58.1 Clinical Features
and Laboratory Investigations Giant axonal neuropathy (GAN) is an early-onset neurodegenerative disorder that affects both the PNS and CNS. The disease has an autosomal recessive mode of inheritance. Patients have characteristic tightly curled hair, often described as frizzy or kinky.
Acquisition of motor milestones is delayed in most, but not all patients. The age at onset of progressive neurological problems is usually below 7 years. Pa- tients develop a clumsy gait and progressive weak- ness of the legs. The weakness spreads to involve the arms as well. Neurological examination reveals signs of peripheral neuropathy with absent reflexes, mus- cular atrophy, weakness, and impaired sensation, most marked distally. There are usually also pyrami- dal signs, with extensor plantar reflexes. Subsequent- ly, dysarthria, nystagmus, ataxia, scoliosis, and intel- lectual decline become apparent. Optic atrophy may occur. Patients may develop bulbar weakness, involv- ing muscles of the face, tongue, and palate. Seizures may occur. Urinary retention and chronic constipa- tion may be vexing problems and are related to in- volvement of peripheral autonomic nerves. Preco- cious puberty may occur. Most patients are of small stature. Patients usually become wheelchair-depen- dent in the first or second decade of life and die be- tween the ages of 10 and 30 years.
Neurophysiological examination reveals signs of a severe axonal neuropathy. Somatosensory, visual, and brain stem auditory evoked potentials show pro- longed conduction times or absence of reproducible responses. Sural nerve biopsy, showing axonal loss and large axonal swellings, which consist mainly of tightly packed neurofilaments, supports the diagno- sis. DNA confirmation is possible.
58.2 Pathology
The brain is unremarkable on external examination.
On sectioning, some dilatation of the lateral ventri- cles and thinning of the corpus callosum may be found. The cerebral and cerebellar white matter may be abnormal with sparing of the U fibers.
Histological examination of the cortex reveals in- creased numbers of astrocytes and scattered Rosen- thal fibers. The Rosenthal fibers are positive in im-
munostaining for glial fibrillary acidic protein. In ad- dition, occasional giant axons are found, measuring up to 100 mm or more in diameter. They are short, globular to fusiform or balloon-like enlargements or long cigar-like or corkscrew-shaped axonal thicken- ings. They stain positively with silver stains and anti- neurofilament antibodies. The cerebral white matter may be diffusely gliotic with a variable loss of myelin, the frontal and parietal lobes being most affected and the U fibers being relatively spared. In other patients, however, absence of myelin loss has been reported.
Rosenthal fibers are aggregated around blood vessels.
Low numbers of giant axons are seen within the cere- bral white matter. The central gray matter structures also contain increased numbers of astrocytes, scat- tered Rosenthal fibers, and occasional giant axons.
Optic nerves and tracts show fiber loss and gliosis.
The cerebellar cortex displays loss of Purkinje and granule cells and hyperplasia of Bergmann astro- cytes. In the cerebellar white matter, loss of nerve fibers and increase of astrocytic processes and Rosenthal fibers is found. Giant axons and Rosenthal fibers are scattered throughout the brain stem. In par- ticular, the pyramidal tracts are shrunken and gliotic, display loss of nerve fibers, and contain many giant axons. The spinal white matter contains excessive numbers of astrocytes. There are subpial clusters of Rosenthal fibers. Giant axons are particularly numer- ous in the posterior columns, especially in the cer- vical region, and the lateral corticospinal tracts, especially in the lower thoracic and lumbar region.
Electron microscopy of the axonal swellings reveals enormous accumulations of neurofilament, often arranged in a whorl-like, interlacing pattern. Nonde- script electron-dense granules are interspersed among filamentous masses. The myelin sheaths of the enlarged axons are abnormally thin and disintegra- tion of myelin lamellae may be seen.
Sural nerve biopsy reveals enlarged axons with spindle-shaped focal distensions of non-myelinated and thinly myelinated nerve fibers. Myelin sheaths around the swellings are abnormally thin and the largest swellings often lack a covering of myelin over a part of their length. Ultrastructurally, the disten- sions are composed of closely packed neurofilaments, which often form a whorl pattern. There are closely associated electron-dense granules. Microtubules, microtubule–mitochondrial complexes, and cisterns of smooth endoplasmic reticulum, instead of being
Giant Axonal Neuropathy
dispersed among the neurofilaments as in normal axoplasm, are frequently seen gathered together with- in the filament-free areas at the center or periphery of the axonal swelling. In muscles, the typical pattern of neurogenic atrophy is found.
In conclusion, the pathology is that of a distal axonopathy most severely affecting peripheral nerves, pyramidal tracts, posterior spinal columns, and the cerebellum. It is important to note that Rosenthal fibers have not been reported in all pa- tients.
58.3 Pathogenetic Considerations
The gene related to giant axonal neuropathy, GAN, is located on chromosome 16q24.1 and encodes a ubi- quitously expressed protein, gigaxonin.
