Post-mortem histological evaluations confirmed neuroimaging and electrodiagnostic assessments and detailed loss of myelin and accumulation of storage product in the CNS and the PNS.

Sphingolipidoses are severe and incurable neurological diseases in which sphingolipids (SLs) accumulate to high and toxic levels by unknown mechanisms. SLs, such as psychosine in Krabbe's disease, could insert in membrane, decreasing fluidity and disrupting functional lipid domains, or induce changes in membrane curvature, leading to membrane fragility and cell signaling/function deregulation.

Expression studies of mutations and haplotypes found in the GALC gene of known patients with KD show a good correlation between severity of the mutation and residual activity measured. With this method, mutations found in individuals identified in newborn screening can be tested to assess whether the mutation is disease causing. The graph shows expression studies of representative mutations.

This study shows that it may be possible to use measures of psychosine and galactocerebrosidase enzyme activity from newborn screening dried blood spot samples to distinguish healthy infants (red circles) from those afflicted with early-infantile Krabbe's disease (solid blue triangles and solid blue circles) who may benefit from intervention.

We performed a global metabolomic analysis from the hindbrains of presymptomatic and postsymptomatic Krabbe's mice. We identified several altered metabolic pathways and a number of novel potential biomarkers that may be beneficial for patients with KD.

After AAV-mediated gene therapy, neurons express and secrete GALC, which is endocytosed by oligodendrocytes where it degrades psychosine. The SRT drug, L-cycloserine, decreases the synthesis of psychosine. BMT decreases the neuroinflammatory response, and supplies low levels of GALC as donor-derived microglia reconstitute the CNS.

Intrathecal AAV-mediated gene therapy synergized with bone marrow transplant (BMT) in the 10–11-day-old twitcher mouse model of Krabbe disease to extend the survival as well as to improve the pathology in the CNS and sciatic nerve.

An L-cycloserine-mediated increase in insulin-like growth factor 2 receptor expression in mouse CNS and an aggressive chemotherapy-based conditioning regimen enhance the efficacy of bone marrow transplantation and gene therapy protocols for treating GALC deficiency in the Twitcher mouse model of Krabbe's disease.

Krabbe's disease is a neurodegenerative disorder that can be treated only with transplantation of umbilical cord blood. Earlier studies have not shown statistically significant improvement of survival of patients treated after the patients had developed symptoms. By using Cox regression analysis, we establish a 2.2-fold improvement of survival in symptomatic patients.

Missense mutations that cause protein misfolding underlie several forms of Krabbe disease. This Review discusses recent studies that have identified a number of small molecules with the potential to act as pharmacological chaperones to correct these folding defects and that may be developed as new therapeutics.

Krabbe's disease (KD) is a demyelinating lysosomal storage disease. Nearly 70% of disease-associated missense mutations can generate instability and misfolding of GALC protein. The consequence is a lower and residual enzymatic activity. In this resides the principle that chaperones are promising therapeutics for KD.

Through a quantitative cell-based HTS against over 46,000 compounds, three small molecules were identified and shown to enhance mutant galactocerobrosidase (GALC) in globoid-cell leukodystrophy (GLD) patients cells. Further studies showed that the small molecules stabilize and increased mutant GALC levels in the lysosomes, being potential therapeutic agents for GLD.

The authors report on autophagy in the human oligodendrocyte cell line MO3.13 treated with PSY and exploitation of Li as an autophagy modulator to rescue cell viability and demonstrate that PSY causes upregulation of the autophagic flux at the level of autophagosome and autolysosome formation and LC3-II expression.

Substrate reduction therapy could be applied to the terminal step in galactosylceramide and psychosine synthesis or to earlier biosynthetic steps. Reduction of galactosylceramide and psychosine production would slow the disease course by lowering the accumulation of substrates not adequately digested, although the degree and the timing of reduction remain to be determined.

This study combines the use of PTC124 and NMDI1 to induce ribosome to bypass premature termination codon, significantly increasing GALC enzymatic activity in oligodendrocytes and fibroblasts from twitcher mouse, a naturally occurring model of Krabbe's disease.

Several studies of neuronal and nonneuronal primary cultures and cell lines have been used to investigate many processes, such as inflammation, apoptosis, and angiogenesis, involved in Krabbe's disease and the direct and indirect roles of accumulation of psychosine.

Zoledronate and/or newly identified inhibitors of uridine diphosphate-galactose ceramide galactosyltransferase may be useful for a substrate inhibition therapy in Krabbe's disease and other lysosomal disorders.

Here, a new condition is proposed in which mild SNPs to the GALC gene result in slight deficiencies of GALC's activity that may lead to accumulation of low quantities of toxic material. Over decades of slow and progressive metabolic deficiency, this may increase neuronal vulnerability, leading to late onset synucleinopathies.

A tight trophic cross-talk exits between endothelial and glial/neuronal compartments in the CNS. β-Galactosylceramidase deficiency in globoid cell leukodystrophy causes accumulation of the toxic metabolite psychosine in the brain, leading to neurotoxic effects, angiosuppression, and endothelial cell damage. Psychosine-independent alterations may also contribute to neuronal and vascular defects in the brain and peripheral tissues, with endothelial dysfunction representing a possible novel pathogenic mechanism in human leukodystrophies.