Evaluating experimental treatment of leukodystrophies

White matter disorders of the brain are increasingly being identified. In children their cause is mostly genetic and if the molecular defect concerns the myelin membrane, they are known as leukodystrophies.1 Leukodystrophies have come into the reach of experimental therapies. In the case of metachromatic leukodystrophy,2 which is caused by the deficiency of a lysosomal enzyme (arylsulfatase A), haematological stem cell transplantation (HSCT) has been advocated as a therapy for more than 20 years and is now being used worldwide. Results of this aggressive treatment modality are still controversial3 and have not been reported in large series of patients. HSCT seems to have beneficial biological effects, probably by transfer of the deficient enzyme to the brain, but it remains difficult to determine which patient will benefit from the procedure and in which time-window. The situation is similar for gene therapy.4 Enzyme replacement therapy for metachromatic leukodystrophy, ineffective when given intravenously, is being developed for intrathecal use.5 For the evaluation of therapies, a difficulty lies in the clinical variability of metachromatic leukodystrophy. In the late-infantile type of metachromatic leukodystrophy, the neurological decline is known to be generally uniform; but there is some variability, for example in lifespan as a result of palliative treatments. In contrast, the late-onset (juvenile and adult) types of metachromatic leukodystrophy show a wide variability in the age at manifestation and the nature of initial symptoms. While motor symptoms, spasticity, and peripheral neuropathy predominate in younger patients, cognitive decline and mood alterations may be the initial symptoms of metachromatic leukodystrophy in older children and young adults. In addition, while the course in young patients is rapidly progressive, the progression of late-onset disease can be slow and even interrupted by many years without apparent deterioration. To overcome these difficulties, clinical data on the effects of these therapies is needed. Kehrer et al.2 describe in quantitative terms the clinical deterioration over time in patients with different types of metachromatic leukodystrophy. In a nationwide effort (the German LEUKONET project) a large cohort of patients could be studied, using a specifically adapted method for quantification of motor performance. While patients with the late-infantile type showed a rather uniform loss of all gross motor function, the decline in patients with the juvenile type was more variable and much slower. These results were not unexpected, but represent a solid framework of data that can be used in present and future therapies to detect modifications of the natural course. Of potential practical importance is the observation that patients with the juvenile type with early gait disturbances had a good chance of remaining stable for more than a year, a period considered to be necessary for HSCT to become effective in the brain and to halt further neurological progression. Once patients with the juvenile type had lost independent walking, subsequent motor decline was as steep as in the late-infantile form, giving HSCT not enough time to halt progression at an acceptable functional level. In this way, results of this study add an empirical element to decisions whether a particular patient is a good candidate or not for therapies such as HSCT. In late-onset metachromatic leukodystrophy, the wide variability of the natural course leaves many questions open, in particular when cognitive deficits prevail. In addition, the effects on the phenotype of the many different mutations of the arylsulfatase A gene, which frequently occur in a compound heterozygous state, have not been thoroughly studied. Such questions in metachromatic leukodystrophy and other leukodystrophies are part of a present European project on therapeutic challenges in leukodystrophies (LEUKOTREAT, http://leukotreat.eu).