Sulfatide levels correlate with severity of neuropathy in metachromatic leukodystrophy

Abstract

ObjectiveMetachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder due to deficient activity of arylsulfatase A (ASA) that causes accumulation of sulfatide and lysosulfatide. The disorder is associated with demyelination and axonal loss in the central and peripheral nervous systems. The late infantile form has an early-onset, rapidly progressive course with severe sensorimotor dysfunction. The relationship between the degree of nerve damage and (lyso)sulfatide accumulation is, however, not established.MethodsIn 13 children aged 2–5 years with severe motor impairment, markedly elevated cerebrospinal fluid (CSF) and sural nerve sulfatide and lysosulfatide levels, genotype, ASA mRNA levels, residual ASA, and protein cross-reactive immunological material (CRIM) confirmed the diagnosis. We studied the relationship between (lyso)sulfatide levels and (1) the clinical deficit in gross motor function (GMFM-88), (2) median and peroneal nerve motor and median and sural nerve sensory conduction studies (NCS), (3) median and tibial nerve somatosensory evoked potentials (SSEPs), (4) sural nerve histopathology, and (5) brain MR spectroscopy.ResultsEleven patients had a sensory-motor demyelinating neuropathy on electrophysiological testing, whereas two patients had normal studies. Sural nerve and CSF (lyso)sulfatide levels strongly correlated with abnormalities in electrophysiological parameters and large myelinated fiber loss in the sural nerve, but there were no associations between (lyso)sulfatide levels and measures of central nervous system (CNS) involvement (GMFM-88 score, SSEP, and MR spectroscopy).InterpretationNerve and CSF sulfatide and lysosulfatide accumulation provides a marker of disease severity in the PNS only; it does not reflect the extent of CNS involvement by the disease process. The magnitude of the biochemical disturbance produces a continuously graded spectrum of impairments in neurophysiological function and sural nerve histopathology.

Mutations in SZT2 result in early‐onset epileptic encephalopathy and leukoencephalopathy

“…It is possible that the progressive atrophy is secondary to the refractory epilepsy rather than a direct effect from SZT2 . In the future, electromyography and nerve conduction studies could be used to explore the role of SZT2 in peripheral demyelination as well, as the loss of reflexes in our patient could be consistent with a peripheral neuropathy, a common feature among several leukodystrophies (Dali et al, ). One previously reported patient was noted to have diminished reflexes as well (Tshuchida et al, ).…”

High-throughput analysis of sulfatides in cerebrospinal fluid using automated extraction and UPLC-MS/MS

“…In the last 15 years several methods have been described using TOF-secondary ion MS (19), MALDI-TOF MS (20,21), HPLC-MS (22)(23)(24)(25)(26), and direct infusion MS (15,27) for measuring ST species in different biological matrices. Quantitative and qualitative analyses of STs by LC-MS/MS have emerged as a powerful tool in research (28) and also in clinical diagnostics (29,30). However, there are only a few studies, mainly performed by Han and coworkers, describing the quantification of STs in CSF (14,15).…”

Challenge of phenotype estimation for optimal treatment of Krabbe disease

“…The most typical onset for Krabbe disease of infantile phenotype is between 3 and 6 months of age, which is earliest among these three diseases. Both peripheral and central nerves are impaired, MCV is low, and CSF protein level is high, which is similar to MLD (Lieberman et al, ; Zafeiriou et al, ; Dali et al, ).…”