Australian breakthrough could improve newborn screening

At 14 months old, Chrissy Cimino’s son Elliott was diagnosed with Angelman syndrome.
 
For months, Elliott struggled to put on weight, was unable to sit upright and never cried or babbled.
 
‘There were a lot of red flags that were missed, and I knew in my gut that something wasn’t right,’ Chrissy said.
 
‘I kept persisting with medical appointments and I did my own research. It was such a relief to have that diagnosis so we could finally start medical interventions.’
 
But if Elliott had been diagnosed through a newborn screening program, Chrissy says his motor and cognitive skills would not have been as diminished.
 
‘We couldn’t get him on the NDIS until he was two-and-a-half, so we missed out on years of intensive physio and speech and occupational therapies,’ she said.
 
‘He is [now] almost five and he still isn’t walking. If he was diagnosed earlier, we could have helped him a lot sooner.’
 
Elliott’s story isn’t the only one.
 
Angelman syndrome, along with Prader Willi syndrome and Dup15q syndrome, are three chromosome 15 imprinting disorders that affect approximately 135 babies each year in Australia.
 
Although rare, these syndromes are characterised by varying degrees of intellectual disability, behavioural problems, seizures and obesity that have serious life-long repercussions for those affected.
 
Unfortunately, many newborns go undiagnosed in their first year of life not only because signs and symptoms can be difficult to pick up, but also because routine newborn bloodspot screening currently excludes these disorders.
 
Associate Professor David Godler from the Murdoch Children’s Research Institute (MCRI) says a key reason for this has been the lack of a low-cost test that can work at the population level.
 
‘Tests are currently only performed on those suspected of having these disorders, and only if features are recognised by a child’s doctor, and subsequently referred for appropriate testing,’ he said.
 
‘This is not the case with newborn screening, where testing is performed on all newborns before symptoms become apparent’.
 
However, this could soon change, with MCRI researchers saying they can now reliably screen for the disorders simultaneously in a new one-step test based on a specialised low-cost screening method called Methylation Specific-Quantitative Melt Analysis (MS-QMA).
 
The MS-QMA method has previously been tested by MCRI researchers as a way to screen for Fragile X. And now their latest study, published in JAMA Open Network, is the first to validate the use of the MS-QMA method for the three chromosome 15 imprinting disorders at a large scale.
 
Associate Professor Godler said the study found the cost, disorder prevalence and accuracy of MS-QMA as a first-tier test were in line with other conditions currently included in newborn screening programs.
 
‘Having a high positive predictive value is important for newborn screening as it ensures that there is lower number of false positive results that need to be repeated,’ he said.
 
‘[That leads] to lower overall laboratory costs, less work for maternity services in obtaining a repeated blood sample and minimises the psychological effect on families.’
 
Fellow MCRI Professor David Amor said adding these chromosome 15 imprinting disorders to newborn screening programs would allow for earlier diagnosis and use of targeted interventions as they emerge, such as gene therapy for Angelman syndrome.
 
‘For Prader Willi, diagnosis in infancy allows for early initiation of growth hormone treatment to improve long term health outcomes,’ he said.
 
‘For Angelman and Dup15q, most infants do not receive an early diagnosis that would allow intervention in the first year of life.
 
‘But such early diagnosis, if available through newborn screening, could prevent the diagnostic odyssey, [as well as] reduce medical costs and the significant stress and anxiety currently experienced by the families while they await a diagnosis.’
 
Although newborn screening is optional in Australia, research suggests participation is very high. Screening occurs 2–3 days after birth and around 1–2% of babies tested require repeat or subsequent diagnostic testing.
 
The possibility of expanding screening to include a greater array of conditions including chromosome 15 imprinting disorders is welcome news to parents of children affected, such as Doris Hamilton-Browne whose son Lewis was diagnosed with Prader Willi at four weeks of age.
 
‘The diagnosis was unexpected and tough to hear but getting answers meant we could intervene early,’ she said.
 
According to Ms Hamilton-Browne, having a test for Prader Willi and other chromosome 15 imprinting disorders on newborn screening programs would remove a lot of angst, guilt and uncertainty for parents.
 
Sydney GP Dr Angela Rassi agrees.
 
‘We have seen the benefits of early detection of other diseases such as cystic fibrosis in the newborn period, particularly in instituting early treatment,’ she said.
 
‘Early detection also enables families to be educated early on in the course of the disease to allow for the best outcomes for these families.’
 
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