The GALC gene, found on chromosome 14 at position 31 (14q31), codes for the enzyme beta-galactocerebrosidase (GALC). GALC is a lysosomal enzyme responsible for the catabolism of galactolipids, especially psychosine, that are heavily distributed throughout the brain. A deficiency in GALC thus causes a buildup of these fatty acids known as globoid macrophages that destroy oligodendrocytes, thereby inhibiting myelin formation.Because of the presence of globoid cells clustered near white matter, Krabbe disease often goes by the name globoid cell leukodystrophy. Furthermore, new research has shown that Krabbe disease and globoid cell leukodystrophy may be distinct disease entities due to the secretion of inflammatory mediators by natural killer cells in some cases. This research has shown that Natural Killer cells have receptors (TDAG8) for certain glycosphingolipids that build up in an individual with leukodystrophy, again due to insufficient GALC levels, and when bound, target the Natural Killer cells for destruction thereby preventing their cytotoxic effects. These sphingolipids have been identified as galactosyl sphingosine and glycosyl sphingosine and are not present in unaffected individuals. Canavan disease
Canavan disease is a lesser-studied type of leukodystrophy that, like MLD and Krabbe disease, is also passed on in an autosomal recessive inheritance pattern. It is due to a mutation in the ASPA gene that encodes aspartoacylase, an enzyme needed to metabolize N-acetyl-L-aspartate (NAA). The mutation causes a deficiency of aspartoacyclase. NAA is involved in the formation of lipids, and if it is not broken down by aspartoacylase, excess levels of it build up causing demyelination.
Special stains for myelin and axonal pathology show the abnormal changes that are characteristic of HDLS are identified in white matter of the neocortex, basal ganglia, thalamus, midbrain, pons and spinal cord. In addition to routine histologic methods (H&E staining), samples are evaluated with immunohistochemistry for ubiquitin, amyloid precursor protein, and neurofilament to characterize axonal changes and myelin basic protein for myelin pathology. Immunohistochemical stains for microglia (CD68 or HLA-DR) and astrocytes (GFAP) are also helpful techniques to characterize white matter pathology. With a similar pathology to POLD, HDLS is commonly grouped as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) so as to give these individually under-recognized conditions heightened attention. Classification
HDLS falls under the category of brain white matter diseases called leukoencephalopathies that are characterized by some degree of white matter dysfunction. HDLS has white matter lesions with abnormalities in myelin sheath around axons, where the causative influences are being continually explored based upon recent genetic findings. Studies by Sundal and colleagues from Sweden showed that a risk allele in Caucasians may be causative because cases identified have thus far been among large Caucasian families. Management
Epidemiology
An average clinical profile from published studies shows that the median onset age for HDLS patients is 44.3 years with a mean disease duration of 5.8 years and mean age of death at 53.2 years. As of 2012, there have been around 15 cases identified with at least 11 sporadic cases of HDLS.