The Role of the Endothelium In Globoid-Cell Leukodystrophy: Unexpected Revelations

Abstract

127 ISSN 1479-6708 10.2217/FNL.13.75 © 2014 Future Medicine Ltd Future Neurol. (2014) 9(2), 127–130 Globoid-cell leukodystrophy or Krabbe disease Globoid-cell leukodystrophy (GLD), or Krabbe disease, is one of the most severe inborn errors affecting lysosomal function and causes catastrophic demyelination throughout the nervous system. Lysosomal diseases occur with a combined frequency of approximately one in 5000 live births; two-thirds of the 70 or so of these individual genetic disorders affect the nervous system and collectively represent a large burden on chronic illness in all populations [1]. First reported 100 years ago by the Scandinavian neurologist Krabbe [2], GLD is an autosomal recessive sphingolipidosis caused by the deficiency of the lysosomal hydrolase, b-galactosylceramidase (GALC) [3,4]. The disease is characterized by loss of oligodendroglia and Schwann cells with relentless demyelination in the brain, spinal cord, nerve roots and peripheral nerves [5]. A pathognomic feature, beautifully annotated by Krabbe, is the presence of large perivascular multinucleated cells of mononuclear–macrophage lineage in the white matter named ‘globoid cells’ [2]. GALC hydrolyses galactosylceramide, which, with sulfatides, is a major myelin lipid; the enzyme also degrades cognate terminal b-galactose-containing sphingolipids, including the unacylated metabolite, b-d-galactosylsphingosine (psychosine) [6]. Psychosine is a bioactive water-soluble sphingolipid with cytotoxic properties: normally undetectable, this sphingoid base occurs at micromolar concentrations in the CNS of patients with GLD and is strongly implicated in the molecular pathogenesis and loss of oligodendrocytes in this disease [7]. Elevated concentrations of its congener, b-d-glucosylsphingosine, have also been implicated in the pathogenesis of the acute neuronopathic variant of Gaucher disease – a rare heritable lysosomal disorder due to acid b-d-glucosylceramidase deficiency, accompanied by spectacular neuronal loss and neuroinflammatory changes [1]. Of note, the globoid cells of Krabbe disease resemble the Gaucher cell found in the spleen, liver and bone marrow of Gaucher patients – a prominent systemic feature of the disease [8]. GLD most frequently presents with an acute demyelinating illness in infancy