Effects of sulfatide on peripheral nerves in metachromatic leukodystrophy

Abstract

AbstractObjectiveTo evaluate the longitudinal correlations between sulfatide/lysosulfatide levels and central and peripheral nervous system function in children with metachromatic leukodystrophy (MLD) and to explore the impact of intravenous recombinant human arylsulfatase A (rhASA) treatment on myelin turnover.MethodsA Phase 1/2 study of intravenous rhASA investigated cerebrospinal fluid (CSF) and sural nerve sulfatide levels, 88‐item Gross Motor Function Measure (GMFM‐88) total score, sensory and motor nerve conduction, brain N‐acetylaspartate (NAA) levels, and sural nerve histology in 13 children with MLD. Myelinated and unmyelinated nerves from an untreated MLD mouse model were also analyzed.ResultsCSF sulfatide levels correlated with neither Z‐scores for GMFM‐88 nor brain NAA levels; however, CSF sulfatide levels correlated negatively with Z‐scores of nerve conduction parameters, number of large (≥7 μm) myelinated fibers, and myelin/fiber diameter slope, and positively with nerve g‐ratios and cortical latencies of somatosensory‐evoked potentials. Quantity of endoneural litter positively correlated with sural nerve sulfatide/lysosulfatide levels. CSF sulfatide levels decreased with continuous high‐dose treatment; this change correlated with improved nerve conduction. At 26 weeks after treatment, nerve g‐ratio decreased by 2%, and inclusion bodies per Schwann cell unit increased by 55%. In mice, abnormal sulfatide storage was observed in non‐myelinating Schwann cells in Remak bundles of sciatic nerves but not in unmyelinated urethral nerves.InterpretationLower sulfatide levels in the CSF and peripheral nerves correlate with better peripheral nerve function in children with MLD; intravenous rhASA treatment may reduce CSF sulfatide levels and enhance sulfatide/lysosulfatide processing and remyelination in peripheral nerves.