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Giant Axonal Neuropathy

, MD, PhD, , PhD, and , PhD.

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Initial Posting: ; Last Update: October 9, 2014.

Estimated reading time: 20 minutes


Clinical characteristics.

Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.


The diagnosis of GAN is suggested by clinical findings and the results of nerve conduction velocity (NCV) studies and brain MRI. The diagnosis is established in individuals with biallelic pathogenic variants in GAN (encoding gigaxonin, a subunit of an E3 ubiquitin ligase) or decreased quantities of gigaxonin on immunodiagnostic testing. Nerve biopsy, the former diagnostic modality, is no longer routinely used.


Treatment of manifestations: A multidisciplinary team including (pediatric) neurologists, orthopedic surgeons, physiotherapists, psychologists, and speech and occupational therapists is recommended; goals are to optimize intellectual and physical development through speech therapy to improve communication, occupational therapy to maximize independence in activities of daily living, physiotherapy to preserve mobility as long as possible, and early intervention and special education; orthopedic surgery as needed for foot deformities; ophthalmologic treatment as needed for diplopia.

Prevention of secondary complications: For wheelchair-bound or bedridden individuals, prophylaxis and frequent examination for decubitus ulcers.

Surveillance: At least yearly reassessment of intellectual abilities, peripheral neuropathy, ataxia, spasticity, and cranial nerve dysfunction.

Genetic counseling.

GAN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with GAN have not been known to reproduce, most likely because they die at a young age. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the GAN pathogenic variants in a family are known.


Suggestive Findings

The diagnosis of giant axonal neuropathy (GAN) is suggested in individuals with the following:

  • Severe early-onset peripheral motor and sensory neuropathy. Nerve conduction studies often show normal to moderately reduced nerve conduction velocity (NCV) but severely reduced compound motor action potentials and absent sensory nerve action potentials.
  • Tightly curled lackluster hair that differs markedly from that of the parents. Note: Microscopic examination of unstained hair shows abnormal variation in shaft diameter and twisting (pili torti) similar to the abnormality seen in Menkes disease (see ATP7A-Related Copper Transport Disorders). The hair in individuals with GAN also shows longitudinal grooves on scanning electron microscopy [Kennerson et al 2010, Kaler 2011, Yi et al 2012].
  • Central nervous system involvement including intellectual disability, cerebellar signs (ataxia, nystagmus, dysarthria), and pyramidal tract signs
  • White matter abnormalities on brain MRI. High signals on T2-weighted sequences in the anterior and posterior periventricular regions as well as the cerebellar white matter are often seen [Demir et al 2005].

Establishing the Diagnosis

The diagnosis of GAN is established in a proband by identification of either biallelic pathogenic variants in GAN, the gene encoding the protein gigaxonin [Bomont et al 2000] (see Table 1) or decreased amounts of gigaxonin on immunodiagnostic testing.

Molecular Genetic Testing

One genetic testing strategy is single-gene testing. Sequence analysis of GAN is performed first, and followed by deletion/duplication analysis if only one or no pathogenic variant is found.

An alternative genetic testing strategy is use of a multigene panel that includes GAN and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Giant Axonal Neuropathy

Gene 1MethodProportion of Probands with a Pathogenic Variant Detectable by Method
GANSequence analysis 270%-90% 3
Deletion/duplication analysis 4Unknown 5

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Using sequence analysis, Bomont et al [2000] identified pathogenic variants in all 22 families analyzed. Except for two heterozygous pathogenic variants in two families, all pathogenic variants (95% of total pathogenic variants) were identified within the 11 exons of GAN. This indicates that the failure to find a pathogenic variant most likely resulted from limitations of the testing methodology rather than genetic locus heterogeneity. Pathogenic variants in these families may be located in regions of the gene that were not sequenced (e.g., introns) or may be of a variant type not detectable by sequence analysis (e.g., larger deletions, duplications).


Testing that identifies exon or whole-gene deletions/duplications are not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) (also known as CGH array) that includes this gene/chromosome segment.


Among the 60 total distinct pathogenic variants identified to date, four large deletions have been reported. Deletions can encompass almost the entire gene [Buysse et al 2010] or only a few exons [Boizot et al 2014].

