Japanese Find Another Mutation That Could Lead to Fabry Disease

A newborn screening study led to Japanese researchers discovering another mutation that may cause Fabry disease.

The study, “A new mutation found in newborn screening for Fabry disease evaluated by plasma globotriaosylsphingosine levels,” was published in the Official Journal of the Japan Society of Human Genetics.

Fabry disease is a storage disorder that results from lack of an enzyme called α-galactosidase A (GLA), or a faulty version of the enzyme. This leads to an accumulation of a molecule called globotriaosylceramide (Gb3) in the skin, eyes, kidneys, ears, lungs, heart and brain.

The result can include kidney dysfunction, cardiomyopathy and cerebrovascular disease. Fabry affects men much more than women.

Enzyme replacement therapy can counter the disease’s progression. This means newborn screening for the disorder is vital, since early treatment can prevent irreversible organ damage.

Fabry disease patients have high levels of globotriaosylsphingosine (lyso-Gb3) in their blood plasma. This makes it a potential biomarker for additional screening and for determining the severity of the disorder.

Researchers at the University of the Ryukyus decided to screen newborns for Fabry disease by measuring GLA activity. They looked at both plasma GLA and lyso-Gb3 concentrations in dried blood spots.

The initial round of screening showed that 13 newborns out of 2,443 — two boys and 11 girls — had low GLA activity. A second set of measurements showed that all of the girls’ GLA activity was normal, however. And since none had a family history of the disease, the researchers decided not to do an additional analysis on them.

They conducted gene tests on the boys, however.

One with no family history of Fabry disease had lower than normal GLA activity. A genomic analysis showed a mutation known as p.E66Q in his GLA gene. Previous research had suggested this was a disease-causing mutation.

The second boy had even lower GLA activity, and genomic analysis showed a mutation known as p.G144D that scientists had not identified before.

Although his plasma GLA activity was low, his plasma lyso-Gb3 concentrations were normal when he was both 11 and 21 months old.

When he was born, the boy showed no signs of Fabry disease. He had normal weight, length, and head circumference. He also had no Fabry signs at 21 months.

A genetic analysis of his family members showed that his mother and maternal grandmother also had an p.G144D mutation in their GLA gene. Both were healthy, however, with normal ranges of plasma lyso-Gb3 concentrations.

Computer algorithms predicted that the boy’s p.G144D mutation would lead to Fabry disease. Additional evidence that he could develop the disorder was studies showing that other mutations in the same position had led to Fabry.

The researchers speculated that the p.G144D mutation “causes Fabry disease as a late-onset type because of the patient’s low plasma GLA activity levels, his slightly high plasma lyso-Gb3 levels and the results in his family analysis.”

They called for “further careful investigation of the boy’s male relatives” for signs of the disease.