Clinical characteristics.

GAN-related neurodegeneration comprises a phenotypic continuum ranging from severe (sometimes called classic giant axonal neuropathy) to milder pure early-onset peripheral motor and sensory neuropathies. The classic giant axonal neuropathy phenotype typically manifests as an infantile-onset neurodegenerative disorder, starting as a severe peripheral motor and sensory neuropathy and evolving into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most affected 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. At the milder end of the spectrum are predominantly motor and sensory neuropathies (with little to no CNS involvement) that overlap with the axonal form of Charcot-Marie-Tooth neuropathies.

Diagnosis/testing.

The diagnosis of GAN-related neuropathy is established in a proband with suggestive findings and biallelic GAN pathogenic variants identified by molecular genetic testing.

Management.

Treatment of manifestations: Supportive care is focused on managing the clinical findings of the individual, and often involves a team including neurologists, orthopedic surgeons, physiotherapists, occupational and physical therapists, psychologists, and speech-language pathologists. Major goals are to optimize intellectual and physical development.

Surveillance: Surveillance is individualized to monitor response to ongoing interventions and identify new manifestations.

Genetic counseling.

GAN-related neuropathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GAN pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the GAN pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

GAN-related neurodegeneration should be suspected in individuals with the following clinical, electrophysiologic, and brain imaging findings, and family history.

Clinical findings

• Early-onset peripheral motor and sensory neuropathy (in all individuals)
• Variable findings typically observed in classic giant axonal neuropathy:
  • Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
  • Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [Bharucha-Goebel et al 2021].

Electrophysiologic findings

• Nerve conduction studies often show normal to moderately reduced nerve conduction velocity but severely reduced compound motor action potentials and absent sensory nerve action potentials.
• Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responses are often abnormal

Brain imaging

• Classic giant axonal neuropathy. In early stages of classic GAN, brain MRI shows hyperintense signal in the cerebellar white matter surrounding the dentate nucleus [Bharucha-Goebel et al 2021]. As the condition advances, high signals on T₂- weighted sequences in the anterior and posterior periventricular regions as well as in the cerebellar white matter are often seen [Demir et al 2005, Echaniz-Laguna et al 2020, Bharucha-Goebel et al 2021].
  Brain MRI and magnetic resonance spectroscopy (MRS) reveal evidence of significant demyelination and glial proliferation in the white matter, but no neuroaxonal loss [Brenner et al 2008, Ravishankar et al 2009].
• Intermediate phenotype. MRI shows mild and diffuse T₂-weighted signal abnormalities in the posterior limb of the internal capsule and periventricular white matter. Infratentorial signal abnormalities are observed in the dentate nucleus and middle cerebellar peduncle [Abu-Rashid et al 2013].
• Milder phenotypes. Brain MRI findings vary from normal in most individuals to signs of mild cerebral and cerebellar atrophy [Zemmouri et al 2000, Aharoni et al 2016, Koichihara et al 2016, Bharucha-Goebel et al 2021].

Milder phenotypes of GAN-related neurodegeneration could be considered in individuals with early-onset peripheral motor and sensory neuropathy where work up for Charcot-Marie-Tooth disorders has proved inconclusive.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of GAN-related neurodegeneration is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in GAN identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic GAN variants of uncertain significance (or identification of one known GAN pathogenic variant and one GAN variant of uncertain significance) does not establish or rule out a diagnosis of GAN-related neuropathy.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (Option 1), whereas genomic testing does not (Option 2).

Clinical Description

GAN-related neurodegeneration, caused by biallelic GAN pathogenic variants, encompasses a phenotypic continuum ranging from classic giant axonal neuropathy (GAN) – a neurodegenerative disorder affecting both the peripheral and central nervous systems at the severe end – to milder phenotypes with early-onset peripheral motor and sensory neuropathy with or without other findings. These phenotypes do not necessarily run true in families; in one family, phenotypes in family members with the same biallelic GAN pathogenic variants ranged from classic giant axonal neuropathy to milder peripheral neuropathy presentations [Tazir et al 2009].

To date, approximately 50 families have been identified with biallelic GAN pathogenic variants [Ben Hamida et al 1990, Zemmouri et al 2000, Kuhlenbäumer et al 2002, Abu-Rashid et al 2013, Koichihara et al 2016, Aharoni et al 2016, Hoebeke et al 2018, Didonna & Opal 2019, Echaniz-Laguna et al 2020, Bharucha-Goebel et al 2021].

Table 2 outlines the findings of classic giant axonal neuropathy, the first described phenotype, which is now known to be at the severe end of the GAN-related neurodegeneration phenotypic continuum.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported for GAN-related neurodegeneration. Famiy members with the same pathogenic variant who had different clinical phenotypes have been reported [Tazir et al 2009].

