DiagnosisThe diagnosis of giant axonal neuropathy (GAN) is suggested in individuals with the following:Severe early-onset peripheral motor and sensory neuropathy 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 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. Note: Some unaffected carriers (heterozygotes) can show mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [Demir et al 2005]. Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responses are often abnormal.EEG often shows increased slow wave activity.Brain MRI often demonstrates white matter abnormalities: high signals on T₂ sequences in the anterior and posterior periventricular regions as well as the cerebellar white matter [Demir et al 2005].MRI and magnetic resonance spectroscopy (MRS) in an 11-year-old revealed evidence for 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].HistopathologyPeripheral 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]. Note: Giant axons and NF accumulation, initially described as specific hallmarks for GAN, are now known to occur in two forms of the peripheral neuropathy Charcot-Marie-Tooth disease (CMT2E and CMT4C). Thus, peripheral nerve biopsy examination is not sufficient to establish the diagnosis of GAN. Other. Giant axons are also observed in the cerebral cortex and other parts of the brain in persons with GAN.Molecular Genetic TestingGene. GAN, encoding the protein gigaxonin, is the only gene in which mutation is currently known to cause giant axonal neuropathy [Bomont et al 2000].Evidence for locus heterogeneity. Currently no evidence for genetic heterogeneity exists (see Table 1, footnote 3).Table 1. Summary of Molecular Genetic Testing Used in Giant Axonal NeuropathyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityGANSequence analysisSequence variants 270%-90% 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice-site mutations.3. Using sequence analysis, Bomont et al [2000] identified point mutations in all 22 families analyzed. Except for two heterozygous mutations in two families, all mutations (95% of total mutations) were identified within the 11 exons of GAN. This indicates that the failure to find a mutation most likely resulted from limitations of the testing methodology rather than genetic locus heterogeneity. Mutations in these families may be located in regions of the gene that were not sequenced (e.g., introns) or may be of a type not detectable by sequence analysis (e.g., larger deletions, duplications). Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandNerve conduction studies Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responsesEEG Brain MRI MRI and magnetic resonance spectroscopy (MRS)Nerve biopsyMolecular genetic testing Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in GAN.}

Natural HistoryGiant 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 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.

Genotype-Phenotype CorrelationsGAN-causing mutations are scattered over the entire gene, and clear correlations between specific mutations and particular phenotypic characteristics have not been reported.

Differential DiagnosisSevere early-onset autosomal recessive hereditary neuropathies (i.e., 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. Five types caused by mutations in six 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 the 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 mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1). CMT4B (OMIM 601382, 604563), characterized by myelin outfoldings seen on nerve biopsy, is caused by mutations in either the myotubularin-related protein 2 gene MTMR2 (CMT4B1) or SBF2 (CMT4B2). CMT4C, a demyelinating neuropathy with onset in the first or second decade associated with scoliosis and respiratory compromise, is caused by mutations in the SH3 domain and tetratricopeptide repeats-containing protein 2 gene (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 mutation in SH3TC2.CMT4E (OMIM 605253) has been described in a few families with autosomal recessive severe congenital hypomyelinating neuropathy and is caused by mutations in the early growth response protein 2 gene (EGR2). X-linked distal hereditary motor neuropathy caused by ATP7A mutations. This disorder is allelic with Menkes disease (see below) [Kennerson et al 2010].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. 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 mutations in the copper-transporting ATPase gene (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. 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. Mutations in PLA2G6 (encoding phospholipase A2) were demonstrated in persons with INAD [Morgan et al 2006]. The study, however, did not find mutations in PLA2G6 in all affected individuals tested, suggesting either incomplete detection of mutations or genetic heterogeneity. Arylsulfatase A deficiency (ARSA, 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. Late-infantile MLD. Onset is between ages one and two years. Typical presenting signs include clumsiness, frequent falls, toe walking, and slurred speech. Weakness and hypotonia are observed initially. 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. MLD is suspected in individuals with progressive neurologic dysfunction and MRI evidence of a leukodystrophy. ARSA is the only gene in which mutation is associated with the disorder. Inheritance is autosomal recessive. MLD is suggested by ARSA enzyme activity in leukocytes that is less than 10% of normal controls using the Baum-type assay. The diagnosis is confirmed by one or more of the following additional tests:Molecular genetic testing of ARSA Urinary excretion of sulfatides Finding of metachromatic lipid deposits in nervous system tissue Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 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 Medical genetics consultationTreatment of ManifestationsTreatment, 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 patients, 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 ComplicationsWheelchair-bound or bedridden individuals require frequent examination for decubitus ulcers and appropriate prophylaxis. SurveillanceThe 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; at least yearly evaluation is recommended.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGAN16q23​.2GigaxoninIPN Mutations, GAN
GAN homepage - Leiden Muscular Dystrophy pagesGANData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Giant Axonal Neuropathy (View All in OMIM) View in own window 256850GIANT AXONAL NEUROPATHY 1; GAN1 605379GAN GENE; GANMolecular Genetic PathogenesisGAN was genetically localized on chromosome 16q24.1 by homozygosity mapping [Ben Hamida et al 1997, Cavalier et al 2000] and subsequently identified by bioinformatic analysis of the Human Genome [Bomont et al 2000]. GAN encodes for a new BTB-Kelch protein named gigaxonin (named by the authors to refer to the giant axons present in the pathology). Normal allelic variants. 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. Bomont et al [2000] described two normal variants within the coding sequence (see Table 2).Table 2. Normal Variants in the GAN Coding SequenceView in own windowExonNucleotide Change Amino Acid ChangeApproximate FrequencyReference Sequences8c.1293C>Tp.= ^{1(Tyr431Tyr) 2 35%NP_071324​.1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. p.= designates that protein has not been analyzed, but no change is expected.2. Variant designation that does not conform to current naming conventionsPathologic allelic variants. Causative mutations 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 mutations have been identified in 49 families of diverse geographic origins, in all GAN exons and including all types of mutations: nonsense, missense, deletion, insertion, and splice site mutation.All currently known GAN mutations 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 whose transcript is ubiquitously expressed in mouse tissues [Bomont et al 2000]. 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]. 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]; 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, Pintard et al 2003, Xu 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.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 IF 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].A GAN mouse model has been attempted; gigaxonin has been depleted by gene disruption of the promotor 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 GANexon1} 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 GAN^ex3-5 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 mouse models and their 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]. 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 disease-causing mutations are distributed over the entire gene and lead to a decreased abundance of gigaxonin, as revealed by immunodetection of gigaxonin in several lymphoblasts cell lines derived from unrelated patients [Cleveland et al 2009]. Accordingly, gigaxonin deficiency would impede ubiquitin-mediated protein degradation of its partners: MAP1B-LC, MAP8, TBCB, and probably other unidentified proteins.