Neil GordonMD FRCP HonFRCPCH, Huntlywood,
3 Styal Road, Wilmslow SK9 4AE, UK.
Correspondence to author at the above address.
Giant axonal neuropathy (GAN) is a chronic progressive dis-
ease of the peripheral nervous system, but lesions can also
occur in the central nervous system (CNS), especially in the
brainstem and cerebellum. Its mode of inheritance is autoso-
mal recessive, with parents of affected children often being
consanguineous, but sporadic cases have been reported.1
Symptoms and signs of GAN
Age at onset may be from soon after birth to up to ten years of
age, or older. The peripheral neuropathy presents with evi-
dence of both motor and sensory involvement, with progres-
sive weakness and hyporeflexia in the first seven years of life;
the cranial nerves are also affected, especially the third and the
seventh. If there are lesions in the CNS, brain and spinal cord,
these can cause nystagmus, ataxia, dysmetria, and dysarthria,
as well as signs of spasticity. Less commonly, there have been
reports of scoliosis, kyphosis, optic atrophy, ophthalmople-
gia, severe learning difficulties, and epilepsy.1The peripheral
nerves are not clinically enlarged. Many affected patients, but
not all, have tightly curled hair, which can mean that keratin fil-
aments are also affected in the pathogenesis of the condition.
Endocrine disturbances can occur, such as precocious puberty,
but these are rare.2Most patients are confined to a wheelchair
or deceased by their teens or third decade.3
Sometimes the symptoms and signs of CNS involvement
can predominate so that giant axonal disease may be a more
appropriate title.4Lampl et al.5,6suggest that giant axonal
neuropathy should be suspected in any patient presenting
with severe learning difficulties, epilepsy, and diffuse neurolog-
ical signs. However, even if there is no clinical sign of CNS
involvement, there may be electroencephalogram (EEG) and
magnetic resonance imaging (MRI) abnormalities.7
The symptomatology can vary considerably. For example,
Ben Hamida et al.8reported a family with GAN in which
none of the patients had abnormal hair, involvement of the
CNS was limited to a pyramidal syndrome without learning
difficulties of any kind, nystagmus or ataxia, and there was
evidence of a lower motor neuron lesion affecting some of
the cranial nerves. In addition, the disease evolved very
slowly with a benign prognosis. These findings lead to the
suggestion that in this family there may have been a different
There may be particular dangers when giving an anaesthet-
ic to patients suffering from GAN. Mitchell and Moskovits9
stress the need for intubation if there is a weak cough reflex,
and warn of possible sensitivity to acetylcholine, suxam-
ethonium, and anticholinesterases. Furthermore, the use of
diazepam may result in prolonged muscle weakness. In their
patient, anaesthesia was induced with thiopentone, and then
halothane, and nitrous oxide in oxygen was used. In the tech-
nique recommended by Diagos et al.,10premedication with
drugs that influence muscle strength was avoided, and intra-
venous anaesthesia was induced by using propofol and
remifentanil. They did not use tracheal intubation if there
was normal facial and neck muscle strength and no history of
Pathology of GAN
Disorganization of the neurofilament network is a minor fea-
ture of several neurodegenerative disorders, such as amy-
otrophic lateral sclerosis, infantile spinal muscular atrophy,
and Charcot-Marie-Tooth disease. Although occasionally mild,
in GAN such changes are usually striking. Histological findings
in peripheral nerve biopsies, including those of autonomic
nerves,11include enlarged axons with an accumulation of neu-
rofilaments.12,13In fact, three types of filament are defective in
this condition: neurofilaments, glial filaments, and intermedi-
ate filaments. The last are found in skin fibroblasts, Schwann
cells, axons, and muscle fibres. The findings suggest that the
disease may be caused by a generalized disorder of cytoplasmic
microfilaments.1Many onion bulb formations of Schwann cells
are present, and ultramicroscopically typical accumulations of
neurofilaments and osmophilic aggregates are found in giant
axons. There is a great variability in the number of myelinated
fibres, as well as in the amount of axonal enlargements among
different fascicles.14Muscle biopsies show evidence of a neu-
rodegenerative disorder, with the presence of small, angulat-
ed, atrophic muscle fibres.13In the CNS, as well as astrocytic
degeneration, there is a loss of Purkinje cells and anterior
horn cells.11Brain demyelination has been reported, and
Rosenthal fibres, so that Alexander’s disease may be suspect-
ed.15,16Parts of the cerebrum most severely affected include
the corticospinal tracts, the middle cerebellar peduncles, the
posterior columns, and the olivocerebellar connections.17
Scanning electron microscopy of the hair revealed an
extraordinary irregular cuticle,18and longitudinal grooves in
Developmental Medicine & Child Neurology 2004, 46: 717–719717
Developmental Medicine & Child Neurology 2004, 46: 717–719
Investigations and diagnosis of GAN
A peripheral nerve biopsy20can confirm the presence of
enlarged axons distended by filaments. The peripheral nerves
appear to be affected first of all in their distal parts with the
abnormalities spreading proximally, so that positive find-
ings will depend on the timing and the site of the biopsy.21
Bonnaure-Mallet et al.22have claimed that it may be possible to
confirm the diagnosis by gingival biopsy. The sample removed
during a dental extraction, and examined by light microscopy
and ultramicroscopy, showed unmyelinated fibres with dis-
tended axons and an accumulation of intermediate filaments
in Schwann cells, fibroblasts, and endothelial cells. Also in this
patient the hair revealed, with scanning electron microscopy, a
longitudinal groove along the shaft, typical of GAN.
