Giant Axonal Neuropathy

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2021-01-18
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Summary

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.

Diagnosis/testing.

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.

Management.

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.

Diagnosis

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
1.

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

2.

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.

3.

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).

4.

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.

5.

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].

Histopathology

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.

Pathophysiology

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.

Prevalence

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.

Management

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.

Surveillance

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 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.