|Year : 2018 | Volume
| Issue : 4 | Page : 304-308
Giant axonal neuropathy: Clinical, radiological, and genetic features
Meenal Garg1, Shilpa D Kulkarni1, Anaita Udwadia Hegde1, Margi Desai2, Rafat J Sayed1
1 Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, India
2 Consultant Electrophysiologist, SRL Diagnostics, Mumbai, India
|Date of Web Publication||2-Nov-2018|
Dr. Meenal Garg
Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Giant axonal neuropathy (GAN) is an inherited neurodegenerative disorder caused by mutations in the GAN gene. It affects both the central and peripheral nervous systems. We discuss clinical, electrophysiological, radiological and genetic features in three new unrelated patients with GAN. Methods: Three pediatric patients with suspected GAN were included. The diagnosis was considered in patients with early onset polyneuropathy and characteristic hair with central nervous system involvement or suggestive neuroimaging findings. Biochemical, metabolic and electrophysiological investigations were performed. Diagnosis was confirmed by targeted sequencing of the GAN gene. Results: All the three patients were found to have biallelic mutations in GAN gene. Peripheral neuropathy, characteristic hair, and cerebellar dysfunction were present in all three while bony deformities, cranial nerve involvement and intellectual disability were seen variably. Neuroimaging showed a spectrum of findings which are discussed. Conclusion: GAN is a clinically and radiologically heterogeneous disease where genetic testing is necessary for a definite diagnosis and counselling. With facilities for testing becoming increasingly available, the spectrum is likely to expand further.
Keywords: Giant axonal neuropathy, gigaxonin, hereditary neuropathy, GAN, magnetic resonance imaging, sensory neuropathy
|How to cite this article:|
Garg M, Kulkarni SD, Hegde AU, Desai M, Sayed RJ. Giant axonal neuropathy: Clinical, radiological, and genetic features. Ann Indian Acad Neurol 2018;21:304-8
|How to cite this URL:|
Garg M, Kulkarni SD, Hegde AU, Desai M, Sayed RJ. Giant axonal neuropathy: Clinical, radiological, and genetic features. Ann Indian Acad Neurol [serial online] 2018 [cited 2020 Jun 6];21:304-8. Available from: http://www.annalsofian.org/text.asp?2018/21/4/304/244879
| Introduction|| |
Giant axonal neuropathy (GAN; OMIM: #256850) is an inherited degenerative disorder which affects both central and peripheral nervous systems. It is an autosomal recessive disorder caused by biallelic mutations in the GAN gene located on chromosome 16q24.1 which encodes gigaxonin, a subunit of E3 ubiquitin ligase. The disease was named after the characteristic giant axons seen on nerve biopsy. However, nerve biopsy alone is considered insufficient for the diagnosis as similar appearance may be seen in other disorders also., We describe three new Indian patients with GAN and compare their clinical, radiological, electrophysiological, and genetic features.
| Methods|| |
Three unrelated children who were suspected clinically of the diagnosis of GAN were included in the study. The diagnosis of GAN was suspected based on the following criteria: early onset polyneuropathy and distinctive hair (tightly curled/kinky/lacklustre and markedly different from parents), in the additional presence of central nervous system (CNS) involvement or suggestive magnetic resonance imaging (MRI) findings. Intellectual disability, seizures, cerebellar signs and optic atrophy were considred markers of CNS involvement. MRI features taken into consideration included abnormalities of cerebral and cerebellar white matter, and dentate nucleus abnormalities.
Electromyography (EMG), nerve conduction studies (NCS), and electroencephalography (EEG) were done in all patients. Other investigations included ophthalmological examination, routine metabolic tests, cerebrospinal fluid (CSF) examination, and MRI of the brain in all patients. Very long-chain fatty acid analysis was done in one patient. Nerve biopsy was refused by the caretakers in each case. Genetic diagnosis was made by targeted sequencing of GAN gene in all patients. Parents were then tested for carrier status.
| Results|| |
[Table 1] compares clinical features of the three patients.
