Toward Reference Intervals of ARSA Activity in the Cerebrospinal Fluid: Implication for the Clinical Practice of Metachromatic Leukodystrophy.

BACKGROUND: Cerebrospinal fluid (CSF) has emerged as a sensitive matrix for the screening of biomarkers for diagnosis and clinical follow-up of diseases with neurological manifestations, including some lysosomal storage disorders. In this study, we assessed the range of values of arylsulfatase A (ARSA) activity in the CSF of pediatric and adult donors, and in pediatric patients who underwent gene therapy for metachromatic leukodystrophy (MLD).

METHODS: A cohort of 56 CSF samples was included in the study: pediatric donors (n = 36), adult donors (n = 9), and MLD patients (n = 11) at different timepoints [pre-gene therapy (GT), post-GT + 1 Year, post-GT + 2 Years, post-GT + 3 Years]. We have used our fluorometric assay for the determination of ARSA activity. The total protein content in the samples was also evaluated.

RESULTS: We discovered that ARSA activity was higher in pediatric donors (geometric mean: 1.039 nmol/mg/h; 95% range: 0.859-1.258 nmol/mg/h) compared to adults (geometric mean: 0.305 nmol/mg/h; 95% range: 0.214-0.435 nmol/mg/h). No ARSA activity was detected in the CSF of MLD patients pre-GT, whereas ARSA activity was stably expressed and almost restored to range of values of pediatric donors in MLD patients post-GT + 3 Years with a geometric mean of 0.822 nmol/mg/h (95% range: 0.580-1.165 nmol/mg/h).

CONCLUSIONS: This study establishes range of values of ARSA activity in the CSF for MLD clinical practice. The observed ranges of ARSA activities in CSF exhibited an unpredicted age dependence and, in turn, revealed the need of using pediatric ARSA activity for evaluating the restoration of the enzyme activity during the therapy of MLD.