Giant axonal neuropathy is characterized by cyto- skeletal abnormality. The hallmark of the disease is the presence of giant axonal swellings, which are densely packed with aberrant neurofilaments, abnor- mal microtubule network, and accumulation of other membranous organelles. Neurofilaments belong to the intermediate filaments. In GAN, an abnormal ac- cumulation of multiple tissue-specific intermediate filaments is found in a wider range of cells than only neurons, suggesting a generalized disorganization of intermediate filament networks. Aggregations of vimentin have been reported in endothelial cells, Schwann cells, and cultured skin fibroblasts, and ag- gregations of glial fibrillary acidic protein are found in astrocytes. Keratin intermediate filaments are altered, leading to the characteristic kinky hair.
The cytoskeletal network is responsible for cell ar- chitecture, intracellular transport, mitosis, cell mobil- ity, and differentiation. It is composed of micro- tubules, actin microfilaments, and intermediate filaments, which interconnect through cross-linking proteins. The properties of the network formed are modulated by different associated proteins. Cyto- skeletal organization and dynamics depend on pro- 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- volved in maintaining the integrity of cytoskeletal structures and promoting neuronal stability. The in- teraction of gigaxonin with MAP1B-LC enhances microtubule stability, required for axonal transport over long distance. In line with this, the neurofilament accumulations in GAN, leading to the segmental distension of axons, mainly affect distal portions of the long tracts. Some of the mutations found in GAN patients have been shown to lead to loss of gigaxonin–MAP1B-LC interaction. The devastating
axonal degeneration and neuronal death found in GAN patients point to the importance of gigaxonin for neuronal survival.
58.4 Therapy
No specific treatment is available. Therapy is support- ive.
58.5 Magnetic Resonance Imaging
The MRI findings described in GAN are variable, probably at least partly depending on the stage of the disease. In some patients, no or minimal cerebral white matter abnormalities are present (Fig. 58.1).
The white matter abnormalities may be diffuse and subtle (Fig. 58.3), sometimes with multifocal spots of more prominent signal change superimposed. In oth- er patients, extensive and confluent white matter ab- normalities are present, symmetrically involving the cerebral white matter in a diffuse fashion (Fig. 58.2) or with a predominance in the frontoparietal region.
The corpus callosum and U fibers tend to be spared.
The posterior limb of the internal capsule, pyramidal tracts, and medial lemniscus in the brain stem, mid- dle cerebellar peduncles, hilus of the dentate nucleus, and cerebellar white matter may display signal changes (Figs. 58.2 and 58.3). The white matter ab- normalities are progressive over time (Figs. 58.1 and 58.2). The lateral ventricles become mildly dilated due to white matter volume loss and the cerebellar vermis becomes atrophic over time.
In our experience the MR images in GAN have a certain resemblance to the images in Alexander dis- ease, which is interesting since both are characterized by Rosenthal fiber deposition. The basal ganglia may have a slightly abnormal signal and a slightly swollen aspect (Figs. 58.1 and 58.3). The areas with high signal on T1-weighted images include the ependymal lining (Fig. 58.1), a thin periventricular
Fig. 58.1. A 6-year-old female patient with GAN. The T2- weighted images (upper two rows) show a diffuse slight signal abnormality of the cerebral white matter. The basal ganglia have a slightly abnormal signal and slightly swollen appear- ance. The T1-weighted images (third row) show that the ependymal lining of the lateral ventricles and the globus pal- lidus have a slightly increased signal. After contrast adminis- tration (fourth row), subtle enhancement of the ependymal lin- ing is seen. Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada.
(Fig. 58.1 see next page)
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Fig. 58.1.
Fig. 58.2.
rim (Fig. 58.3), and the globus pallidus (Figs. 58.1 and 58.3). The thin periventricular rim may have a low signal on T2-weighted images (Fig. 58.3). The ependy- mal lining shows subtle contrast enhancement (Figs. 58.1 and 58.3). Areas in the dorsal medulla may also show contrast enhancement (Fig. 58.2), which is often seen in Alexander disease.
Fig. 58.2. At the age of 14 years, diffuse cerebral signal abnor- malities are seen in the same girl, sparing the corpus callosum and to some extent the U fibers. The posterior limb of the in- ternal capsule, pyramidal tracts and medial lemniscus in the brain stem, hilus of the dentate nucleus, and cerebellar white matter are also involved. The contrast-enhanced T1-weighted images reveal contrast uptake in multiple spots with the cere- bellum, pons, and the dorsal part of the medulla. Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada. (Fig. 58.2 see last page)
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Fig. 58.3. The T2-weighted images (upper two rows) of her brother, who also suffers from GAN, at the age of 3 years, show diffuse slight signal abnormalities in the cerebral white matter with sparing of the U fibers and corpus callosum. The posteri- or limb of the internal capsule, pyramidal tracts and medial lemniscus in the brain stem, hilus of the dentate nucleus, and cerebellar white matter are also involved.There is a thin rim of low signal around the lateral ventricles on the T2-weighted images, most evident in the posterior region. This rim has an increased signal on T1-weighted images (third row) and en- hances after contrast (fourth row).The globus pallidus also has a slightly increased signal on T1-weighted images (third row).
Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada.
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Fig. 58.3.
