Monitoring lyso-Gb1 may aid choice to begin ERT in Gaucher disease
A study measured molecule's levels each month in three newborns
Measuring levels of glucosylsphingosine (lyso-Gb1), a diagnostic biomarker of Gaucher disease, in children confirmed by newborn screening programs to have the disease may aid a decision about when to start enzyme replacement therapy (ERT).
That’s according to a study in Italy that measured lyso-Gb1 levels monthly in three newborns with genetically confirmed Gaucher. At up to 20 months, or almost two years, the children didn’t have disease symptoms and ERT hadn’t yet been started.
“We hypothesize that a trend toward stable increase of [lyso-Gb1], confirmed at repeated evaluation, rather than a single threshold, could be convincing for starting ERT even before clinical manifestation of the disease,” the study’s researchers wrote. The study, “Prospective Monitoring of Lyso-Gb1 on DBS Sample in Three Children Recognized at Newborn Screening for Gaucher Disease and Untreated,” was published in Children.
Gaucher disease is caused by mutations in the GBA1 gene that lead to a deficiency in glucocerebrosidase (GCase), an enzyme needed to break down certain fatty molecules, including glucocerebroside (Gb1) and lyso-Gb1. Without it, the molecules build up to toxic levels inside cells, causing damage and driving disease symptoms.
Treatment commonly involves ERT, wherein a functional version of GCase makes up for the faulty enzyme and restores the ability to break down Gb1 and other fatty molecules.
When to begin ERT in Gaucher disease
The introduction of newborn screening programs, which detect GBA1 mutations in dried blood spot samples, has opened up the possibility of children with Gaucher being treated with ERT before symptoms start.
“However, ERT is a long-term, most likely lifelong treatment, with challenging costs for the public health system, and is also extremely stressful for families,” the researchers wrote. “It is therefore of the uttermost importance to develop a protocol to decide when ERT should be started in children with confirmed diagnosis of [Gaucher disease], but lacking clinical manifestations.”
Here, researchers in Italy investigated if monitoring lyso-Gb1 levels in children with Gaucher identified by newborn screening could be a biomarker to help decide when to start ERT. Three newborns with a genetically confirmed Gaucher diagnosis and low GCase activity were analyzed.
Two newborns had two copies of the p.Asn409Ser mutation, while the other had a p.Asn409Ser mutation in one gene copy and a p.Leu88Phe mutation in the other. People with at least one copy of the p.Asn409Ser almost always have Gaucher disease type 1, the most common type of Gaucher that usually doesn’t affect the nervous system.
Blood lyso-Gb1 levels were measured during newborn screening and every four weeks thereafter. Initial levels were higher than 25.15 nanomoles per liter (nmol/L), the upper limit of normal, in all the children. They then dropped in the first three months of life and normalized by the fourth month in two children. After a drop to less than half the initial value, lyso-Gb1 levels fluctuated in the third child, remaining below 50 nmol/L at the last follow-up.
At the time the study was written, all three remained free from any disease manifestations at ages 8, 11, and 20 months, with normal physical growth and blood cell counts every other month, and ERT hadn’t yet been started.
“As center policy, we decided not to start ERT immediately at confirmation of the diagnosis in the absence of clinical manifestation of the disease,” the researchers wrote. “We confirm that the use of dried blood spot samples can be very useful in [Gaucher disease] patient monitoring, before and during ERT, being well accepted by patients.”
