058_Valk_Giant_Axonal 08.04.2005 16:12 Uhr Seite 436 Chapter 58 Giant Axonal Neuropathy 58.1 Clinical Features munostaining for glial fibrillary acidic protein. In ad- and Laboratory Investigations dition, occasional giant axons are found, measuring up to 100 mm or more in diameter. They are short, Giant axonal neuropathy (GAN) is an early-onset globular to fusiform or balloon-like enlargements or neurodegenerative disorder that affects both the PNS long cigar-like or corkscrew-shaped axonal thicken- and CNS. The disease has an autosomal recessive ings. They stain positively with silver stains and anti- mode of inheritance. Patients have characteristic neurofilament antibodies. The cerebral white matter tightly curled hair, often described as frizzy or kinky. may be diffusely gliotic with a variable loss of myelin, Acquisition of motor milestones is delayed in most, the frontal and parietal lobes being most affected and but not all patients. The age at onset of progressive the U fibers being relatively spared. In other patients, neurological problems is usually below 7 years. Pa- however, absence of myelin loss has been reported. tients develop a clumsy gait and progressive weak- Rosenthal fibers are aggregated around blood vessels. ness of the legs. The weakness spreads to involve the Low numbers of giant axons are seen within the cere- arms as well. Neurological examination reveals signs bral white matter. The central gray matter structures of peripheral neuropathy with absent reflexes, mus- also contain increased numbers of astrocytes, scat- cular atrophy, weakness, and impaired sensation, tered Rosenthal fibers, and occasional giant axons. most marked distally. There are usually also pyrami- Optic nerves and tracts show fiber loss and gliosis. dal signs, with extensor plantar reflexes. Subsequent- The cerebellar cortex displays loss of Purkinje and ly, dysarthria, nystagmus, ataxia, scoliosis, and intel- granule cells and hyperplasia of Bergmann astro- lectual decline become apparent. Optic atrophy may cytes. In the cerebellar white matter, loss of nerve occur. Patients may develop bulbar weakness, involv- fibers and increase of astrocytic processes and ing muscles of the face, tongue, and palate. Seizures Rosenthal fibers is found. Giant axons and Rosenthal may occur. Urinary retention and chronic constipa- fibers are scattered throughout the brain stem.In par- tion may be vexing problems and are related to in- ticular, the pyramidal tracts are shrunken and gliotic, volvement of peripheral autonomic nerves. Preco- display loss of nerve fibers, and contain many giant cious puberty may occur. Most patients are of small axons. The spinal white matter contains excessive stature. Patients usually become wheelchair-depen- numbers of astrocytes. There are subpial clusters of dent in the first or second decade of life and die be- Rosenthal fibers. Giant axons are particularly numer- tween the ages of 10 and 30 years. ous in the posterior columns, especially in the cer- Neurophysiological examination reveals signs of a vical region, and the lateral corticospinal tracts, severe axonal neuropathy. Somatosensory, visual, and especially in the lower thoracic and lumbar region. brain stem auditory evoked potentials show pro- Electron microscopy of the axonal swellings reveals longed conduction times or absence of reproducible enormous accumulations of neurofilament, often responses. Sural nerve biopsy, showing axonal loss arranged in a whorl-like, interlacing pattern. Nonde- and large axonal swellings, which consist mainly of script electron-dense granules are interspersed tightly packed neurofilaments, supports the diagno- among filamentous masses. The myelin sheaths of the sis. DNA confirmation is possible. enlarged axons are abnormally thin and disintegra- tion of myelin lamellae may be seen. Sural nerve biopsy reveals enlarged axons with 58.2 Pathology spindle-shaped focal distensions of non-myelinated and thinly myelinated nerve fibers. Myelin sheaths The brain is unremarkable on external examination. around the swellings are abnormally thin and the On sectioning, some dilatation of the lateral ventri- largest swellings often lack a covering of myelin over cles and thinning of the corpus callosum may be a part of their length. Ultrastructurally, the disten- found. The cerebral and cerebellar white matter may sions are composed of closely packed neurofilaments, be abnormal with sparing of the U fibers. which often form a whorl pattern. There are closely Histological examination of the cortex reveals in- associated electron-dense granules. Microtubules, creased numbers of astrocytes and scattered Rosen- microtubule–mitochondrial complexes, and cisterns thal fibers. The Rosenthal fibers are positive in im- of smooth