Patient 1 is a 12-year-old Muslim girl born of a third-degree consanguineous marriage, with normal birth and early development. She presented with progressive gait imbalance since 5 years of age, pes cavus, loss of fine motor skills, and slowing of speech. Examination showed coarse woolly hair [Figure 1], cerebellar signs, absence of deep tendon reflexes, positive Babinski sign, and loss of posterior column sensations.
Patient 2 is an 11-year-old Muslim girl also born of third-degree consanguineous parents. She was a preterm very low-birth-weight child and the second of twins, with a prolonged stay in neonatal intensive and special care units. She demonstrated gross global developmental delay since infancy and had a history of 2 episodes of seizures at 5 years of age. She then developed progressive gait and postural imbalance beginning at around 5–6 years. She is intellectually disabled and stunted and underweight (both weight and height <3rd percentile for age and sex). She is mildly dysmorphic with arched eyebrows, triangular facies, and retrognathia and has coarse frizzy hair [Figure 1]. Hypotonia, facial weakness, nystagmus, scoliosis, bilateral tendo-achilles contractures, absent tendon reflexes, and equivocal plantar response were noted on examination.
Patient 3 is a 12-year-old Hindu girl born of nonconsanguineous marriage with a normal birth history. She had delayed early mental and motor development and started losing her acquired motor milestones around 4–5 years of age. She developed increasing gait difficulty culminating in inability to stand and sit without support. She has facial and bulbar involvement, mental retardation, kinky hair [Figure 1], and short stature. Scoliosis, foot deformities, neuropathy, and cerebellar signs were also noted.
Nerve conduction studies/electromyography
[Table 2] compares the electrophysiological findings in the three patients. All three patients showed axonal type of sensorimotor polyneuropathy. For two patients, older NCS records were available and demonstrated a progressive axonal neuropathy, initially sensory and later involving motor neurons also. EMG demonstrated findings of chronic denervation with partial reinnervation.
Metabolic tests/cerebrospinal fluid
Metabolic tests including routine blood analysis, lactates, ammonia, Vitamin B12, Vitamin E, and CSF analysis were normal in all patients. Very long-chain fatty acids were analyzed in patient 2 suspecting a peroxisomal disorder and were also normal.
EEG was abnormal in patient 2 showing epileptiform discharges in the form of spikes and sharp waves in posterior regions with a normal sleep background; this patient also had a history of seizures. The other two patients had a normal EEG.
Magnetic resonance imaging
MRI of the brain was abnormal in all the three patients. Patient 1 had extensive T2/fluid-attenuated inversion recovery (FLAIR) hyperintense and T1 hyperintense periventricular white matter changes without restricted diffusion or contrast enhancement [Figure 2]d. Similar changes were seen in dentate nucleus and medulla with sparing of basal ganglia and thalami. Superior cerebellar peduncles were mildly involved. T2-weighted spinal MRI did not reveal any abnormality.
|Figure 2: Magnetic resonance imaging brain. (a-c) T2-weighted axial section, T2-weighted sagittal section, and fluid-attenuated inversion recovery axial section of patient 2 showing demyelination in frontoparietal and cerebellar white matter. Cavum septum pellucidum is seen. Dentate nucleus and globus pallidus hyperintensities are appreciated. (d) Extensive periventricular white matter hyperintense changes seen on fluid-attenuated inversion recovery axial section of patient 1. (e and f) Fluid-attenuated inversion recovery axial sections show involvement of dentate nucleus and parieto-occipital white matter in patient 3|
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Patient 2 had patchy T2 hyperintense lesions in the cerebellar white matter and frontal and parietal white matter. Ill-defined T2 hyperintensities were seen in basal ganglia, mainly the globus pallidus. Heterogeneous lesions were seen in dentate nucleus, with central hyperintensity and peripheral T2 hypointense and T1 hyperintense lesions. Cavum septum pellucidum was noted [Figure 2]a,[Figure 2]b,[Figure 2]c. Subtle calcification was seen in dentate nuclei and bilateral thalami on computerized tomography scans. Magnetic resonance spectroscopy (MRS) showed few tiny lactate peaks in basal ganglia. No restricted diffusion was seen. Screening spinal MRI was normal.
