Giant Axonal Neuropathy

Clinical History and Diagnosis

An 8-year-old boy, from the South Indian state of Andhra Pradesh, presented with complaints of gradually progressive walking difficulty accompanied by weakness starting from the age of 5 years. He was born of consanguineous marriage between first cousins and had a normal birth and developmental history. Between the ages of 5 and 8 years, the symptoms progressed, leading to frequent falls along with difficulty in lifting heavy objects and decreased scholastic performance. On examination, he had thick, black, curly rough (frizzy) hair (Figure 1A), which was significantly different from his parents, and long curly eyelashes. He stood with a characteristic posture formed by the combination of genu valgus, pes equino-valgus, and pes planus. Neurologic examination revealed bilateral partial ptosis, bilateral gaze evoked nystagmus, bifacial weakness, generalized hypotonia, weakness of distal muscles of upper and lower limbs, absent stretch reflexes and extensor plantar response. He also had finger nose incoordination and walked with a broadly based gait. Fundus examination was normal.

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Figure 1.

(A) Clinical photograph shows the “Frizzy” hair that is thick, curly and lackluster. (B) Brain MRI (T2-weighted coronal images) shows bilateral symmetric hyperintense signal changes involving the cerebellar white matter and hilum of the dentate nuclei (arrows). (C) Sural nerve biopsy demonstrates several giant axons of varying sizes. The distended axoplasm is enveloped by attenuated or completely absent myelin sheath (arrows). (D) Electron micrograph showing neurofilament accumulation in the distended axon of myelinated fiber (asterisk) and normal-diameter myelinated nerve fiber (black arrows). Closer view (inset) highlights linear arrays of densely packed neurofilaments in the axoplasm displacing other organelles to the periphery. (C: toluidine blue, ×40; D: uranyl acetate lead citrate, ×5400; D inset: ×28 000)

He was investigated with nerve conduction studies, which showed an axonal sensorimotor neuropathy. Needle electromyography was not carried out. T2-weighted magnetic resonance imaging (MRI) (Figure 1B) showed bilateral symmetric white matter signal changes in the cerebellum and periventricular regions along with involvement of the posterior limb of the internal capsule. Diffusion restriction or contrast enhancement on magnetic resonance imaging were not found. Sural nerve biopsy demonstrated moderate fiber loss with numerous distended axons (Figure 1C) in all the funicles enclosed by thinned out or absent myelin sheaths. Electron microscopy of the nerve biopsy showed giant axons with tightly packed intermediate filaments pushing the other organelles to the periphery (Figure 1D). Molecular genetic testing for mutations in giant axonal neuropathy gene (GAN) was not carried out.

Discussion

Giant axonal neuropathy is an autosomal recessive neurodegenerative disorder of childhood first reported by Asbury and Berg et al. ³ It has been reported worldwide without any racial/ethnic predilection, and the true prevalence is unknown. There are a limited number of reports of giant axonal neuropathy from India. ^4,5 The clinical features in the classical form of giant axonal neuropathy are characterized by onset before 7 years of age, symptoms of a distally predominant peripheral neuropathy, including hypotonia, muscle atrophy, tendon contractures, and areflexia along with signs of central nervous system involvement. ⁶ Cranial nerve palsies resulting in facial weakness, optic atrophy, and ophthalmoplegia are also known to occur. The central nervous system involvement is dominated by signs of cerebellar dysfunction and include nystagmus, dysarthria, dysmetria, and ataxia. The other signs of central nervous system involvement reported include pyramidal tract signs, intellectual disability, and epilepsy. Other less common features include precocious puberty and gastrointestinal manifestations. ^1,6 The less severe form of giant axonal neuropathy has a presentation similar to axonal type of Charcot-Marie-Tooth disease (CMT 2) and has a slowly progressive course. ⁶ Most affected children have tightly curled (frizzy) hair caused by intermediate filament abnormalities. ^1,6 These pilar anomalies occur early, usually before the onset of neurologic signs, and are of diagnostic significance in giant axonal neuropathy. The absence of curly hair has been sometimes reported to be associated with a milder phenotype of giant axonal neuropathy, suggesting that straight-haired patients with giant axonal neuropathy may be potentially underdiagnosed. ⁶

The striking feature of giant axonal neuropathy is the abnormalities in the cytoskeletal network as evidenced by the presence of giant axons associated with the aggregation of neurofilaments on peripheral nerve biopsy. ⁷ Axons that are at least 2 to 3 times the size of normal large-diameter axons is considered pathologic. Giant axons reach up to 50 μm in size, but are typically 20 to 30 μm in size. ⁸ Other than nerve biopsy, gingival and skin biopsies also can show giant axons. Scanning electron micrograph of the hair shafts reveals irregular cuticle, pili torti, and longitudinal grooves.

The differential diagnoses of giant axonal neuropathy include disorders that share its clinical and pathologic features and are shown in Table 1. ^{9 –11} The central nervous system signs correlate with documented magnetic resonance imaging findings of abnormalities in the cerebral and cerebellar white matter. This mainly includes nonspecific neuronal loss, demyelination, and gliosis in the cerebellum and globus pallidus, sometimes extending into the cervical spinal cord. ^1,12

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Table 1.