Abnormalities in auditory, visual, and somatosensory-evoked
potentials can be found and so confirm involvement of the
CNS.23Conduction velocity of motor nerves is either normal
or slightly decreased and sensory action potentials are usual-
ly absent. Electromyography is often consistent with a neuro-
genic disturbance but can be more suggestive of a myopathic
disorder, and auditory-evoked responses can indicate a brain-
If there is involvement of the CNS, the EEG may show
slowing as well as focal spikes and sharp waves, especially if
seizures have occurred, but may be abnormal even if there
is no such history. In that event, the abnormal EEG associat-
ed with changes in electronystagmography and the auditory
evoked responses will suggest lesions in the connections
between the brainstem and cerebellum.26Computed tomog-
raphy may reveal general atrophy and hypodense defects in the
cerebellar and cerebral white matter. On MRI there may be
additional evidence of demyelination, mostly in the parieto-
occipital and cerebellar regions.27Proton magnetic reso-
nance spectroscopy can assess metabolic alterations in the
brain that reflect histopathological changes, such as neu-
roaxonal damage or loss, active demyelination, and glial pro-
liferation, although these are not specific to GAN and occur in
other conditions with active demyelination.28
Other rare conditions may have to be considered in the dif-
ferential diagnosis, such as infantile neuroaxonal dystrophy
(Seitelberger’s disease), which has more evidence of cerebral
involvement and more scattered lesions in the peripheral
nerves differing, especially on ultramicroscopic examination,
in their pathological appearance.29However, it has been sug-
gested that, as in both conditions there are accumulations of
neurofilaments within axons, they may represent a spectrum
in the evolution of intermediate filament pathology.30Other
types of neuropathy have to be excluded, such as toxic neu-
ropathies due to glue sniffing for example,31hereditary motor
sensory neuropathy usually of dominant inheritance (Charcot-
Marie-Tooth disease),32those secondary to vitamin B12defi-
ciency, diabetes mellitus, and amyloid polyneuropathies.13
When the CNS is affected, other types of spinocerebellar
degeneration may cause difficulties, as well as Alexander’s dis-
ease,31Fazio-Londe disease with cranial nerve involvement,
and Menkes’ syndrome, although the abnormal hair is quite
different in appearance.3
Genetics of GAN
GAN is inherited in an autosomal recessive manner. The GAN1
locus has been localized by homozygosity mapping to chro-
mosome 16q24.1 in a family by Ben Hamida et al.,33and by
Flanigan et al.34after a study of five families. It was referred to
as GAN1 by the former33because of possible heterogeneity.
This heterogeneity in GAN was confirmed by Tazir et al.35who
described an Algerian family in whom three siblings were
affected. Nerve biopsy showed a moderate loss of myelinated
fibres and several giant axons filled with neurofilaments, but
there was no involvement of the CNS, MRI was normal, and
none of the children had abnormal hair. There was no linkage
to chromosome 16q24.1, and the title of GAN2 was pro-
posed. The heterogeneity has led to the suggestion that there
may be a link between GAN and insulin-dependent diabetes
mellitus, which also demonstrates heterogeneity, and that
chronic hyperglycaemia might cause a similar neuropathy in
Bomont et al.37have reported the identification of the gene
GANin affected patients, which encodes a novel, ubiquitous-
ly expressed protein named gigaxonin. They found several
different mutations, and suggested that gigaxonin is a distinct
cytoskeletal protein that may represent a general pathologi-
cal target for other neurodegenerative disorders with alter-
ations in the neurofilament network, although its true function
is unknown.38Kuhlenbäumer et al.39reported a mutation that
caused a change of isoleucine to threonine, interfering with
the functioning of the gigaxonin gene; they speculate that
certain heterozygous mutations of this kind may cause a mild
subclinical neuropathy, revealed by abnormal nerve conduc-
tion velocities, in heterozygous individuals.
Possible pathogenetic mechanisms of GAN
Causes of this condition with progressive axonal loss are still
unclear. Possibilities include disturbed phosphorylation of inter-
mediate filaments, defective protease, a defect in a protein
involved in neurofilament assembly, and metabolic derange-
ment of the slow axonal transport.33,1The first possibility is
supported by desmin immunostaining of muscle fibres, which
shows abnormal aggregation in the subsarcolemmal space
and in the middle of the muscle fibres.18
The role of ubiquitin, which is a major component of
Rosenthal fibres, is unknown but it may be involved in the
elimination of abnormal proteins and other substances.13As
already mentioned, the role of gigaxonin is likely to be of
importance. Ding et al.40have shown that the binding of
gigaxonin to microtubule-associated protein 1B may be
essential in maintaining the integrity of cytoskeletal struc-
tures and promoting neural stability. If this process is dis-
rupted by mutations in the relevant gene, then an axonal
neuropathy may well result.
Disordered thiol metabolism in GAN has been suggested
by Tandan et al.41as toxins such as acrylamide and hexacar-
bons, agents that bind to thiol groups, can cause a similar
pathology. If so, treatment with sulfhydryl compounds, such
as penicillamine, which stabilize thiols, might be possible.
These authors have proposed that the condition can result
from an inborn error of the metabolism of enzyme-linked
sulfhydryl-containing proteins, causing an impaired produc-
tion of energy needed for the normal organization of inter-
GAN is a good example of a rare condition in which genetic
discoveries are beginning to elucidate possible causes. Until
more is known about these, treatment can only be experimental.
As with all such rare conditions, its exact incidence is uncer-
tain. Further research may not only establish a definite cause
but also help to establish the aetiology of other neuropathies
with a similar pathology.
Accepted for publication 30th April 2004.
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