Adult Onset Hallervorden-Spatz Disease With Neurofibrillary Pathology

Abstract

Three adults with progressive cognitive decline and extrapyramidal dysfunction were studied. They were all mentally retarded women without known chromosomal abnormalities, ranging in age at the time of onset from 31 to 42 yrs with an average duration of illness of 6 yrs. Neurological signs were stereotyped and consisted of a unilateral equinovarus foot posture followed by progressive dementia, rigidity and quadriparesis. Identical pathological findings were noted in all cases. There was marked deposition of iron-containing pigments in the globus pallidus and reticulate zone of the substantia nigra. Numerous axonal spheroids were noted in these areas and in the gracile and cuneate nuclei. In addition to these typical changes of Hallervorden-Spatz disease (HSD), abundant neurofibrillary tangles (NFTs) were found within the hippocampus, neocortex, nuclei of basal forebrain, subthalamic nucleus and brainstem reticular formation. Rare Hirano bodies and granulovacuolar degeneration were noted within the hippocampus; neuritic plaques and amyloid deposits were absent. Ultrastructurally the NFTs were mostly paired helical filaments (PHFs) with a diameter of 20 to 25 nm and a half-periodicity of 80 nm. Straight filaments and incompletely twisted forms were also seen. Immunocytochemistry with polyclonal antibodies to PHFs was positive in a distribution identical to that of Bodian-positive NFTs. Biochemical analysis of frozen frontal cortex from 1 case revealed a 94% depletion of the cholinergic marker enzyme choline acetyltransferase. Somatostatin-like immunoreactivity was within normal range. Study of 1 case with laser microprobe mass analysis revealed evidence of aluminium accumulation in tangle-bearing hippocampal neurons. Adjacent tangle-free neurons failed to show comparable accumulations. These findings indicate that adult onset HSD occurring in mentally retarded individuals may represent a distinct clinicopathological entity associated with neurofibrillary pathology without amyloid deposition.

Straight and paired helical filaments in Alzheimer disease have a common structural unit.

“…Filaments morphologically similar to Alzheimer PHFs and SFs have also been observed in Guam disease (17), in progressive supranuclear palsy (18)(19)(20), in post-encephalitic Parkinsonism (21), and in Hallervorden-Spatz disease (22). The SFs in Pick disease, a progressive senile dementia, share epitopes with the Alzheimer PHF (23), as do those of progressive supranuclear palsy (24).…”

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

“…More recently and more controversially, adverse effects of chronic exposures to lower levels of Al have been described. The finding of high levels of Al in the brains of patients with AD relative to controls has been reported [see above] and levels of Al are also found higher in less common neurological disorders including the Guamanian Parkinsonian-ALS complex and Hallervorden-Spatz disease (Eidelberg et al, 1987;Garruto et al, 1988). This has raised the question of whether Al plays a contributory role in the initiation and progression of a variety of neurological disorders (Kawahra and Kato-Negishi, 2011).…”

Topographical relationship between beta-amyloid and tau protein epitopes in tangle-bearing cells in Alzheimer disease.

“…Abundant plaques and tangles are also found either alone or in combination in various brain regions in diseases other than Alzheimer disease. Thus, /3-amyloid deposits are observed in cerebral blood vessels and brain in the Dutch form of cerebral amyloidosis (30,31) and in cerebral blood vessels in arteriovenous malformations (32), whereas tau protein-immunoreactive neurofibrillary tangles are seen in subcortical regions in progressive supranuclear palsy (33) and in Hallervorden-Spatz disease (34). /3-Amyloid precursors and the microtubule-associated tau proteins are found normally in nerve cells throughout the central nervous system.…”