Abstract Details

Title Effects of sulfatide accumulation on peripheral nerves in metachromatic leukodystrophy

Topic Child Neurology and Developmental Neurology

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 6-001

Background MLD is a lysosomal storage disease affecting the CNS and PNS. It is associated with deficient activity of arylsulfatase A (ASA), which breaks down sulfatide. Deficient ASA activity causes sulfatide and lysosulfatide to accumulate leading to demyelination and axonal loss.

Objective To evaluate the toxic effects of sulfatide and lysosulfatide on the central (CNS) and peripheral (PNS) nervous systems in children with metachromatic leukodystrophy (MLD) and to explore the impact of treatment with intravenous recombinant human arylsulfatase A (rhASA) on myelin turnover.

Design/Methods Relationships between cerebrospinal fluid (CSF) and sural nerve sulfatide levels and 88-item Gross Motor Function Measure (GMFM-88) total score, sensory and motor nerve conduction, brain N-acetylaspartate levels, and nerve morphometry were investigated using data obtained from 13 children during a phase 1/2 and extension study of intravenous rhASA (NCT00418561; NCT00633139; NCT00681811).

Results There was a positive correlation between Z-scores for GMFM-88 and brain N-acetylaspartate levels; however, neither measure correlated with CSF sulfatide levels. Both CSF and sural nerve sulfatide levels negatively correlated with Z-scores of nerve conduction velocities, combined amplitudes and number of large (≥7µm) myelinated fibers. CSF sulfatide levels negatively correlated with myelin/fiber diameter slope and positively correlated with nerve g-ratios (inner axonal diameter to total outer diameter) and cortical latencies of somatosensory evoked potentials, but not with central conduction time. Quantity of endoneural litter positively correlated with sural nerve sulfatide and lysosulfatide levels. At 26 weeks after intravenous rhASA treatment, there was an overall 2% decrease in nerve g-ratio and a 55% increase in number of inclusion bodies per Schwann cell unit.

Conclusions Lower sulfatide levels in the CSF and peripheral nerves correlate with better peripheral nerve function in children with MLD; treatment with intravenous rhASA may enhance sulfatide and lysosulfatide processing in peripheral nerves. Study and writing funded by Takeda; intended for HCPs.

Authors/Disclosures
Christian Krarup, MD, DMSc, FRcP, FAAN (Rigshospitalet) PRESENTER	Dr. Krarup has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Shire/Takeda. Dr. Krarup has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Shire/Takeda. Dr. Krarup has received publishing royalties from a publication relating to health care.
Christine I. Dali, MD	Dr. Dali has received personal compensation for serving as an employee of Orphazyme A/S .
	No disclosure on file
	No disclosure on file
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Norman W. Barton, MD, PhD	Dr. Barton has received personal compensation for serving as an employee of Takeda Pharmaceutical Co. LTD. Dr. Barton has received stock or an ownership interest from Takeda Pharmaceutical Co. LTD.
	No disclosure on file