MRI of patient 3 [Figure 2]e and [Figure 2]f showed T2 hyperintense changes in the parieto-temporo-occipital periventricular white matter, cerebellar white matter, and dentate nucleus with white matter volume loss.
Targeted sequencing of GAN gene was done in all three patients. In patient 1, a homozygous single base-pair insertion in exon 3 of the GAN gene (chr16:81388261-81388262insA) that results in a frameshift and premature truncation of the protein 6 amino acids downstream to codon 180 (p. Glu180ArgfsTer6) was detected. Her parents are heterozygote carriers of this mutation. In view of clinical and investigational profile and predicted damaging nature of the mutation, it is considered causative of the disease.
Patient 2 had a homozygous nonsense variation in exon 3 (chr16:81388211) which causes premature truncation of the protein at codon 162 (p. Arg162Ter). Patient 2 showed a nonsense truncating homozygous mutation of GAN gene which has been previously reported in a Japanese patient with GAN. Parents were heterozygous carriers for the mutation.
In patient 3, heterozygous missense variations were detected. The first was in exon 9 of the GAN gene (chr16:81399058; G > G/A) that results in the amino acid substitution of lysine for glutamic acid at codon 493 (p. Glu493 Lys). The second mutation was located in exon 11 (chr16:81411134; C > C/A;) that results in the amino acid substitution of glutamic acid for alanine at codon 576 (p. Ala576Glu;). Patient 3 has missense heterozygous mutations, one of which has been recently reported as pathogenic in a patient with GAN. In view of strong clinical suspicion and the fact that parents are carriers of these mutations, it is likely that the other mutation is a novel missense mutation for GAN.
In all the three patients, genetic testing was then extended to include other hereditary neuropathies and related neurological disorders; this was especially important in view of consanguinity. However, no other pathological mutations except in GAN gene were found in any of the patients. None of the carriers were symptomatic.
| Discussion|| |
GAN is a rare, fatal neurodegenerative disorder. It results from mutations in the gene encoding gigaxonin, but the exact pathogenic mechanisms underlying the disease are unclear. Gigaxonin belongs to the BTB-KELCH domain family of E3 ubiquitin ligases and is involved in degrading protein substrates through the ubiquitin-proteasome system. Three types of filaments, namely, intermediate filaments, neurofilaments, and glial filaments have been found to be abnormal in GAN. Histologically, aggregates of abnormal filaments have been found in the giant axons. Recent studies suggest that patients with GAN lack the ability to degrade these filaments which secondarily cause the disease manifestations.
All patients presented with the phenotype of early-onset predominantly sensory neuropathy, cerebellar signs, and typical hair. These are the most commonly described phenotypic features in GAN.,, However, they differed in many other clinical features. Two patients had developmental delay right from infancy. One of them also had a significant perinatal history but no suggestive MRI features of the same; thus, it is unclear whether this contributed to her pathology. All children began with gait abnormalities slowly progressing to significant motor difficulties, sometimes accompanied by scoliosis and foot deformities. Two patients had cranial nerve involvement in the form of facial nerve involvement and one had bulbar signs. Extensive cranial nerve involvement has been described in GAN. Seizures were seen in one patient and mental retardation in two. Patient 1 did not have any clinical features of CNS disease and presented with a pure peripheral disease. However, MRI features showed white matter and cerebellar involvement. Such subclinical CNS involvement in GAN has been described previously also. Thus, although GAN involves both CNS and PNS, clinically it may rarely resemble a pure peripheral or CNS disease. Precocious puberty is another feature which has been reported in female children with GAN, but none of our patients manifested the same.
NCS and EMG demonstrated an axonal sensorimotor neuropathy characteristic of GAN initially involving sensory followed by motor neurons.,, The neuropathy is relentlessly progressive and disabling. Secondary demyelination has been previously described but was not seen in our patients.