Immunodetection of Gigaxonin

With the increased identification of large deletions within GAN, the risk of false negative results with genomic testing (e.g., multigene panels and exome sequencing) becomes significant. Thus, an alternative diagnostic test was needed to allow detection of all types of pathogenic variants, including large deletions and those that affect gene expression as well (i.e., pathogenic variants in the promoter, regulatory regions within introns).

To meet these needs a new immunodiagnostic test was developed using a specific antibody to quantitate gigaxonin in immortalized lymphoblast cells (derived from blood) [Boizot et al 2014]. In several individuals with molecularly confirmed GAN markedly decreased quantities of mutated gigaxonin were observed (mean residual value was 13.1% of control values). Subsequently, in seven families with a sensorimotor axonal neuropathy of unknown etiology that resembled GAN/CMT2, this test was fully penetrant and specific for GAN: all individuals with low levels of gigaxonin in the range observed in GAN (and only those individuals) were subsequently identified to have biallelic pathogenic variants in GAN by sequence analysis or deletion/duplication analysis.

In summary, this new test holds promise as a fast diagnostic tool that may be used prior to or in concert with the molecular genetic testing of GAN. Of note, studies on a larger cohort are needed to confirm its prognostic value. Additionally, the test methods are being adapted to allow testing of fresh blood samples (rather than immortalized cells derived from patient blood samples).

Clinical Characteristics

Clinical Description

Giant axonal neuropathy (GAN) is a neurodegenerative disorder affecting both the peripheral and central nervous systems. GAN is classified within the hereditary motor and sensory neuropathies.

GAN typically begins before age five years and progresses to death, usually by early adulthood. Milder forms of the disease have been reported with later age of onset, extended survival, or modest deterioration of central nervous system [Ben Hamida et al 1990, Zemmouri et al 2000]. Individuals present with a motor and sensory peripheral neuropathy that may also involve the cranial nerves, resulting in facial weakness, optic atrophy, and ophthalmoplegia. Tendon reflexes are often absent; Babinski's sign may be present as a result of CNS involvement.

The majority of affected individuals show signs of CNS involvement including intellectual disability, cerebellar signs (ataxia, nystagmus, dysarthria), epileptic seizures, and signs of pyramidal tract damage.

Most affected individuals have characteristic tightly curled lackluster hair, unlike their parents.

Most affected individuals become wheelchair dependent in the second decade of life and die in the third decade. They eventually become bedridden with severe polyneuropathy, ataxia, and dementia. Death results from secondary complications, such as respiratory failure.

Other findings. Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responses are often abnormal.

EEG often shows increased slow wave activity.

Neuroimaging. Brain MRI and magnetic resonance spectroscopy (MRS) in an individual age 11 years revealed evidence of significant demyelination and glial proliferation in the white matter, but no neuroaxonal loss [Alkan et al 2003]. MRS of another individual at ages nine and 12 years revealed signs of damage or loss of axons accompanied by acute demyelination in the white matter and generalized proliferation of glial cells in both gray and white matter [Brockmann et al 2003].


Peripheral nerve biopsy exhibits reduced density of nerve fibers and the presence of giant axons (i.e., distorted nerve fibers with large axonal swellings ≤50 µm) [Asbury et al 1972, Berg et al 1972].

Ultrastructural examination of giant axons reveals severe disorganization of neurofilaments (NFs), including loss of parallel orientation along the axons and abnormal clumping [Donaghy et al 1988].

Reduction of myelin thickness in giant axons, onion-bulb formation by multiple Schwann cell processes, and segmental demyelination and remyelination may also suggest Schwann cell dysfunction.

Note: Giant axons and NF accumulation, initially described as specific hallmarks for GAN, are now known to occur in several forms of the peripheral neuropathy, including the Charcot-Marie-Tooth disease forms CMT2E and CMT4C.

Thus, peripheral nerve biopsy examination is not sufficient to establish the diagnosis of GAN.

Central nervous system. Giant axons are also observed in the cerebral cortex and other parts of the brain in persons with GAN.


