Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort

Abstract

Metachromatic leukodystrophy (MLD) is a rare inborn error of metabolism leading to severe neurological symptoms and early death. Hematopoietic SCT (HSCT) is considered a treatment option, but results are inconsistent and comparison with natural history is practically missing. We compare a girl with juvenile MLD 10 years after allogeneic HSCT not only with her untreated sister, but also with a large cohort of untreated patients. The girl received HSCT at the age of 5 years when first motor signs appeared. Over 10 years she was stable with respect to her clinical course and gained cognitive abilities. Magnetic resonance imaging (MRI) showed clear regression of white matter changes and magnetic resonance spectroscopy (MRS) demonstrated a reversal of the initial choline increase and N-acetyl-aspartate (NAA) decrease. Only axonal demyelinating neuropathy showed some progression. Her gross motor function and MRI-scores were clearly better compared with her sister and the cohort of untreated patients. Difference to her sister became apparent only 4 years after HSCT. We conclude that HSCT, early in the course of disease, can lead to stabilization of juvenile MLD with a course clearly different from the natural history. HSCT may prevent disease progression, if performed sufficient time before loss of walking, which typically initiates rapid deterioration.

Demyelination load as predictor for disease progression in juvenile metachromatic leukodystrophy

“…But the further progression of demyelination, and especially the involvement of specific WM areas, seems to correlate well with specific aspects of clinical deterioration. In the evaluation of therapeutic effects and cerebral changes on follow‐up, the demyelination load was already demonstrated to be more sensitive than the MRI scoring system 8, 28. Still, the sensitivity and specificity of new (more myelin‐specific) MRI parameters might be important to evaluate further in detecting functionally relevant WM changes in the brain as suggested recently, for example, diffusion‐weighted imaging, MR spectroscopy, magnetization transfer imaging, myelin water imaging, cortical thickness determination, and GM/WM volumetry 12, 29, 30, 31…”

“…Given the variability in the clinical course, this is not only important for patient counseling, but also for treatment decision as discussed above. It has been shown that the treatment effect of HSCT, currently the only clinically available treatment option for juvenile MLD, might take some time to have an effect 8, 32, 33. Therefore, it seems essential to have additional parameters in order to predict whether the individual patient will deteriorate rapidly or might still have a wide enough window of opportunity for HSCT.…”

“…Clinical and MRI data of patients with MLD were collected within the German leukodystrophy network leukonet since 2006 8, 11. The study was approved by the local ethics committee (401/2005).…”

“…In MLD, these MRI changes can be quantified visually with the MRI severity score 5. More recently, the “demyelination load” was established and validated as an MR parameter in order to quantify the demyelinated white matter (WM),6, 7 which might detect subtle changes in the extent of demyelination more sensitively than the visual MR scoring system 8…”

Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy

“…1 HSCT is currently the only treatment in clinical use for late-juvenile and adult MLD, but the long-term results that have been published are few and inconclusive. [6][7][8][9][10][11][12][13] …”