By David N. Leff

From its medical name ¿ Hallervorden-Spatz syndrome ¿ you might not suspect that its authors, histologist Julius Hallervorden (1882-1965) and neurologist Hugo Spatz (1888-1969) were deeply implicated in the euthanasia practiced by the Nazis during World War II.

When a transport of children was gassed, Hallervorden dissected some of their bodies for scientific evaluation. He told the Allies in December 1946, ¿Look, chaps, if you are killing these people anyway, at least take their brains out so the material can be used! There was wonderful material among those brains ¿ imbeciles, deformities and early childhood diseases!¿

One early childhood disease is Hallervorden-Spatz syndrome (HSS), described by their two authors in 1922. A research paper on the subject in the August 2001 issue of Nature Genetics signs off with this observation: ¿Finally, in response to the unethical activities of Julius Hallervorden and Hugo Spatz during World War II, we propose a new name for HSS based on knowledge of the underlying biochemistry. We suggest that the group of disorders be known as pantothenate kinase-associated neurodegeneration (PKAN).¿

That Nature Genetics paper is titled: ¿A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome.¿ Its senior author is medical and molecular geneticist Susan Hayflick, at the Oregon Health & Science University in Portland.

¿HSS is a very rare autosomal recessive inherited disease,¿ Hayflick told BioWorld Today. ¿So rare that its prevalence is not known with confidence, but my estimate is one case in 100,000 to 200,000 of the population. It¿s a worldwide affliction, without a specific ethnic concentration.

¿Our paper,¿ she observed, ¿reports discovery of the pantothenate kinase gene, and the enzyme it encodes. These are dysfunctional in various HSS patients. So by discovering that that enzyme can¿t function, we found what one might hope to replace in order to make these patients better.¿

They could hardly feel worse. ¿HSS is life threatening,¿ Hayflick pointed out. ¿It¿s extremely disabling, beginning during childhood. Patients are unable to control their bodily movements, so they end up writhing, in wheelchairs, unable to speak clearly, with their condition steadily deteriorating ¿ until they die. There is no treatment whatsoever for the disease.

¿The cardinal pathologic features of HSS,¿ she observed, ¿are iron deposition, specifically in the basal ganglia, which are the movement control centers of the brain. The other pathologic feature is axonal spheroids. Axons are the long-distance communication cables of the neurons. In HSS, they are exploded, grossly swollen. They appear to have some defect in transport or other abnormality that results in ballooning of the axons.¿

Extended Amish Family Helps Find HSS Gene

To nail down the elusive PANK2 gene of the syndrome, Hayflick and her co-authors began by exploring southwestern New York state and northwestern Pennsylvania, for susceptible members of an Amish community. ¿We went out in the field and contacted these people in situ,¿ she recounted. ¿They were not located in the Lancaster, Pa., community that many people associate with the Amish, but in a more remote community. I wouldn¿t say they have considerable HSS prevalence in that community. In the one extended family of 30 members that we studied, which is in and of itself quite large, we found seven affected children.

¿We took blood and isolated its DNA,¿ Hayflick narrated. ¿Then our first task was mapping the gene, placing it on a region of one of the chromosomes. This was done in 1996 by my group, using standard linkage analysis linking the phenotype in the disease to one marker on the human genome. We were able to map it in 1997. And then we faced the ways and means to get from the map region, which contained several hundred genes, to the individual target gene. This was a matter of gathering samples from families around the world. That enabled us to tighten up the chromosomal region to an area that had about 25 genes in it.

¿Then,¿ she went on, ¿we systematically went through those gene sequences, scanning for misspellings, and we were able to identify this novel PANK2 gene on the short arm of human chromosome 20. The protein it encodes, the pantothenate kinase enzyme, puts a phosphate group on vitamin B₅. If the abnormal, mutated enzyme is present in cells in a low concentration ¿ poorly functional with only 5 percent capacity, then possibly overloading that protein with vitamin B₅ substrate, which is a simple, water-soluble vitamin, may be therapeutic. So we¿re looking now at possibly therapeutic compounds.

¿My hope is that this isn¿t going to be a kind of gene therapy treatment,¿ Hayflick said, ¿but rather a chemical or pharmaceutical treatment. And perhaps something that would benefit from stem-cell therapy as well ¿ but that¿s a much more complicated approach.

¿There are a number of avenues we¿re pursuing,¿ she went on. ¿One is developing sensible treatments for this disorder, such as bypassing the enzyme block with various vitamins. Also, we¿re very interested in the role of this gene and its pathway in more common neurodegenerative disorders, like Parkinson s disease [PD], where iron overload seems to build up with aging. So we¿re looking now at a cohort of PD patients with various types of their disease, to see if we can identify any alterations in this HSS pathway in those individuals.¿

She and her co-authors are making a null mouse model in which the gene disabled in HSS patients will also be disabled in mice.

Parkinson¿s Disease Shows Overlaps With HSS

¿Both of the universities involved in our finding,¿ Hayflick noted, ¿Oregon Health and Science University and the University of California, San Francisco, have moved to patent these results. We¿re certainly interested in exploring a relationship with a pharmaceutical or biotechnology organization. The short-term promise is focused not so much on therapy but in a diagnostic test. And if this turns out to be a significant gene alteration in patients with PD, which affects 3 percent of the U.S. population, or the population worldwide, the test aspect of it is the first area where I can see large-scale applicability.¿

As for deep-sixing the eponymic Hallervorden-Spatz syndrome name in favor of pantothenate kinase-associated neurodegeneration, Hayflick advised, ¿Mendelian Inheritance in Man, a standard database of genetic diseases and traits, has enthusiastically adopted PKAN ¿ adding HSS as a synonym.¿