Structural examination of giant axons often reveals exclusion of mitochondria, endoplasmic reticulum vesicles, and microtubules (MTs) from NF-enriched regions.

Intermediate filament (IF) disorganization in GAN not only involves NFs, but also all IF types examined to date, in neuronal and non-neuronal cells. Those alterations extend to GFAP, NFs, keratin, desmin, and vimentin in human and suggest a key role for gigaxonin in maintaining IF architecture.

Skin-derived primary fibroblasts of affected individuals revealed abnormal aggregation of vimentin as an ovoid mass visible on electron or light microscope examination [Pena et al 1983]. This human-derived cell type represents a valuable cellular model to study IF organization in GAN. Studies on multiple fibroblasts revealed that vimentin aggregation is partial and conditional, is aggravated upon MT destabilization [Bomont & Koenig 2003], and does not depend on TBCB, a partner of gigaxonin [Cleveland et al 2009].

Genotype-Phenotype Correlations

GAN pathogenic variants are scattered over the entire gene, and clear correlations between specific GAN pathogenic variants and particular phenotypic characteristics have not been reported.


GAN is a very rare disorder; the true prevalence is not known. To date, about 50 families have been reported worldwide; see, for example: Bomont et al [2000], Kuhlenbäumer et al [2002], Bomont et al [2003], Bruno et al [2004], and Demir et al [2005].

Differential Diagnosis

Severe early-onset autosomal recessive hereditary neuropathies such as those classified as Charcot-Marie-Tooth hereditary neuropathy type 4 (CMT4) may be considered in the differential diagnosis of giant axonal neuropathy (GAN), especially in the (rare) absence of both the characteristic hair abnormalities and prominent CNS abnormalities. (In the past the term Dejerine-Sottas syndrome was used to designate severe childhood-onset genetic neuropathies of any inheritance; the term is no longer in general use.) See CMT overview.

CMT4 is a genetically heterogeneous disorder inherited in an autosomal recessive manner. Ten subtypes caused by pathogenic variants in one of ten genes are recognized:

  • CMT4A comprises a peripheral neuropathy typically affecting the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Even proximal muscles can become weak. The age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. The neuropathy can be either of the demyelinating type with reduced NCVs or the axonal type with normal NCVs. Vocal cord paresis is common. The disease is caused by mutation of GDAP1.
  • CMT4B (OMIM 601382, 604563, 615284), characterized by myelin outfoldings seen on nerve biopsy, is caused by mutation of MTMR2 (CMT4B1), SBF2 (CMT4B2), or SBF1 (CMT4B3).
  • CMT4C is a demyelinating neuropathy characterized by early-onset severe spine deformities. The majority of affected children present with scoliosis or kyphoscoliosis between ages two and ten years. CMT4C is caused by mutation of SH3TC2. Although the presence of giant axons and neurofilament (NF) accumulation in the nerve biopsy are usually indicative of GAN, this diagnosis is excluded by further clinical investigation and identification of biallelic pathogenic variants in SH3TC2.
  • CMT4E (OMIM 605253) has been described in a few families with autosomal recessive severe congenital hypomyelinating neuropathy and is caused by biallelic pathogenic variants of EGR2.

ATP7A-related distal motor neuropathy, an adult-onset distal motor neuropathy, is allelic with Menkes disease and occipital horn syndrome.

Menkes disease is a rare X-linked recessive disorder with prominent CNS involvement and hair changes resembling those of GAN. Menkes disease is a disorder of copper transport caused by pathogenic ATP7A. Serum copper concentration and serum ceruloplasmin concentration are low. Infants with classic Menkes disease appear healthy until age two to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit typical neurologic changes and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, often lightly pigmented). Temperature instability and hypoglycemia may be present in the neonatal period. Death usually occurs by age three years.

Classic infantile neuroaxonal dystrophy (INAD or Seitelberger disease) is an infantile-onset disease of the CNS and peripheral nervous system with neurologic symptoms resembling GAN but without the characteristic hair changes of GAN. A characteristic pathologic feature is the presence of axonal spheroids made of vesiculotubular structures, tubular membranous material with clefts; these axonal spheroids are found in both the CNS and the peripheral nervous system, including the cutaneous or conjunctival nerve twigs. Pathogenic variants in PLA2G6 (encoding phospholipase A2) were demonstrated in persons with INAD [Morgan et al 2006]. The study, however, did not find pathogenic variants in PLA2G6 in all affected individuals tested, suggesting either incomplete detection of pathogenic variants or genetic heterogeneity.

