidence rates fallen?
Cascade screening alone wouldn’t be enough to reduce incidence rates, researchers concluded in the 1970s. The method has had varied success, with a “significant proportion of potential carriers being unaware of their reproductive status and personal health risks”, they wrote, adding that a Netherlands-based study found “only 34% of potential female DMD carriers at 50% risk had been seen or offered testing”.
It’s only triggered when an index case is identified and most familial cases occur in the absence of family DMD history.
High rates and variability of dystrophin gene mutation — which often leads to absence of functional dystrophin protein and, subsequently, DMD — can make some cases undetectable to cascade screening, prevent reproductive choice optimisation and thus, contribute to unchanging disease incidence.
Additionally, DMD patients’ relatives were less likely to access screening and counselling as they got further away in the pedigree (i.e. index case, versus first and second degree relatives).
Communication and health literacy-related factors also affected overall cases — potentially impacting family members’ participation in cascade screening — and “theoretically preventable” cases.
“Two children in our cohort were born due to miscommunication and/or misunderstanding of maternal carrier risk, secondary to difficulties in ascertaining and/or communicating carrier risk based on [creatine kinase] alone despite a strong family history of neuromuscular disease (prior to the advent of molecular technologies to determine causative variants), resulting in lost opportunities for timely genetic counselling in this subgroup,” the authors wrote.
Delayed DMD diagnosis in foetus/children’s older siblings, preventing parents from conducting screening or making reproductive choices about younger siblings, along with parents’ choice to refuse prenatal and antenatal testing, further stabilised “theoretically preventable” case rates.
“While the clinical landscape encompasses advanced therapeutic approaches in development that provide hope, corticosteroids are currently the only disease modifying therapy adopted as standard of care.”
Even with symptomatic management, proactive surveillance and comorbidity intervention, “mean survival is limited mainly by cardiorespiratory complications, to 29 years of age (for males born after 1970)”.
“The role of targeted variant analysis and cascade screening is aimed at restoring reproductive confidence for non-carriers and identifying ‘at risk’ carriers, to inform of their reproductive options (prenatal testing, PGD, egg/ embryo donation) and effectively manage high disease risk to reduce long-term morbidity and mortality,” the authors wrote.
“This particularly improves reproductive opportunities for the majority of (familial) cases, with these options becoming particularly relevant as healthcare policy extends to publicly funded preimplantation genetic diagnosis (PGD) for single gene disorders such as DMD in Australia from November 2021.”
Given the limited outcomes with current screening methods, “innovative approaches” to DMD risk detection at preconception or early pregnancy carrier screening, prenatal exome sequencing and newborn screening, are needed to reduce disease incidence, the authors concluded.