Clinical and Histopathologic Differential diagnoses of Giant Axonal Neuropathy. ^{9 –11}

Diseases	Clinical features	Diagnostic tests
Early onset Charcot-Marie-Tooth type of hereditary neuropathies
Charcot-Marie-Tooth disease type 2E (CMT 2E)	Age of onset: infancy to childhood; peripheral neuropathy presenting with foot deformities, high-stepping gait, clawing of hand episodic deterioration	Axonal type of neuropathy; giant axons on peripheral nerve biopsy; mutations in neurofilament light chain gene (NEFL)
Charcot-Marie-Tooth disease type 4A (CMT4A)	Peripheral neuropathy typically affecting lower extremities earlier and more severely than the upper extremities; age of onset: infancy to early childhood; progressive course leading to disability within the first or second decade	Demyelinating type of neuropathy; hypomyelination and onion bulbs on sural nerve biopsy; mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1)
Charcot-Marie-Tooth disease type 4B (CMT4B)	Ophthalmoplegia, vocal cord paralysis; facial/bulbar weakness; scoliosis; proximal/distal weakness; abnormal auditory evoked potentials	Characterized by myelin outfoldings seen on nerve biopsy; mutations in myotubularin-related protein 2 gene (MTMR2); Charcot-Marie-Tooth type 4B1 gene (CMT4B1) or SET binding factor 2 gene (SBF2)
Charcot-Marie-Tooth disease type 4C (CMT4C)	Demyelinating neuropathy with onset in the first or second decade, scoliosis and respiratory compromise	Giant axons and neurofilament accumulation on nerve biopsy; mutations in SH3 domain and tetratricopeptide repeats 2 gene (SH3TC2)
Charcot-Marie-Tooth disease type 4E (CMT4E)	Autosomal recessive severe congenital hypomyelinating neuropathy	Giant axons on nerve biopsy; early growth response protein 2 gene (EGR2)
Disorders with both peripheral and central nervous system involvement
Infantile neuroaxonal dystrophy	Infancy-onset disorder with prominent central and peripheral nervous system involvement resembling giant axonal neuropathy but without the characteristic hair changes	Characteristic pathologic feature of axonal spheroids made of vesiculotubular structures and tubular membranous material with clefts on nerve or skin biopsy; mutations in the phospholipase A2 gene group VI (PLA2G6)
Metachromatic leukodystrophy	Autosomal recessive lysosomal storage disorder with both central and peripheral nervous system involvement; late-infantile form presents with clumsiness and gait difficulty; later on complete regression of milestones, leading to spasticity; juvenile form often has cognitive and behavioral changes; demyelinating peripheral neuropathy characteristically associated	Deficiency of the lysosomal enzyme arylsulfatase A; characteristic finding of metachromatic deposits on nerve biopsy; bilateral symmetric white matter signal changes on magnetic resonance imaging; molecular testing of the aryl sulfatase A gene (ARSA)
Disorders with same hair abnormalities as giant axonal neuropathy
Menkes syndrome	Rare X-linked recessive disorder with prominent central nervous system involvement and short sparse, coarse twisted often lightly pigmented hair. Often present at the age of 2- 3 mo with loss of developmental milestones, hypotonia, and failure to thrive	Low serum copper and ceruloplasmin; hair microscopy: pili torti; tortuous blood vessels on magnetic resonance angiography; mutations in the copper-transporting ATPase gene
Disorders with pathologic findings of giant axons
Toxic neuropathies	Mixed axonal and demyelinating peripheral neuropathy caused by industrial toxins	History of occupational exposure to the toxins
Charcot-Marie-Tooth disease type 2E, 4C, and 4E	Same as above	Same as above
BAG3-associated myofibrillar myopathy	Rapidly progressive proximal and axial myopathy, cardiomyopathy, and respiratory compromise along with sensorimotor axonal neuropathy	Mutations in Bcl-2-associated athanogene-3 (BAG3); features of myofibrillar myopathy on muscle biopsy

Abbreviation: CMT, Charcot-Marie-Tooth.

The giant axonal neuropathy gene (GAN) on chromosome 16q24.1 encodes a ubiquitously expressed protein called gigaxonin formed of 2 domains, an N-terminus BTB-POZ domain, and a C-terminus Kelch-repeat domain that stabilizes the microtubule network by directing ubiquitin-mediated degradation of cytoskeletal proteins. ² Several disease-causing mutations were identified in this gene, resulting in loss of function of gigaxonin. The exact role of gigaxonin is not clear, but its loss is thought to produce the large scale disruption of intermediate filament architecture associated with giant axonal neuropathy. ²

The diagnosis of giant axonal neuropathy is established based on the clinical findings supplemented by abnormalities in the nerve conduction studies, brain imaging, pathologic findings and the genetic testing. Although giant axonal neuropathy begins with severe peripheral motor and sensory neuropathy, the disease slowly progresses into central nervous system impairment, leading to profound disability. Patients usually become wheelchair bound in the first or second decade of life and die between the ages of 10 and 30 years. ⁶ The milder form with a peripheral neuropathy presentation often have a longer life span. The management of giant axonal neuropathy, hence, is mainly supportive and aims to optimize both physical and intellectual development and aid activities of daily living. Prevention of secondary complications is imperative in wheelchair bound or bedridden patients with periodic assessment for decubitus ulcers, spasticity, cognition, and cranial nerve dysfunction. Owing to the autosomal recessive pattern of inheritance, genetic counseling proves to be of utmost importance to the families.