Ceramide levels predict clinical severity in adult-onset Krabbe disease independent of extensive white matter hyperintensities.

BACKGROUND

Krabbe disease (KD) can be classified into early-infantile, late-infantile, juvenile, and adult form subtypes. Adult form KD is relatively rare and lacks systematic characterization of clinical, imaging, and lipidomic features. This cross-sectional study aimed to define characteristic white matter hyperintensities and plasma lipidomic profiles to identify potential correlations with clinical severity.

METHODS

Eleven patients with adult-onset from eight pedigrees were enrolled. Galactocerebrosidase (GALC) variants were identified by whole-exome sequencing. Clinical, electrophysiological and MRI evidence were collected, with MRI severity quantified using a modified scoring system. Plasma lipidomic profiles were obtained by liquid chromatography-tandem mass spectrometry were analyzed for correlations with clinical severity scores and imaging features.

RESULTS

All adult KD patients harbored GALC variants, including two novel variants (p. Gly512Cys, p. Asn280Valfs*12). The p. Leu634Ser variation was the most prevalent (six pedigrees) without founder effect. All patients manifested leukodystrophy and half exhibited extensive white matter hyperintensities. MRI severity score didn't correlate with Spastic Paraplegia Rating Scale (SPRS) or onset age. While psychosine (PSY) remained normal, ceramide and sphingosine elevations were observed. Ceramide negatively correlated with onset age (R = -0.815, P = 0.048) and positively with duration-adjusted SPRS (R = 0.979, P = 0.004).

CONCLUSIONS

Extensive white matter hyperintensity is a characteristic radiological feature of adult-onset Krabbe disease. PSY levels cannot serve as biomarker of adult-onset KD. Elevated plasma ceramides and sphingosine warrant exploration as candidate biomarkers of disease severity.