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