NEURODEGENERATION WITH AXONAL SPHEROIDS AND IRON DEPOSITION (NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; HALLERVORDEN-SPATZ DISEASE).
Hallervorden-Spatz disease (HSD) is a progressive neurodegenerative disease first described in two sisters in 1922 (1). The onset of symptoms is during the first two decades of life and mean survival is approximately 11 years; The clinical features may include progressive motor disorder characterized mainly by "extrapyramidal" signs, typically dystonia, choreoathetosis, tremor, dysarthria, muscular rigidity, and mental deterioration evolving to dementia. Other clinical features may include seizures, corticospinal tract involvement with spasticity and retinitis pigmentosa (2).
Approximately one half of HSD cases are familial with an autosomal recessive pattern of inheritance. Recently a locus harboring the putative HSD gene was identified, by homozygocity mapping, on chromosome 20p12.3-p13. (3). Adult-onset HSD cases have been described and in rare cases acanthocytosis is also present. HSD-like cases with acanthocytosis, retinitis pigmentosa and pallidal degeneration with or without hypoprebetalipoproteinemia, have also been described (4, 5). Clinical criteria have been proposed to aid in the diagnosis of HSD but it is often difficult to arrive at the correct diagnosis without postmortem brain examination (6, 7). There is, currently, no treatment for HSD and management is directed at controlling specific symptoms.
Neuroimaging is very helpful in establishing the diagnosis. On T2-weighted MRI sequences symmetrical hypointensities, corresponding to the iron accumulation, are seen in the globus pallidus, surrounded by small areas of hypointense signal, corresponding to the cavitated and gliotic lesions, giving the so called "eye-of the tiger" sign. Similar symmetrical hypointensities are also found in the substantia nigra.
The main pathology in HSD is deposition of iron containing pigment in the substantia nigra and in the globus pallidus, with formation of axonal spheroids, neuronal loss and gliosis. The iron pigment may be found free in the neuropil, around blood vessels, within neurons or dystrophic axons and within astrocytes. The dystrophic axons vary in diameter from 20 to 120 microns. Ultrastructurally they are composed of distended axons with mitochondria, tubulo-membranous structures, lysosomes, amorphous matrix material and few neurofilaments. Most of the axonal spheroids in HSD and especially those larger than 30 microns are negative for neurofilaments and ubiquitin, by immunohistochemistry. Lewy bodies and neurofibrillary tangles have been observed in some HSD cases (8).
As a result of the affiliation of both Hallervorden and Spatz with the Third Reich and the usage of brains, as part of their research, from numerous mental patients that had been executed by the Nazis, alternative names have been proposed (9-11). Among these are "Neurodegeneration with axonal spheroids and iron deposition" and "Neurodegeneration with Brain Iron Accumulation 1 (NBIA 1)".
Contributed by Zissimos Mourelatos MD and Jeffrey A. Golden MD