JPM, Vol. 13, Pages 91: Genetic Approaches for the Treatment of Giant Axonal Neuropathy

Since the first documented case in 1972, several dozens of patients with GAN have been reported, with a strong clinical heterogeneity and diverse prognosis [2,3,22]. The classic GAN typically manifests as an infantile to early-childhood onset neurodegenerative disorder with a decline in motor and sensory function. During infancy, clinical assessment usually reveals motor and sensory neuropathy with moderate axonal degeneration (Table 1) [2,3,22,23]. Progressive distal motor weakness is the initial symptom in all cases. Diffused muscle atrophy, most predominantly in distal muscles, flaccid, paralysis, severely decreased muscle strength, low muscle tone, and loss of reflexes (areflexia) may be observed as the disease advances (Table 2) [3,22,23,24,25,26,37,38]. Diagnosis of PNS degeneration in early infancy and sensorimotor pathway involvement in teens resemble more commonly inherited peripheral neuropathy called Charcot-Marie-Tooth (CMT) diseases [27]. Owing to similarities in clinical presentation between patients with GAN and CMT or Friedreich ataxia, CTM Disease Pediatric Scale and Friedreich Ataxia Rating Scale and Gross Motor Function measure may be implemented for physical examination [4,37]. Though, making PNS deterioration unique from some of the other peripheral neuropathies, GAN also leads to proximal motor weakness, evidenced by pectoralis chest-wall muscle wasting, winged scapula, and exhibition of myopathic or “waddling” gait disturbances and positive Gower’s sign during the attempt to achieve erect position, indicative of pelvic girdle and quadriceps muscle weakness [2,4,6,25,28]. Consistent with PNS clinical presentation, an electromyogram (EMG) demonstrates neuropathic changes indicative of multiple peripheral nerve damage with chronic denervation, mainly involving the sensorimotor branches of limbs [29]. Nerve conduction studies show markedly decreased to absent compound muscle action potentials and sensory nerve action potentials of the upper and lower limb, and prolonged motor and sensory nerve conduction velocities, even to the demyelinating range [23,25,26,29,39]. The electron microscopy of the sural nerve and skin/muscle fiber biopsy shows abnormally large axons in their paranodal junction and decreased myelinated axons (Table 1) [23,26,40] The general morphology of nerve fibers may be maintained, although lacks normally identifiable sidearms that extend from healthy NF from increased NF packing, which is critical for modulating NF spacing and managing the mechanical integrity of nerve cells [4,41]. The enlarged axons exhibit significantly decreased myelin sheath thickness and are filled with disorganized NF aggregates, distending axon and axoplasm, and widening periaxonal space [26,41]. This causes the pathological hallmark of GAN, a ‘giant’ axon. These axons also contain a reduced number of microtubules and other remaining axonal organelles such as mitochondria are pushed out into sub-axolemmal space [4,6,41]. The swelling can occur both in myelinated and unmyelinated axon fibers, often beginning at the node of Ranvier and having a segmental swelling appearance [2,4]. Some fibers can be found surrounded by basal lamina, which has an important role in regeneration and remyelination [22,42]. This agrees with EMG that shows partial reinnervation beside demyelinated or lesions fibers, especially in the patient with CMT-like presentation [22,29]. Not limited to the disorganization of NF, other types of disorganized intermediate filament (IF) accumulation can be found in various peripheral nerves and cells.GAN also differs from other neuropathies due to CNS involvement including pyramidal signs, positive Babinski signs indicative of deficit in the upper motor neuron, and positive Romberg signs associated with dorsal column lesion (Table 2) [2,22]. Among these, cerebellar involvement is most extensive, including truncal ataxia, incoordination, fine movement impairment, tremor, dysmetria, nystagmus, and oculomotor apraxia [25,37,39]. Cranial nerve impairment is also described in patients with GAN, causing facial weakness, ptosis, and ophthalmoplegia, involving facial, oculomotor, trochlear, and abducens nerves [6,26,29,30]. Many patients have vision loss with optic atrophy, as well as dysarthria, dysphonia, dysphasia, and hearing impairment, reflecting the combination of both central and peripheral dysfunction [25,30]. Severe CNS involvement may include vertigo, intellectual disability, spasticity, seizures/epilepsy, and dementia (Table 2) [4,29,39,40]. Neuroimaging study demonstrates slowly progressive diffuse leukoencephalopathy with demyelination and atrophy, and signal abnormalities throughout cerebrum, cerebellum, and notably in spinal cord [22,30,41]. One of the early signs in disease is the signal abnormalities (increased T2 signal intensity) detected with magnetic resonance imaging (MRI) [25,26,39]. T2 hyperintense lesion involve internal capsule, globus pallidus of the basal ganglia, thalami, brainstem. and spinal cord, where frontoparietal and periventricular white matter and dentate nucleus of cerebellum affected most prominently [25,43]. T1 hyperintense lesion and decreased T1 signal at varying parts of the brain associated with brain atrophy may be also observed. Similarly, the fractional anisotropy value is low reflecting increased diffusivity due to intracellular water increase from axonal distension and demyelination [43]. Spinal cord atrophy in posterior column, medial lemniscus spinocerebellar tracts, and cortical spinal tracts, involving abnormality in inferior olivary, gracile and cuneate nuclei, and cerebellar peduncles along pathways are prominent [40,43]. As axonal transport is impaired, peripheral nerves, posterior columns, cerebellum and pyramidal tracts are most severely affected [4]. Besides axonal loss, loss of Purkinje cells and other neuronal cells are also reported [40]. Secondary demyelination may also be present due to nerve cell body loss [4,26]. In addition to IF aggregations in CNS that leads to aforementioned axonal demyelination and atrophy, there is also a prominent presence of Rosenthal fibers which is an astrocyte pathology described in Alexander disease [6,23,40]. The electroencephalogram (EEG) study further supports clinical signs. Evoked potentials show increased latency in auditory, visual, and somatosensory evoked response, suggesting lesion in brainstem and higher cortices [44]. EEG may also show epileptiform transients discharges in the form of spikes and sharp waves in patient with or without history of epilepsy (Table 1) [26,29]. GAN also alters brain metabolites. Major detectable brain metabolites with magnetic resonance spectroscopy (MRS) include the predominantly neuroaxonal compound N-acetylaspartate (NAA), the energy metabolites creatine and Cho compounds involved in membrane turnover, and osmolyte myoinositol (Ins) [43]. The Cho and Ins typically increase with respect to demyelination and glial proliferation while NAA decreases with axonal damage/loss [43]. While these typical GAN clinical findings are prevalent, individuals with genetically confirmed GAN can be affected more mildly [4,22]. Milder cases can be regarded as CMT-plus phenotype and is becoming increasingly recognized. The disease may present with slow onset and progression of peripheral neuropathy with minimal CNS involvement. [29,39,40,41].GAN is also associated with gastrointestinal (GI) and systemic issues including constipation, reflux, regurgitation, diabetes, renal tubular acidosis, and lactose intolerance [30,32,34,45,46].Some patients may also suffer from precocious puberty, arched feet, scoliosis, tendon contracture, and lumbar hyper-lordosis [8,22,23,25,29]. GAN patients often have a characteristic physical appearance with kinky hair, long eyelashes, a high forehead, pale skin, and facial diplegia [26]. Kinky hair and long eyelashes are frequently observed features but not in all cases and are most likely due to abnormal keratin accumulation (Table 2) [32]. Ichthyosis and keratosis pilaris can also occur, although minor [21]. Despite heterogenicity in phenotype within GAN, the relationship between phenotypic differences and the rate of disease progression is yet to be known.

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