endoplasmic reticulum, instead of being 058_Valk_Giant_Axonal 08.04.2005 16:12 Uhr Seite 437 58.5 Magnetic Resonance Imaging 437 dispersed among the neurofilaments as in normal axonal degeneration and neuronal death found in axoplasm,are frequently seen gathered together with- GAN patients point to the importance of gigaxonin in the filament-free areas at the center or periphery of for neuronal survival. the axonal swelling. In muscles, the typical pattern of neurogenic atrophy is found. In conclusion, the pathology is that of a distal 58.4 Therapy axonopathy most severely affecting peripheral nerves, pyramidal tracts, posterior spinal columns, No specific treatment is available.Therapy is support- and the cerebellum. It is important to note that ive. Rosenthal fibers have not been reported in all pa- tients. 58.5 Magnetic Resonance Imaging 58.3 Pathogenetic Considerations The MRI findings described in GAN are variable, probably at least partly depending on the stage of the The gene related to giant axonal neuropathy, GAN,is disease. In some patients, no or minimal cerebral located on chromosome 16q24.1 and encodes a ubi- white matter abnormalities are present (Fig. 58.1). quitously expressed protein, gigaxonin. The white matter abnormalities may be diffuse and Giant axonal neuropathy is characterized by cyto- subtle (Fig. 58.3), sometimes with multifocal spots of skeletal abnormality. The hallmark of the disease is more prominent signal change superimposed. In oth- the presence of giant axonal swellings, which are er patients, extensive and confluent white matter ab- densely packed with aberrant neurofilaments, abnor- normalities are present, symmetrically involving the mal microtubule network, and accumulation of other cerebral white matter in a diffuse fashion (Fig. 58.2) membranous organelles. Neurofilaments belong to or with a predominance in the frontoparietal region. the intermediate filaments. In GAN, an abnormal ac- The corpus callosum and U fibers tend to be spared. cumulation of multiple tissue-specific intermediate The posterior limb of the internal capsule, pyramidal filaments is found in a wider range of cells than only tracts, and medial lemniscus in the brain stem, mid- neurons, suggesting a generalized disorganization of dle cerebellar peduncles, hilus of the dentate nucleus, intermediate filament networks. Aggregations of and cerebellar white matter may display signal vimentin have been reported in endothelial cells, changes (Figs. 58.2 and 58.3). The white matter ab- Schwann cells, and cultured skin fibroblasts, and ag- normalities are progressive over time (Figs. 58.1 and gregations of glial fibrillary acidic protein are found 58.2).The lateral ventricles become mildly dilated due in astrocytes. Keratin intermediate filaments are to white matter volume loss and the cerebellar vermis altered, leading to the characteristic kinky hair. becomes atrophic over time. The cytoskeletal network is responsible for cell ar- In our experience the MR images in GAN have a chitecture, intracellular transport, mitosis, cell mobil- certain resemblance to the images in Alexander dis- ity, and differentiation. It is composed of micro- ease, which is interesting since both are characterized tubules, actin microfilaments, and intermediate by Rosenthal fiber deposition. The basal ganglia filaments, which interconnect through cross-linking may have a slightly abnormal signal and a slightly proteins. The properties of the network formed are swollen aspect (Figs. 58.1 and 58.3). The areas with modulated by different associated proteins. Cyto- high signal on T1-weighted images include the skeletal organization and dynamics depend on pro- ependymal lining (Fig. 58.1), a thin periventricular tein self-associations and interactions with a variety of binding partners such as microtubule-associated proteins (MAPs). Gigaxonin binds directly to microtubule-associat- ᮣ ed protein 1B light chain (MAP1B-LC), a protein in- Fig. 58.1. A 6-year-old female patient with GAN. The T2- volved in maintaining the integrity of cytoskeletal weighted images (upper two rows) show a diffuse slight signal structures and promoting neuronal stability. The in- abnormality of the cerebral white matter. The basal ganglia teraction of gigaxonin with MAP1B-LC enhances have a slightly abnormal signal and slightly swollen appear- microtubule stability, required for axonal transport ance. The T1-weighted images (third row) show that the over long distance.In line with this,the neurofilament ependymal lining of the lateral ventricles and the globus pal- accumulations in GAN, leading to the segmental lidus have a slightly increased signal. After contrast adminis- distension of axons, mainly affect distal portions tration (fourth row),subtle enhancement of the