Final Diagnosis -- Neurodegeneration with Axonal Spheroids and Iron Deposition

FINAL DIAGNOSIS:

NEURODEGENERATION WITH AXONAL SPHEROIDS AND IRON DEPOSITION (NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; HALLERVORDEN-SPATZ DISEASE).

DISCUSSION

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)".

REFERENCES

  1. Hallervorden J and Spatz H. (1922). Eigenartige erkrankung im extrapyramidalen system mit besonderee beteiligung des globus pallidus und der substancia nigra. Ein beitrag zu den ezienhungen zwischen diesen beiden zentren. A. Ges. Neurol. Psychiat. 79:254
  2. Dooling EC, Schoene WC, Richardson EP Jr. (1974) Hallervorden-Spatz syndrome. Arch. Neurol. 30:70
  3. Taylor TD, Litt M, Kramer P, Pandolfo M, Angelini L, Nardocci N, Davis S, Pineda M, Hattori H, Flett PJ, CilioMR, Bertini E, and Hayflick SJ. (1996) Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat. Genet. 14:47
  4. Higgins JJ, Patterson MC, Papadopoulos NM, Brady RO, Pentchev PG and Barton NW. (1992) Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Neurology 42:194
  5. Orrell RW, Amrolia PJ, Heald A, Cleland PG, Owen JS, Morgan-Hughes JA, Harding AE and Marsden CD. (1995) Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: a report ofthree patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome). Neurology 45:487
  6. Halliday W. (1995) The nosology of Hallervorden-Spatz disease. J. Neurol. Sci., 134(Suppl):84
  7. Swaiman KF. (1991) Hallervorden-Spatz syndrome and brain iron metabolism. Arch. Neurol. 48:1285
  8. Lowe J, Lennox G and Leigh PN. (1997) Disorders of movement and system degenerations. n Graham DI and Lantos PL. ed. Greenfieldís Neuropathology. London, UK: Arnold, 337
  9. Peiffer B. (1991) Neuropathology in the Third Reich. Memorial to those victims of national- socialist atrocities in Germany who were used by medical science. Brain Pathol. 1:125
  10. Muller-Hill B. (1988). Murderous science. Oxford. Oxford University Press
  11. Harper PS. (1996). Naming of syndromes and unethical activities: the case of Hallervorden and Spatz. Lancet 348:1224

Contributed by Zissimos Mourelatos MD and Jeffrey A. Golden MD



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