Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression


The potential of allogeneic hematopoietic stem cell transplantation (HSCT) to ameliorate the natural course of late infantile metachromatic leukodystrophy (MLD) is debated. We here report on the disease progression after a very early HSCT in a pre-symptomatic newborn with late infantile MLD. MLD is an inherited metabolic disorder caused by the deficiency of the lysosomal enzyme arylsulfatase A (ASA) leading to demyelination of the central and peripheral nervous system. In the late-infantile form, onset of symptoms begins between 6 months and 2 years. The disease progresses within a few years to hypotonia, speech abnormalities, loss of mental abilities, blindness, convulsions, paralysis, dementia and finally to death. There is considerable debate about the potential of allogeneic HSCT to ameliorate the natural course of MLD. It has been reported that in asymptomatic late-infantile and early-juvenile forms of the disease, neurocognitive function may be preserved by HSCT; however, motor function loss frequently progresses. Late-juvenile and adult-onset forms progress slower owing to endogenous residual enzyme activity. It has been suggested that these forms are more likely to be stabilized with HSCT, but more longterm follow-up evaluations are needed. We here report on the disease progression after a very early HSCT in a presymptomatic newborn with late infantile MLD. In a newborn girl of non-consanguineous parents, ASA enzyme levels were determined because her 5-year-old brother had the late-infantile form of MLD. The diagnosis of MLD was confirmed (see Supplementary Information). The affected brother presented with neurological symptoms at the age of 1 2 years. Eye movement abnormalities and regression of motor and cognitive skills progressed rapidly resulting in blindness, spastic tetraplegia and oxygendependency at the age of 4. He died at the age of 6, being in a vegetative state for almost a year. At a postnatal age of 7 weeks, our patient had no neurological abnormalities and HSCT was scheduled. Magnetic resonance imaging (MRI) of the brain, evoked potentials, electromyography and nerve conduction velocities and electroencephalogram (EEG) all yielded normal results. Myeloablative conditioning consisted of intravenous busulfan, cyclophosphamide, fludarabine and rabbit antithymocyte globulin. Cyclosporine A was given as graftversus-host disease (GvHD) prophylaxis. The patient received a T-cell depleted graft from a matched (10/10 alleles) unrelated donor (with normal ASA activity). The transplant course was uneventful. Despite initial complete donor chimerism at 1 month after HSCT, a gradual decrease was documented from 100 to 60% and finally to approximately 45% donor in all tested peripheral blood cell lineages (lymphocytes, granulocytes and monocytes; see Supplementary Information). Her ASA enzyme levels decreased in parallel, but always remained within the normal (and heterozygous) range. In an attempt to increase donor chimerism she received a donor lymphocyte infusion (DLI). A month later, at the age of 11 months, her neurological examination was without abnormalities. She was able to sit, crawl and walk with a walking aid. MRI of the brain at that age, however, showed white matter abnormalities in the frontal and occipital regions, compatible with leukodystrophy. Although this was suggestive for first appearance of MLD lesions, late effects of the conditioning and transplant course could not be ruled out. A second and third DLI was given with intervals of 6 and 8 weeks, respectively, which resulted in increasing donor chimerism. Four weeks later, she suddenly presented with thrombocytopenia with amegakaryocytosis in the marrow and very high thrombopoietin (706E/ml, normal range 4–32E/ml). Although there were no clinical signs of GvHD, we speculated that the amegakaryocytosis was an allogeneic-immune reaction against hematopoietic progenitors in the marrow. Two days later, she had a severe hemorrhagic bleeding in the pons and mesencephalon with acute hydrocephalus needing external bilateral ventricular drainage and subsequent ventriculostomy. The amegakaryocytosis was corrected by an additional CD34þ selected peripheral blood stem cell boost from the same unrelated donor. Donor chimerism further increased and stabilized at 92% in the mononuclear cells and 100% in the granulocyte and monocyte fractions, respectively. The cerebral bleeding had clearly contributed to the acute neurological deterioration. The recovery was slow and a spastic left-sided hemiplegia, axial hypotonia, bilateral Babinski signs, ophthalmic weakness and swallowing problems persisted. Only a few months later, she lost her speech abilities, her level of cognition deteriorated and she was continuously drooling. This chronic and subsequently progressive neurological deterioration caused by the white-matter disease itself, became clearer with time. Approximately 2-years after HSCT, she developed epilepsy with complex partial seizures and on the EEG a partial status epilepticus was seen in the right hemisphere, which was treated with valproate. In the following months, further neurological deterioration was evident. The MRI scans, performed after the intracranial hemorrhage and 8 months later, showed progression of the white matter abnormalities, typical for MLD. Importantly, the donor-derived ASA enzyme levels in leukocytes in our patient were at all times, after HSCT, Bone Marrow Transplantation (2007) 39, 309–310 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00

DOI: 10.1038/sj.bmt.1705581
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@article{Bredius2007EarlyMT, title={Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression}, author={Robbert G. M. Bredius and Laura A E M Laan and Arjan C Lankester and B. J. H. M. Poorthuis and M J D van Tol and Rudolph Maarten Egeler and W. F. M. Arts}, journal={Bone Marrow Transplantation}, year={2007}, volume={39}, pages={309-310} }