2 proteins may be familial amyloid polyneuropathy biomarkers
Abnormal blood levels of GDF-15, Umod seen with disease
People with familial amyloid polyneuropathy (FAP) and other forms of hereditary transthyretin amyloidosis (hATTR) have abnormal blood levels of two proteins, called growth differentiation factor-15 (GDF-15) and uromodulin (Umod), a small study reports.
The preliminary findings from 16 patients in Italy suggest GDF-15 and Umod may serve as biomarkers of hATTR, which might help diagnose patients early, when treatments are most effective, the researchers said.
The study, “Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: a pilot study,” was published in Scientific Reports.
Amyloidosis is a group of conditions wherein toxic protein clumps called amyloid fibrils accumulate in tissues, leading to organ damage. hATTR is made up of forms of amyloidosis caused by mutations in the TTR gene. This results in a faulty form of the transthyretin protein being produced that forms toxic clumps that accumulate in different tissues and organs.
FAP is a form of hATTR wherein toxic transthyretin aggregates build up mostly in the nerves outside the brain and spinal cord, leading primarily to neurological symptoms. When these clumps accumulate mostly in the heart, the disease is called hATTR cardiomyopathy, and when there is both neurological and heart involvement, it is classified as mixed. Kidney problems are also common among hATTR patients.
While disease-modifying therapies may slow disease progression in FAP and other forms of hATTR, they work better if they’re given at the disease’s early stages.
“For this reason, there is an urgent need for reliable biomarkers to reach an early diagnosis and to monitor disease severity and progression,” the researchers wrote.
Possible hATTR biomarkers
Circulating markers of inflammation and metabolism may work as early disease biomarkers, studies have suggested, leading researchers in Italy to evaluate whether levels of GDF-15 and Umod showed potential as biomarkers of hATTR.
GDF-15 is involved in inflammation, tissue repair after acute injury, and cellular responses to stress. It’s been linked with other forms of amyloidosis. Umod, a kidney-specific protein, is an early marker of kidney function. Blood levels of cystatin C, a marker of kidney function impairment, also were measured.
The analysis was part of a larger biomarker validation study called Exploring Biomarkers in Hereditary Transthyretin Amyloidosis (NCT05929209) at a single site in Rome.
The sub-study included 16 hATTR patients (median age, 69.5; 81.3% men) and 26 healthy participants (median age, 50; 50% men), who served as controls. All 16 patients had neurological symptoms and 10 also had heart involvement, and were classified as having a mixed profile. Six patients carried Val30Met, the most common FAP-causing mutation.
All but two patients were on disease-modifying therapies: eight on Onpattro (patisiran), five on tafamidis meglumine (sold as Vyndaqel in regions other than the U.S.), and one on Tegsedi (inotersen).
The hATTR patients had significantly lower, by about half, median levels of Umod compared with healthy controls. The opposite was seen for GDF-15, with median blood levels about twice as high among hATTR patients. Blood cystatin C levels were also significantly higher in the patient group relative to the control group.
The researchers then assessed how Umod and GDF-15 levels correlated with the estimated glomerular filtration rate (eGFR), a measure of kidney function where higher values indicate better function.
When eGFR was calculated based on blood levels of cystatin C and creatinine, another kidney function marker, higher Umod levels were were seen to be significantly associated with higher eGFR. But higher GDF-15 levels were significantly linked to lower eGFR, indicating poorer kidney function. Also, lower Umod levels and higher GDF-15 levels were significantly associated with higher cystatin C levels.
No significant correlation was found between either Umod or GDF-15 levels and the eGFR, when calculated based on creatinine levels alone. There were also no significant associations with heart damage biomarkers.
When researchers looked at possible links between the blood biomarkers and patients’ clinical data, they found that more severe neurological damage in the arms, as assessed using the Sudoscan device, was significantly linked to higher GDF- 15 levels.
No other correlations were seen regarding the type of mutation (Val30Met vs. others), clinical profile (FAP vs. mixed), or disease severity.
The findings “suggest that modifications in [blood] levels of GDF-15 and Umod are characteristic of [hATTR],” the researchers wrote. “Larger and longitudinal [across time] studies, including patients with more pronounced, if not exclusive, [heart] involvement, are needed to determine whether these markers can be used in clinical settings in addition to those already validated to assess disease severity and treatment response.”
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