Arylsulfatase A deficiency (ARSA deficiency, metachromatic leukodystrophy, MLD) is a disorder of impaired breakdown of sulfatides that occur throughout the body but are found in greatest abundance in nervous tissue, kidneys, and testes. Onset ranges from late infancy to adulthood. ARSA is the only gene in which mutation is associated with the disorder. Inheritance is autosomal recessive.

  • Late-infantile MLD. Onset is between ages one and two years. Typical presenting signs include weakness, hypotonia, clumsiness, frequent falls, toe walking, and slurred speech. Later signs include inability to stand, difficulty speaking, deterioration of mental function, increased muscle tone, pain in the arms and legs, generalized or partial seizures, compromised vision and hearing, and peripheral neuropathy. The final stages include tonic spasms, decerebrate posturing with rigidly extended extremities, feeding by gastrostomy tube, blindness, and general unawareness of surroundings. Expected life span is about 3.5 years after onset of symptoms but can be up to ten or more years with current treatment approaches.
  • Juvenile MLD. Onset is between age four years and sexual maturity (age 12-14 years). Initial manifestations include decline in school performance and emergence of behavioral problems, followed by clumsiness, gait problems, slurred speech, incontinence, and bizarre behaviors. Seizures, more commonly partial seizures, may occur. Expected life span is ten to 20 or more years after diagnosis.
  • Adult MLD. Onset occurs after sexual maturity; therefore, it would not be confused with GAN.

Several neurotoxic substances (e.g., n-hexane and acrylamide) cause a mixed axonal and demyelinating peripheral neuropathy with axonal swelling and NF accumulation. Toxicity from n-hexane can result from occupational exposure or, rarely, from recreational gasoline vapor inhalation [Chang et al 1998]. However, chronic exposure to these toxic substances is extremely unlikely in children around the age of onset of GAN, therefore excluding this type of neurotoxicity as a risk factor for GAN.


Evaluations Following Initial Diagnosis

To establish the extent of disease and the needs of an individual diagnosed with giant axonal neuropathy (GAN), the following evaluations are recommended:

  • Assessment of development/cognitive abilities to establish the extent of disease and monitor progression or attempted intervention
  • Consultation with a clinical geneticist and/or genetic counselor

The following investigations may be used to confirm clinically apparent problems but also to uncover subclinical involvement of PNS and CNS lesions which are not clinically apparent:

  • Clinical and electrophysiologic (sensory and motor NCVs, electromyography) examination of the peripheral motor and sensory nervous system (including assessment of the function of cranial nerves) to establish the extent of disease and monitor progression
  • Neuroophthalmologic examination to look for nystagmus resulting from cerebellar dysfunction or strabismus caused by involvement of cranial nerves III, IV, or VI
  • EEG, somatosensory and motor evoked potentials, and brain MRI to determine the degree of CNS involvement

Treatment of Manifestations

Treatment, focused on managing the clinical findings, often involves a team including (pediatric) neurologists, orthopedic surgeons, physiotherapists, psychologists, and speech and occupational therapists. Major goals are to optimize intellectual and physical development and, later in life, to slow the inevitable deterioration of these capacities.

Note: Early intellectual development is nearly normal in many affected children, enabling them to attend a normal school initially; however, significant intellectual impairment usually occurs before the second decade of life.

Treatment includes the following:

  • Speech and occupational therapy to improve communication and activities of daily living
  • Early intervention and special education directed to the individual's disability. Frequent reassessment is needed because of the progressive nature of the disorder. Special education often becomes necessary between ages five and 12 years.
  • Physiotherapy (typically for distal weakness, ataxia, and spasticity) to preserve mobility as long as possible
  • Orthopedic surgery as required for foot deformities (Note, however, that most affected individuals become wheelchair bound between ages ten and 20 years for other reasons.)
  • Appropriate ophthalmologic treatment (e.g., surgery or glasses), especially if diplopia occurs

Prevention of Secondary Complications

Wheelchair-bound or bedridden patients require frequent examination for decubitus ulcers and appropriate prophylaxis.


