Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the "giant" axons caused by accumulations of intermediate filaments. The disease is progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot-Marie-Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as "giant axonal neurodegeneration."

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A ganglioglioma is a tumor consisting of neuronal cells in various degrees of differentiation mixed with glial elements which may participate in the neoplastic process.24 Gangliogliomas are rare in man2.4s5 and domestic animals.lJ In man, they usually present in the cerebrum of a child or young adult and are rarely found in the spinal cord.24 In domestic animals gangliogliomas have been documented in unusual sites, e.g., an intraocular tumor in the dog,5 but not in the spinal cord.A Holstein steer, normal at birth, was weak and ataxic in both rear limbs at 3 months of age. By 4 months of age, the calf was paraplegic. Temperature, pulse, and respiratory rates were normal. Withdrawal reflexes in the front and rear limbs were considered normal during neurologic examination. Patellar reflexes were hyperactive (3+/4). Anal reflex and tail tone were normal. The steer required assistance to stand, and at a walk, the front limbs appeared normal, but the hindlimbs were markedly weak and ataxic. Lateral radiographs of the thoracolumbar vertebral column appeared normal. Analyses of cerebrospinal fluid aspirated from the atlanto-occipital and lumbosacral spaces were normal. The calf was euthanized.Moderate muscle atrophy of both hindlimbs was present at necropsy. A 1 x 3 cm red-tan mass was within the spinal cord between T12 and L1. It was moderately firm, caused distortion of the surrounding spinal cord, and could not be easily separated from the adjacent parenchyma. Sections of the mass, spinal cord, and major organs were fixed in 10% neutral buffered formalin, embedded in paraffin, and sectioned at 4 to 6 pm. Sections were stained with hematoxylin and eosin (HE) for light microscopic examination. Other sections of the mass and spinal cord were examined using the Bielschowsky silver method and by immunoperoxidase techniques using monoclonal antibody against the 200 KD neurofilament protein subunit and a polyvalent antiserum against glial fibrillary acid (GFA) protein.The neoplasm consisted of several cell types characteristic of ganglioglioma (Fig. 1). Some cells had typical neuronal nuclei which were large, vesiculated, and eccentrically located with distinct nucleoli. In some cells Nissl substance was present. The ganglionic nature of these cells was confirmed by Bielschowsky silver impregnation for neurites (Fig. 2), and neuronal processes were also immuno-positive with the neurofilament protein monoclonal antibody. Variation in size and shape of these cells, some of which were binucleate, random orientation, and abundant tortuous neurites indicated that they were neoplastic and not pre-existing neurons entrapped by tumor cells. A second group of cells were neoplastic astrocytes which were immunopositive for GFA protein (Fig. 3). In addition to these two types of cells, there were also smaller cells with small darkly staining nuclei and scanty cytoplasm, resembling lymphocytes (Fig.

As part of a natural history study of giant axonal neuropathy, we hypothesized that the Friedreich Ataxia Rating Scale and the Gross Motor Function Measure would show a significant change over 6 months, reflecting subjects' decline in motor function. The Friedreich Ataxia Rating Scale was performed on 11 subjects and the Gross Motor Function Measure was performed on 10 subjects twice with a six-month interval. A paired two-tailed t-test was used to assess the difference in each subject's score. Significant changes were found over six months of 11.7 ± 11.0 (P = 0.006) for the Friedreich Ataxia Rating Scale and -10.0 ± 13.5 (P = 0.043) for the Gross Motor Function Measure, reflecting subjects' decline in motor function on examination and by report. These standardized assessments of clinical function are the first to be validated in giant axonal neuropathy and will be used in an upcoming gene therapy clinical trial.

The majority of Mitchell's fictional works contained references to neurologic topics but most contained brief references. The number of references to Mitchell's specific scientific interests (phantom limb syndrome, causalgia) was small, although more generally, references to the neurology of battle injuries occurred more frequently.