Definition of leukodystrophies - LEUKOTREAT, therapeutic strategies for leukodystrophy affected patients

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Last update : 09/02/2015


Inherited neurodegenerative diseases affecting the white matter (WM) and its main component, the myelin, named leukodystrophies (LDs) represent a heterogeneous group of rare disorders that affect young children and often adults. The overall incidence of LDs is approximately 1 in 10 000 of the population and a prevalence estimated to 1000 new cases per year for Europe.


Severity of the disease is related to the axonal dysfunction due to myelin deficiency or destruction. In most cases severe motor and cognitive impairments rapidly occurs that result in premature death, often within 2-5 years of disease onset. The medico-social cost is estimated at 150 000 € per year for each affected patient and there is a high risk of family recurrence.


The devastating effect of myelin damage is also observed in more common, non genetic WM disorders. Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease due to an autoimmune process targeting the myelin of the central nervous system (CNS). WM disorders of the premature babies (WDP) result in failure of CNS myelin development due to the particular susceptibility of the immature WM when they have to face cellular stress (anoxia, infection…). Finally, in neurodegenerative disorders such as motoneuron diseases, the major role of glial dysfunctions in disease initiation or progression has been demonstrated.


Leukodystrophies (LDs) are very heterogeneous: see ELA page on the different types of leukodystrophies.


All LDs result in confluent destruction (demyelination) or failed development (dysmyelination) of CNS myelin from various origins. LDs have been initially classified according to staining characteristics of myelin breakdown products in neuropathological analysis. Later on, LDs related to biochemical defects of intracellular organelles leading to primary and predominant defects in myelin biogenesis (mainly peroxisomal or lysosomal disorders) were identified by biochemical markers measurable in the peripheral blood. More recently, brain MRI, detecting pathological changes in myelin due to its high lipid content, has introduced a classification based on MRI recognition pattern.


Progress in LD recognition and molecular biology has accelerated identification of causative genes with an emerging genetic classification of LDs. Identification of primary gene defects in LDs has allowed establishment of cellular and transgenic animal models. Subsequently, major advances in LDs pathophysiological mechanisms but also in comprehension of myelin development and maintenance have been done.


From this perspective, the group of LDs with genetically defined defects represents a unique model to test therapeutic strategies. Thus the LeukoTreat project tackled leukodystrophies with:

  1. A known molecular defect defined by biochemical or genetic markers,
  2. Established relevant cellular and/or animal models,
  3. A sufficiently deciphered pathophysiological mechanism.

All these three conditions prerequisite for therapeutic approaches.


In addition, LeukoTreat partners chose LDs with distinct primary gene defects in order to better define the targets of the potential therapeutic effect in term of glial cell types and pathophysiological pathways for further application to other LDs, common WM disorders or neurodegenerative diseases. According to this criteria, Leukotreat partners chose 3 groups of leukodystrophies:

  • The first two groups are characterized by predominant myelin destruction:
  1. The peroxisomal and lysosomal leukodystrophies including X-linked adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) and Krabbe disease (GLD);
  2. The vacuolating leukodystrophies including Alexander disease (AxD), childhood ataxia with CACH/VWM (centralhypomyelination/vanishing white matter)syndrome, and Canavan Disease (CD).
  • The third group is characterized by an abnormal myelin formation:
  1. The hypomyelinating leukodystrophies including diseases due to defects in myelinproduction such as Pelizaeus-Merzbacher disease (PMD) /spastic paraplegia type 2 (SPG2).