Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe Disease).

Globoid cell leukodystrophy (GLD, Krabbe disease, Krabbe's disease) is caused by genetic mutations in the gene encoding, galactosylceramidase (GALC). Deficiency of this enzyme results in central and peripheral nervous system pathology, and is characterized by loss of myelin and an infiltration of globoid cells. The canine model of GLD provides a translational model which faithfully recapitulates much of the human disease pathology. Targeted lipidomic analysis was conducted in serum and cerebrospinal fluid (CSF) over the lifetime of GLD affected and normal canines, and in brain tissue at humane endpoint to better understand disease progression and identify potential biomarkers of disease. Psychosine, a substrate of GALC and primary contributor to the pathology in GLD, was observed to be significantly elevated in the serum and CSF by 2 or 4 weeks of age, respectively, and steadily increased over the lifetime of affected animals. Importantly, psychosine concentration strongly correlated with disease severity. Galactosylceramide, glucosylceramide, and lactosylceramide were also found to be elevated in the CSF of affected animals and increased with age. Psychosine and galactosylceramide were found to be significantly increased in brain tissue at humane endpoint. This study identified several biomarkers which may be useful in the development of therapeutics for GLD.

Intrathecal antibody responses to GalC in Guillain-Barré syndrome triggered by Mycoplasma pneumoniae.

Mycoplasma pneumoniae (Mp) triggers Guillain-Barré syndrome (GBS) and elicits anti-galactocerebroside (GalC) antibodies. Specifically anti-GalC IgG is associated with Mp-GBS, possibly because of its better ability to cross the blood-nerve barrier (BNB). We here investigated CSF for the presence of anti-GalC in GBS. Intrathecal anti-GalC was found in 46% of Mp-GBS patients (n=6/13), in contrast to 16% of GBS controls (n=4/25) and 0% of non-GBS controls (n=0/7). The antibodies most likely originated from increased BNB permeability and/or intrathecal synthesis. Intrathecal anti-GalC IgG was specifically associated with Mp-GBS, further supporting that anti-GalC IgG contributes to the pathogenesis of GBS.

Late cerebral graft versus host reaction in a bone marrow transplanted girl with Hurler (MPS I) disease.

A girl with Hurler disease (MPS IH) underwent allogeneic stem cell transplantation at 13 months of age with her one HLA-B antigen mismatch mother as donor. The procedure was complicated by cerebral hemorrhage and a ventricular-peritoneal shunt device was inserted. Mild GVH reactions were rapidly reversed. One year after transplantation ventriculitis was suspected and the shunt was replaced by a ventricular drainage catheter. Antibiotics had no effect and graft-versus-host disease (GVHD) was diagnosed. All symptoms were reversed by prednisolone and cyclosporine. Increased albumin and pleocytosis in the cerebrospinal fluid (CSF) normalized concomitantly. Electron microscopy of the CSF sediment showed debris consisting of numerous complex aggregates of thin lamellae and electron dense fragments with a tight lamellar texture. Biochemical analysis of the CSF sediment proved that the debris contained galactosylceramide and sulfatide. The electron microscopic and biochemical findings were interpreted to represent stripping of central myelin as a result of subacute GVHD in the central nervous system and its desquamation from the brain parenchyma into the ventricular CSF through the post-hemorrhage defect. From reversal of the GVHD at 2 years of age until follow-up at 10 years of age the clinical condition remained stable with no recurrence or deterioration.