Computer-assisted test offers new individualized way to track Fabry
But with 'moderate' accuracy, it's recommended only to aid monitoring
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Using a computer-assisted test on biopsy data from people with Fabry disease can automatically measure the amount of fatty buildup seen in the skin, helping to monitor the rare inherited condition, a new study shows.
However, while this “automated image analysis” successfully spotted this buildup in both men and women carrying disease-causing mutations, its diagnostic accuracy was only moderate, the researchers found. Further, patients’ skin levels did not reliably reflect overall disease severity, treatment status, or areas of damage in the brain, the team noted.
According to the scientists, the study findings don’t support the new method’s use as a stand-alone diagnostic test. Still, the researchers say this technology-assisted analysis may be useful as “a complementary tool for individualized monitoring in FD [Fabry disease].”
Studies have shown that the accumulation of fatty molecules in skin “correlates with disease severity in FD,” the researchers noted.
The study, “Automated quantification of skin Gb3 load and white matter lesion assessment in Fabry disease,” was published in the Orphanet Journal of Rare Diseases.
A genetic disorder, Fabry is caused by mutations in the GLA gene. This gene provides instructions for making alpha-galactosidase A (alpha-Gal A), an enzyme that helps break down certain fatty molecules, including globotriaosylceramide (Gb3).
In people with Fabry, alpha-Gal A is absent or does not work properly. As a result, Gb3 can build up to toxic levels inside cells, damaging multiple tissues and organs, most often the kidneys, heart, skin, and central nervous system, which comprises the brain and spinal cord.
People with brain involvement can develop white matter lesions, or areas of altered brain tissue that can be detected on MRI scans and are thought to arise from damage to small blood vessels.
Earlier testing methods had inconsistent results
Because skin is readily accessible, researchers have been interested in whether Gb3 deposits in skin biopsy samples could help diagnose or monitor Fabry. Earlier methods, however, often relied on manual or semi-quantitative analysis, which can lead to inconsistent results.
Now, researchers in Germany tested whether an automated image analysis method could measure Gb3 buildup in skin biopsies. The team also assessed whether skin Gb3 levels could help diagnose Fabry or reflect broader disease involvement, including white matter lesions in the brain.
In total, 149 adults carrying GLA mutations — 60 men and 89 women — were involved in the analysis. The men had a median age of 41, while the women’s median age was 44. All were followed at the Fabry Center for Interdisciplinary Therapy at University Hospital Würzburg between 2006 and 2020.
The participants were divided into three groups based on whether their mutations were considered disease-causing, not disease-causing, or of unknown significance.
The researchers then compared their skin biopsy results with those of 19 people with idiopathic small fiber neuropathy — nerve damage of unknown cause that can lead to pain, burning, tingling, or numbness — and 32 healthy people, who served as controls.
The skin biopsy samples were stained to reveal Gb3 deposits; the team then used automated software to measure the amount of Gb3 buildup.
Men with more pain had greater fatty buildup in skin
The results showed that dermal Gb3 load — the amount of Gb3 detected in the skin’s dermis layer — was higher in both men and women with disease-causing GLA mutations than in all other groups.
Among those with disease-causing GLA mutations, men had higher skin Gb3 levels than women, the data showed.
One disease-causing mutation, called N215S, did not show the same pattern. Despite being classified as disease-causing and commonly linked to a later-onset, mainly heart-related form of Fabry, N215S was not associated with increased skin Gb3 deposits, the researchers noted.
Among men with disease-causing mutations, those reporting Fabry-associated pain had higher skin Gb3 levels than those without pain, the data showed. This association was not seen in women or in people with non-disease-causing mutations or mutations of unknown significance.
Skin Gb3 levels were also not associated with overall disease severity. Men and women with severe symptoms had skin Gb3 loads similar to those of those with no or mild symptoms, the team noted.
Assessing accuracy of computer-assisted testing
The researchers also assessed whether skin Gb3 load could help in diagnosing Fabry.
Among untreated patients with disease-causing mutations, the analysis showed a sensitivity of 67% and specificity of 95% in men. In women, the sensitivity was 78%, and the specificity was 81%. A test’s sensitivity is its ability to correctly identify people who have a disease, while specificity refers to correctly identifying those who do not have it.
Skin Gb3 load also did not appear to change consistently in response to Fabry-specific treatments, such as enzyme replacement therapy or chaperone therapy. In patients who had more than one biopsy over time, Gb3 levels increased, decreased, or remained stable regardless of treatment status or sex, the researchers found.
The team also tested whether skin Gb3 buildup could serve as a marker of brain involvement. Brain MRI data were available for 26 men and 47 women.
More than half of men and women with MRI data had no white matter lesions. A moderate-to-high lesion load was found in 15% of men and 26% of women. Overall, most white matter lesion volumes were low, the data showed.
When researchers compared skin Gb3 levels with white matter lesion volumes, they found no correlation in men or women, regardless of variant group.
Overall, and while the small number of patients was one of the study’s limitations, these findings support the potential for an “automated dermal Gb3 quantification” to “detect cutaneous Gb3 accumulation in pathogenic [disease-causing] GLA variant carriers,” the researchers wrote.
The method’s diagnostic accuracy, however, remains “moderate, and it does not reliably reflect systemic [whole-body] involvement in” Fabry disease, the team concluded.
Carolyn Purcell
Leg pain,Spinal Stenosis, Neuropathy