Newborn screening risk of false negatives highlighted in case report
Boy in Japan tested negative but later found to have severe SMA type 1A
Newborn screening might not be able to detect certain rare genetic mutations that cause spinal muscular atrophy (SMA), according to a case report that recommends doctors be aware of potential false-negatives in screening and know how to spot the typical symptoms of the disease.
Researchers describe the case of an infant boy in Japan who returned a negative screen for SMA, but later developed symptoms of the neuromuscular disease and was found to have disease-causing mutations that current newborn screening (NBS) programs aren’t designed to detect.
While disease-modifying treatment led to improvements, the boy remained delayed in his motor abilities.
Ultimately, the goal is to develop better newborn screening for SMA, researchers say. In the meantime, “greater awareness of the potential for false-negative SMA cases in NBS and of SMA-related symptoms will aid in earlier diagnosis and treatment initiation.”
The case study, “Spinal Muscular Atrophy Type I With False Negative in Newborn Screening: A Case Report,” was published in Cureus.
SMA therapies more effective when started earlier in disease course
NBS programs are thought to be critical for the early diagnosis and treatment of SMA.
Countries around the world are beginning to adopt such programs as data emerge indicating that the sooner SMA therapies are started — particularly when initiated before symptoms emerge — the greater their benefits.
With NBS, a small drop of blood is collected from a newborn while they’re still in the hospital. A technique called polymerase chain reaction is used to look for mutations in the SMN1 gene that are the cause of SMA.
However, the technique is not infallible. It is designed to detect only the most common type of SMA-causing mutation, which accounts for about 95% of all patients. This mutation involves a complete deletion of an entire portion of SMN1 called exon 7 in both copies of the gene.
However, about 5% of cases are caused by different types of genetic abnormalities in SMN1. These cannot be detected by the current NBS protocol.
In the report, the scientists described the case of a newborn boy in Japan whose SMA-causing mutations were not captured by newborn screening.
The boy was born healthy, with no apparent muscle weakness. NBS was performed after he was born and returned negative for all conditions, including SMA.
At about two weeks old, he began to show signs of poor movement in the hands and feet, and had a feeble cry, both of which are signs of the low muscle tone (hypotonia) and muscle weakness that characterize SMA in infants.
Clinicians should be aware that patients with these mutations may present as false-negative in NBS.
Boy showed signs of low muscle tone and muscle weakness
A doctor confirmed signs of muscle weakness when the boy was about a month old, and he was referred to the researchers’ hospital for further examination. There, the boy showed signs of hypotonia and muscle weakness, and lacked spontaneous movement.
He also showed other SMA-related symptoms including a lack of reflexes, involuntary tongue movements, and paradoxical breathing, when the chest contracts during inhalation but expands during exhalation.
Together, these symptoms prompted the doctors to suspect he had SMA.
Based on the findings from a more in-depth genetic sequencing analysis, the scientists determined the boy had two mutations on SMN1, and that certain sections of the gene were deleted. These genetic changes were not ones that could be captured by NBS.
The boy was also determined to have two copies of SMN2, the backup gene that can partially compensate for SMN1‘s loss.
Based on these genetic findings and the boy’s clinical presentation, the researchers determined he likely had SMA type 1A, a severe form of the disease.
Boy’s motor development remained delayed
While his motor function did improve slightly about a month after receiving Zolgensma, his motor development remained delayed. He had not required respiratory support since receiving the gene therapy.
The scientists believe that the boy continued to show impairments because treatment was started after he was already showing symptoms.
“Clinicians should be aware that patients with these mutations may present as false-negative in NBS,” the researchers wrote.
“It is important for general pediatricians and physical examiners conducting health checkups for infants to be aware of the existence of false-negative SMA cases and the typical symptoms of SMA.”
Suspected SMA should quickly be followed by in-depth genetic testing, to enable earlier treatment, the team noted.