J,mrnal o[ the Neurological Sciences, 104 ( 1991) 1-8 ~ 1991 Elsevier Science Publishers B.V. 0022-510X/91/$03.50 JNS 03565 Neuroaxonal dystrophy in neuronal storage disorders" evidence for major GABAergic neuron involvement Steven U. Walkley 1, Henry J. Baker 2, Mario C. Rattazzi 3, Mark E. Haskins 4 and Jang-Yen Wu 5 ~ Department i!! Neuroseience, Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College ~41 Medicine. Bronx, N Y 10461 (U.S.A.), ~-Department q/" Comparative Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27103 (U. S.A,), 3Departments o/'Pediatrics" and Research, North Shore University Hospital, Cornell University Medical Colle,~e, Manhasset. N Y I I030 (U. S.A.), 4 Departmem ql Pathobiology, School ~71 Veterinao, Medicine. UniversiO' of Pennsylvania, Philadelphia, PA 19104 (U. S.A .), and >Department ol PhysioloKv and Cell Biology. Universi O' (!/" Kansas, Lawrence, KS 66045 (U.S.A.) (Received 7 January, 1991) (Revised. received 28 February, 1991) (Accepted 4 March, 1991) Key words. Axonal spheroid; Neuroaxonal dystrophy; GABAergic neuron; Axonal pathology; Gangliosidosis: Mucopolysaccharidosis; >Mannosidosis: Neuronal storage disease Summary The formation of focal granular enlargements within axons (axonal spheroids or "torpedoes"; neuroaxonal dystrophy) is a well known phenomenon occurring in a variety of neurological diseases. The relative susceptibility of different types of neurons to this kind of axonal pathology, however, is largely unknown. An immunocytochemical study directed at localizing glutamic acid decarboxylase (GAD), the synthetic enzyme for the inhibitory neurotransmitter, 7-aminobutyric acid (GABA), in various CNS regions in feline models oflysosomal storage disorders has revealed vast numbers of axonal spheroids containing this enzyme. In some storage diseases (GM1 and GM2 gangliosidosis), GAD-immunoreactive spheroids were a common occurrence in many brain regions, whereas in other disorders these structures were more limited in distribution (:~-mannosidosis), or were absent (mucopolysaccharidosis type I). Axonal spheroids unreactive for GAD were encountered in large numbers in subcortical white matter in GM2 gangliosidosis, but were infrequently observed in the other diseases. The incidence and distribution of GAD-immunoreactive spheroids in the various diseases under study were found to correlate closely with the type and degree of neurological deficits exhibited by affected animals. This study indicates that the neuroaxonal dystrophy occurring in some types of storage disorders commonly involves axons of GABAergic neurons and suggests that a resulting defect in neurotransmission in inhibitory circuits may be an important factor underlying brain dysfunction in this family of diseases. Introduction Neuronal storage disorders are inherited diseases occurring in man and a variety of animals and are generally characterized by normal appearance at birth, followed by slowly progressive neurological deterioration and death. Clinical presentation and progression vary widely and a full understanding of the specific mechanisms underlying brain dysfunction has not been achieved. The spectrum of clinical symptoms characterizing these disorders includes mental CorresT~ondence to: Dr. S.U. Walkley, Department of Neuroscience, Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, NY 10461 (U.S.A.). Tel.: (212)430-4025; Fax: (212)824-3058. retardation/dementia, ataxia, tremor and other movement disorders, visual, auditory and other sensory impairments, and seizures. Investigations using animal models to explore the patho- genesis of these diseases have suggested abnormalities affecting select neurotransmitter systems (Singer etal. 1981; Jope etal. 1986), membrane fluidity (Wood etal. 1985), and calcium homeostasis (Koenig et al. 1987), but direct causal relationships between these observed changes in brain and specific clinical impairments have yet to be established. Other studies have suggested that accumulat- ing gangliosides may interfere with second messenger sys- tems (e.g., protein kinase C) and cause abnormal cell function and/or cell death (Hannun and Bell 1987). How- ever, direct evidence linking protein kinase C inhibition in vivo, neuronal dysfunction, and development of clinical