Nomenclature

The term "axonal CMT (plus) syndrome" may be used to refer to predominantly motor and sensory neuropathy phenotypes (with little to no CNS involvement) that overlap with axonal forms of Charcot-Marie-Tooth neuropathy [Bharucha-Goebel et al 2021].

Prevalence

To date, about 50 families with GAN-related neurodegeneration have been reported worldwide. The actual prevalence is not known.

Hereditary Disorders in the Differential Diagnosis of Classic Giant Axonal Neuropathy

At onset, classic giant axonal neuropathy (GAN) presents with features (e.g., neuropathic deficits, giant axons, and neurofilament aggregation) similar to those associated with several severe, early-onset hereditary motor and sensory neuropathies [Lescouzères & Bomont 2020]. These neuropathies and other disorders of interest in the differential diagnosis of classic GAN are summarized in Table 3.

Differential Diagnosis of Milder GAN-Related Neurodegeneration Phenotypes

Milder GAN-related neurodegeneration phenotypes overlap with Charcot-Marie-Tooth (CMT) hereditary neuropathy and should be considered in the broader differential diagnosis of CMT. More than 80 different genes are associated with CMT (see Causes of Charcot-Marie-Tooth Hereditary Neuropathy) with a subset of these associated with giant axons, even more closely mimicking GAN-related neurodegeneration [Fabrizi et al 2004, Azzedine et al 2006, Ylikallio et al 2013, Klein et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GAN-related neurodegeneration, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care is focused on managing the clinical findings of the individual, and often involves a team including (pediatric) neurologists, orthopedic surgeons, physiotherapists, occupational and physical therapists, psychologists, and speech-language pathologists. Major goals are to optimize intellectual and physical development.

Surveillance

Surveillance is individualized and involves monitoring response to ongoing interventions and identifying new manifestations. Surveillance may involve some or all of the recommendations in Table 6.

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 ClinicalTrials.gov 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.

Mode of Inheritance

GAN-related neurodegeneration is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are typically heterozygotes (i.e., carriers of one GAN pathogenic variant).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GAN pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent:
  • And the child has compound heterozygous GAN pathogenic variants, the child may have one inherited variant and one de novo pathogenic variant [Shi et al 2020].
  • And the child appears to have homozygous GAN pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy for chromosome 16 [Miyatake et al 2015].
• Heterozygotes are clinically 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

• If both parents are known to be heterozygous for a GAN pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Significant intrafamilial clinical variability has been reported in GAN-related neurodegeneration. In one family, phenotypes in family members with the same biallelic GAN pathogenic variants ranged from classic giant axonal neuropathy to milder peripheral neuropathy presentations [Tazir et al 2009].
• If the proband has GAN-related neurodegeneration as the result of uniparental isodisomy, only one parent is heterozygous for a GAN pathogenic variant, and neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being a clinically asymptomatic carrier and an approximately 50% chance of being unaffected and not a carrier; the risk to sibs of a proband of being affected is unknown but is presumed to be less than 1%.

Offspring of a proband

• Individuals with classic giant axonal neuropathy are not known to reproduce.
• The offspring of an individual with a milder GAN-related neurodegeneration phenotype are obligate heterozygotes (carriers) for a pathogenic variant in GAN.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for a GAN pathogenic variant, the parent's family members are at risk of being carriers.

Carrier Detection

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

Note: Some clinically asymptomatic 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 and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GAN encodes gigaxonin, a BTB-Kelch protein [Adams et al 2000]. Gigaxonin controls the turnover of specific proteins by targeting them to the proteasome for degradation. While all the substrates have yet to be identified, a key substrate, cytoskeletal intermediate filaments, which include neurofilaments (NFs), have been found to accumulate in neurons and glial fibrillary acidic protein (GFAP) in glial cells [Opal & Goldman 2013, Israeli et al 2016, Didonna & Opal 2019]. Accumulation of these proteins impairs mitochondrial bioenergetics, organelle motility, and cell survival [Israeli et al 2016]. Although gigaxonin also interacts 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, Cleveland et al 2009], studies suggest that they do not play an important role in GAN-related neurodegeneration. More recent evidence suggests that GAN controls the levels of Atg16L involved in autophagy [Scrivo et al 2019].

Mechanism of disease causation. Loss of function

Author Notes

An overview of current work in the lab and contact information can be found on our website.

Acknowledgments

We acknowledge the generous funding from the Hannah’s Hope Fund, the Muscular Dystrophy Association, and the NIH, which supports our ongoing research and understanding of GAN-related neurodegeneration and other neurologic disorders.

Author History

Pascale Bomont, PhD; Institute for Neurosciences of Montpellier (2012-2021)
Gregor Kuhlenbäumer, MD, PhD; University of Kiel (2003-2021)
Puneet Opal, MD, PhD (2021-present)
Vincent Timmerman, PhD; University of Antwerp (2003-2021)

Revision History

• 14 October 2021 (bp) Comprehensive update posted live
• 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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