The following should be monitored in persons with GAN:

  • Intellectual development/deterioration
  • Progression of the peripheral neuropathy, ataxia, spasticity, and cranial nerve dysfunction

The frequency of the monitoring should depend on disease progression; annual or more frequent evaluation is recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Giant axonal neuropathy (GAN) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one GAN pathogenic variant.
  • Heterozygotes are asymptomatic, but can display mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [Demir et al 2005].

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. No individuals with GAN are known to have reproduced.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the GAN pathogenic variants in the family.

Note: Some unaffected carriers (heterozygotes) can show mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [Demir et al 2005].

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GAN pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for GAN are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Hannah's Hope Fund for Giant Axonal Neuropathy
    19 Blue Jay Way
    Rexford NY 12148
    Phone: 518-383-9053
  • National Library of Medicine Genetics Home Reference
  • Child Neurology Foundation (CNF)
    2000 West 98th Street
    Bloomington MN 55431
    Phone: 877-263-5430 (toll-free); 952-641-6100

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Giant Axonal Neuropathy: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
GAN16q23​.2GigaxoninIPN Mutations, GAN
GAN homepage - Leiden Muscular Dystrophy pages

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Giant Axonal Neuropathy (View All in OMIM)


Gene structure. The full GAN cDNA (AF291673) is 4677 nt long with an open reading frame of 1791 nt encoding a protein of 597 amino acids (AAG35311.1) [Bomont et al 2000]. GAN is organized in 11 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Bomont et al [2000] described two normal variants within the coding sequence (see Table 2).

Table 2.

Benign Variants in the GAN Coding Sequence

ExonNucleotide ChangeAmino Acid ChangeApproximate FrequencyReference Sequence
8c.1293C>Tp.= 1
(Tyr431Tyr) 2

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


p.= designates that protein has not been analyzed, but no change is expected.


Variant designation that does not conform to current naming conventions

Pathogenic variants. Pathogenic variants in GAN (Table A) were first reported by Bomont et al [2000] and later by Kuhlenbäumer et al [2002], Bomont et al [2003], Bruno et al [2004], Demir et al [2005], and others. To date a total of 47 pathogenic variants have been identified in 49 families of diverse geographic origins, in all GAN exons and including all types of variants: nonsense, missense, insertion, and splice site variants, as well as deletions that can encompass several exons.

Most currently known GAN pathogenic variants are listed in the Mutation Database of Inherited Peripheral Neuropathies [Nelis et al 1999]. (See Table A.)

Normal gene product. GAN encodes for gigaxonin, a new BTB-Kelch protein named by the authors to refer to the giant axons present in the pathology [Bomont et al 2000].

The development of specific antibodies for gigaxonin revealed its low and preferential expression in neuronal tissues and during embryogenesis in mouse [Bomont et al 2003, Ganay et al 2011].

Its N-terminus BTB domain (broad-complex, tramtrack and bric a brac domain) mediates homodimerization of gigaxonin [Cullen et al 2004] and its C-terminal Kelch domain is composed of six Kelch repeats [Bomont et al 2000].

The resolution of the crystal structure of another BTB-Kelch protein [Li et al 2004] confirmed the predicted tertiary structure conserved in Kelch proteins, namely a beta-propeller. Whereas Kelch repeats display a high variability in sequence, their three-dimensional organization exposes multiple surfaces for protein-protein interaction with partners that likely determine Kelch protein function. Thus, through interaction with distinct proteins, the Kelch-repeat superfamily is involved in many aspects of the cell function, including coordination of cell morphology, differentiation and growth, regulation of oxidative stress, and contribution to viral pathogenesis [Adams et al 2000].

