Elsevier

The Lancet

Volume 356, Issue 9231, 26 August 2000, Pages 713-718
The Lancet

Articles
Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy

https://doi.org/10.1016/S0140-6736(00)02629-5Get rights and content

Summary

Background

The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3–5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration.

Methods

12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5–10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment.

Findings

MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal.

Interpretation

5–10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.

Introduction

Childhood cerebral X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disorder that affects central nervous system myelin and adrenal cortex. Of the several clinical phenotypic forms of X-linked adrenoleukodystrophy (X-ALD), 30–40% of children under 10 will develop the childhood cerebral form.1, 2 X-ALD is biochemically associated with defective peroxisomal β-oxidation of very-long-chain fatty acids (VLCFA) that accumulate in plasma, brain, and adrenal cortex.

Various therapies, including immunosuppression with cyclophosphamide and interferon beta3, 4, 5 and low-fat diet with lipid supplement (Lorenzo's oil) that normalises plasma VLCFA6, 7, 8 have been used in attempts to modify the inexorable evolution of the disease. None has proved to be effective.

The reversal by bone-marrow transplant (BMT) of early neurological, neuropsychological, and neuro-radiological manifestations of childhood-onset cerebral X-ALD in one patient after 2 years of observation was reported by one of these authors in 19909 A previous attempt to treat a child with ALD who was in an advanced stage of cerebral X-ALD was not beneficial and raised concern that BMT might have accelerated the neurological deterioration.10 The rationale for BMT in X-ALD has relied on the hypothesis that functional bone-marrow cells from the donor could cross the blood-brain-barrier in the recipient and exert favourable effects on the mechanisms leading to demyelination. Subsequently, short-term benefits of BMT in childhood cerebral X-ALD were reported.11, 12 For the first time, we report long-term outcomes (4·5–10 years after engraftment) in 12 ALD patients transplanted in the early stage of the disease.

Section snippets

Patients

Although the following criteria were not fully developed at the time of initial BMT, retrospectively we can now classify the severity of X-ALD patients into four categories:

  • 1)

    Patients with “no cerebral disease”. These include patients with or without Addison's disease in whom brain magnetic resonance imaging (MRI) and neuropsychological tests are normal. These patients are not candidates for BMT. About half of this group will develop neurological signs involving the spinal cord in

MRI

The MRI studies were rank-ordered by Loes score13 from least involved to most severe (table 1). The Loes method quantifies the degree of demyelination. The median Loes score at baseline was 4·0; the median score at 1–2 years after transplantation was 7·5; the most recent median score was also 7·5. A change was noted from baseline to 1–2 years but no change was observed between 1–2 years after BMT and most recent follow-up. However, within this group, the Loes scores for three patients improved

Discussion

Our study of twelve transplanted and grafted cerebral X-ALD patients confirms the long-term beneficial effect of BMT when done early in the disease course.

The MRI results indicate that BMT can halt or even reverse demyelination at a very early stage. There were two patients who had complete resolution of moderate degrees of demyelination. In patients with more extensive demyelinating lesions, BMT halted the deterioration within 6–12 months. The abnormal motor function in five of the 12

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