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. 2017 Jul 21;7(1):6149.
doi: 10.1038/s41598-017-06604-2.

C26-Ceramide as highly sensitive biomarker for the diagnosis of Farber Disease

Claudia Cozma  1 , Marius-Ionuț Iurașcu  2 , Sabrina Eichler  2 , Marina Hovakimyan  2 , Oliver Brandau  2 , Susanne Zielke  3 , Tobias Böttcher  3 , Anne-Katrin Giese  3 , Jan Lukas  3 , Arndt Rolfs  2   3
Affiliations

C26-Ceramide as highly sensitive biomarker for the diagnosis of Farber Disease

Claudia Cozma et al. Sci Rep. .

Abstract

Farber disease (FD) is a rare autosomal recessive disease caused by mutations in the acid ceramidase gene (ASAH1). Low ceramidase activity results in the accumulation of fatty substances, mainly ceramides. Hallmark symptoms at clinical level are periarticular nodules, lipogranulomas, swollen and painful joints and a hoarse voice. FD phenotypes are heterogeneous varying from mild to very severe cases, with the patients not surviving past their first year of life. The diagnostic aspects of FD are poorly developed due to the rarity of the disease. In the present study, the screening for ceramides and related molecules was performed in Farber affected patients (n = 10), carriers (n = 11) and control individuals (n = 192). This study has the highest number of enrolled Farber patients and carriers reported to present. Liquid chromatography multiple reaction mass spectrometry (LC/MRM-MS) studies revealed that the ceramide C26:0 and especially its isoform 1 is a highly sensitive and specific biomarker for FD (p < 0.0001). The new biomarker can be determined directly in the dried blood spot extracts with low sample consumption. This allows for easy sample preparation, high reproducibility and use in high throughput screenings.

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Conflict of interest statement

Claudia Cozma, Marius-Ionuț Iurașcu, Sabrina Eichler, Marina Hovakimyan, Oliver Brandau, Tobias Böttcher and Arndt Rolfs are employees of Centogene AG.

Figures

Figure 1
Figure 1
TIC (total ion chromatogram) profile of C26-ceramide isoforms in samples from genetically confirmed Farber patient vs normal control: (A)-in DBS; (B)-in clear plasma. In DBS, both isoforms were present in both samples from healthy controls (blue) and Farber patients (red), the two internal standards are represented in grey. Isoform 1 was dominant in the Farber samples, while isoform 2 was dominant in healthy controls.
Figure 2
Figure 2
Investigations of the two isoforms of C26:0 ceramide found in DBS extracts: (A)-TIC of a LC/MRM-MS analysis and high resolution MS/MS of pure trans-C26:0 ceramide; (B)-LC/MRM_MS of C26:0 ceramides in DBS extract from a Farber patient and LC/IM-MSe characteristics of the two C26:0 ceramides isoforms. C-MSe mass spectrum of the C26:0 ceramide isoforms in DBS.
Figure 3
Figure 3
Box plots demonstrating C26:0 ceramide levels in the blood of NC, FP and FC, grouped according to the donors’ ages in newborns (up to 6 months), juveniles (6 months to 17 years) and adults (>17 years). NC = healthy controls, FP = Farber patients, FC = Farber carriers.
Figure 4
Figure 4
Box plots demonstrating levels of total C26:0 ceramide and its isoforms in the blood of NC, FP, JIA and patients affected by various LSDs. NC = heathy controls, FP = Farber patients, FC = Farber carriers.
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