BTB-containing proteins (including gigaxonin) have been shown to be part of an enzymatic complex involved in the clearance of unfolded/short-lived proteins, namely E3 ubiquitin ligase [Furukawa et al 2003]. Interacting with the Cul3 subunit of the E3 ligase through the BTB domain and with partners through the Kelch domain, gigaxonin would be the substrate adaptor of this E3 ligase, allowing the degradation of specific substrates by the proteasome subsequent to addition of a ubiquitin chain. Supporting this hypothesis, an excess of gigaxonin has been shown to completely destroy several intermediate filament networks (including vimentin and neurofilaments) in cells, through interaction with gigaxonin and by a mechanism involving the proteasome [Mahammad et al 2013].

Through its Kelch domain, gigaxonin has been shown to interact with three proteins involved in microtubule (MT) homeostasis and dynamics: the MT-associated proteins MAP1B and MAP1S and the tubulin chaperone TBCB [Ding et al 2002, Allen et al 2005, Wang et al 2005, Ding et al 2006]. In overexpression systems, their abundance is regulated by gigaxonin via a process of ubiquitination. The role of MAP1B, MAP1S, and TBCB in neurodegeneration and intermediate filament aggregation has been investigated in cellular models for GAN. Whereas gigaxonin depletion in embryonic cortical neurons derived from a mouse knockout model resulted in massive neuronal death, the contribution of MAP1B and MAP1S to neuronal death is moderate [Allen et al 2005, Ding et al 2006]. Unlike its counterpart TBCE, the tubulin chaperon TBCB has been shown to modestly destabilize MTs and is not responsible for the vimentin aggregation in fibroblasts derived from affected individuals [Cleveland et al 2009].

Altogether, these studies suggest that the known substrates are not playing an important role in GAN and that the key effectors of gigaxonin have still to be identified.

Mouse model. A GAN mouse model has been attempted; gigaxonin has been depleted by gene disruption of the promoter and exon 1 [Dequen et al 2008] and in exons 3-5 [Ding et al 2006, Ganay et al 2011]. Mouse models show a mild form of the disease, with late onset and mild behavioral deficits and no giant axons.

  • The GAN∆exon1 model did not have an overt neurologic phenotype or neuronal loss; it exhibited modest hind-limb muscle atrophy, a 10% decrease of muscle innervation, and a 27% loss of motor axons at age six months [Dequen et al 2008].
  • Motor and sensory deficits, evaluated over time with different behavioral tests in the GANex3-5 mouse model have revealed late (≥1 year), modest but persistent motor deficits in the murine 129/SvJ-genetic background, while sensory impairment was found in C57BL/6 animals [Ganay et al 2011].

Aggregation of NFs was observed in the GAN mouse models and its quantification revealed a dramatically increased abundance of NFs in neuronal tissues [Dequen et al 2008, Ganay et al 2011]. Ultrastructural examination of gigaxonin-depleted axons showed the massive disorganization of NFs seen in human: an altered orientation along the axons, and increased diameter [Ganay et al 2011].

Overall, the GAN mouse models fail to reproduce the severity of disease found in humans but recapitulate the NF aggregation characteristic of the human pathology.

Abnormal gene product. GAN pathogenic variants are distributed over the entire gene and lead to a decreased abundance of gigaxonin, as revealed by immunodetection of gigaxonin in several lymphoblast cell lines derived from unrelated patients [Cleveland et al 2009].

A study of the effects of the pathogenic variants in several patients revealed that decreased amounts of gigaxonin are caused by a general mechanism of instability of either the transcript (for biallelic nonsense variants or deletions) or the tri-dimensional structure of the protein [Boizot et al 2014].

Regarding the proposed function of gigaxonin as an E3 ligase adaptor, gigaxonin deficiency would impede ubiquitin-mediated protein degradation of its partners: MAP1B-LC, MAP8, TBCB, and probably other unidentified proteins. Identifying the substrates of gigaxonin will be essential to advance the understanding of GAN disease pathogenicity.


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Chapter Notes

Revision History

  • 9 October 2014 (me) Comprehensive update posted live
  • 21 June 2012 (me) Comprehensive update posted live
  • 11 August 2009 (cd) Revision: sequence analysis available clinically
  • 2 July 2007 (me) Comprehensive update posted live
  • 28 February 2005 (me) Comprehensive update posted live
  • 9 January 2003 (me) Review posted live
  • 5 August 2002 (vt) Original submission
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