Neuroaxonal dystrophy in young adults: A clinicopathological study of two unrelated cases

Abstract

The clinical and pathological features of two unrelated sporadic cases of neuroaxonal dystrophy occurring in young adults are described. Initial clinical manifestations in both patients were those of primary psychiatric disorders. They subsequently developed extrapyramidal symptoms, dementia, cerebellar ataxia, and corticospinal dysfunction, but neither demonstrated myoclonic seizures. In one patient the diagnosis was made before death by brain biopsy. On pathological examination both patients showed a generalized distribution of spheroids within the central nervous system and, in one, in the peripheral nerves. In both patients, Lewy bodies were demonstrated in the pigmented brainstem nuclei. In addition, one patient showed ultrastructurally verified Lewy bodies in the cerebral cortex. Although these two cases could be considered examples of juvenile neuroaxonal dystrophy, we prefer to regard them as transitional forms in a disease spectrum with classic infantile neuroaxonal dystrophy and Hallervorden-Spatz disease at the two extremes.

Spontaneous Murine Neuroaxonal Dystrophy: a Model of Infantile Neuroaxonal Dystrophy

“…GFAP, a marker for differentiated astrocytes, has been used to demonstrate areas of reactive gliosis in various CNS diseases, including INAD (Williamson et al, 1982). GFAP immunoreactivity was substantially increased in the NAD mice.…”

“…Interpretation of the ultrastructural composition of spheroids has been paramount in classifying human NADs, despite speculation that different variants all manifest a single disorder of retrograde axonal transport (Williamson et al, 1982;Malandrini et al, 1995).…”

“…Inherited, primary or endogenous neuroaxonal dystrophies (NADs) form a group of debilitating and ultimately fatal neurodegenerative diseases affecting human beings (Vuia, 1977;Williamson et al, 1982;Kimura et al, 1987;Taylor et al, 1996) and animals, including horses, cats, rats, several breeds of dog (Cork et al, 1983;Schmidt et al, 1983;Chrisman et al, 1984;Carmichael et al, 1993;Sacre et al, 1993;Franklin et al, 1995;Adams et al, 1996) and several inbred and genetically engineered mouse strains (Yamazaki et al, 1988;Dal Canto and Gurney, 1994;Schmidt et al, 1998;Dragatsis et al, 2000;Liedtke et al, 2002;Matsushima et al, 2005). The characteristic pathological feature of NAD in all species is the swollen axon or "spheroid", often found throughout the central and peripheral nervous systems (Summers et al, 1995).…”

“…The term "spheroid" refers nonspecifically to swollen axons seen by light microscopy and does not describe the nature of the underlying axonal damage or distinguish between potential causative mechanisms. Although spheroids develop in all variants of endogenous NADs, differences in age of onset, clinical manifestations, and distribution of lesions separate one form from another (Vuia, 1977;Williamson et al, 1982;Kimura et al, 1987;Taylor et al, 1996). A number of neuropathological conditions including infectious, demyelinating, toxic or traumatic injuries can damage normal axons and produce spheroids.…”

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

“…There was only minimal loss of neuromelanin in the SN, red nucleus and other brainstem areas which was compatible with normal aging. Numerous published reports have described Lewy body pathology in the brains of patients with NBIA [66][67][68][69][70][71]. However, in the recent series of gene proven-cases Lewy bodies were absent (in contrast to PLA2G6, see below).…”