Patient 2 had an abnormal EEG. Old EEG done at 5 years of age (at the time of seizures) showed generalized burst of epileptiform activity, sharp waves and spikes in the posterior region, and slowing in posterior regions. EEG at the time of diagnosis showed only posterior spikes and sharp waves with intermittent slowing. Demir et al. reported focal or generalized EEG abnormalities characterized by sharp wave paroxysms, sharp and slow wave, and spike-slow wave discharges in 3 out of their 6 patients, but none of them had seizures.
MRI in the 3 patients represented a heterogeneous picture but was contributory to the suspicion of GAN in each patient. White matter demyelination in the anteroposterior periventricular regions, frontoparietal regions, parieto-occipital regions, and cerebellum,,, is commonly reported feature in patients with GAN. Subcortical white matter involvement is rare, and was also not seen in our patients. Corpus callosal abnormalities were seen in one patient and have also been reported earlier. Thalamic abnormalities have been previously described, but we did not find any reports of calcification in thalami and dentate nucleus as were seen in patient 2. This patient also showed T2 hyperintense signals in basal ganglia which have not been reported although Ravishankar et al. described a single patient with T1 hyperintense globus pallidus abnormality. We did not find any significant MRS abnormalities in patient 2 which have been described before., There were also no diffusion abnormalities in the two patients.
Genetically, all patients showed homozygous or heterozygous biallelic point mutations in GAN gene and their parents were found to be harboring the same mutations, some of which have not been described before. No deletions and duplications were noted. In view of clinical feature and carrier status of patients, these mutations are very likely to be pathogenic. Furthermore, the absence of any other pathogenic mutations seen in the extended panel leads credence to the pathogenicity of GAN mutations. In an endogamous Indian population, it is likely that many more of such mutations are waiting to be discovered.
| Conclusion|| |
GAN is a clinically, radiologically, and genetically heterogeneous disease with an expanding clinical and genetic spectrum., Patients classically present with central as well as peripheral nervous system involvement but either of them may be subclinical. In addition, the nonspecificity of giant axons for diagnosis and recent evidence of overlap with Charcot–Marie–Tooth disease further complicate the picture.
Although there is no effective treatment at present, diagnosis is important for genetic counseling and to avoid other unnecessary testing. As genetic diagnosis becomes more common and techniques are refined, it is likely that more patients and newer presentations will be seen. Insights into pathological and genetic mechanisms may pave the way for discovering treatment options in this devastating disease.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kuhlenbaumer G, Timmerman V, Bomont P. Giant axonal neuropathy. Gene Rev 2013 (updated 2014). In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Bean LJH, Stephens K, et al
., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2016.
Asbury AK, Gale MK, Cox SC, Baringer JR, Berg BO. Giant axonal neuropathy – A unique case with segmental neurofilamentous masses. Acta Neuropathol 1972;20:237-47.
Sabatelli M, Bertini E, Ricci E, Salviati G, Magi S, Papacci M, et al.
Peripheral neuropathy with giant axons and cardiomyopathy associated with desmin type intermediate filaments in skeletal muscle. J Neurol Sci 1992;109:1-0.
Fabrizi GM, Cavallaro T, Angiari C, Bertolasi L, Cabrini I, Ferrarini M, et al.
Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology 2004;62:1429-31.
Akagi M, Mohri I, Iwatani Y, Kagitani-Shimono K, Okinaga T, Sakai N, et al.
Clinicogenetical features of a Japanese patient with giant axonal neuropathy. Brain Dev 2012;34:156-62.
Koichihara R, Saito T, Ishiyama A, Komaki H, Yuasa S, Saito Y, et al.
A mild case of giant axonal neuropathy without central nervous system manifestation. Brain Dev 2016;38:350-3.
Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-cullin 3-roc1 ubiquitin ligases. Nat Cell Biol 2003;5:1001-7.
Gordon N. Giant axonal neuropathy. Dev Med Child Neurol 2004;46:717-9.
Mahammad S, Murthy SN, Didonna A, Grin B, Israeli E, Perrot R, et al.
Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. J Clin Invest 2013;123:1964-75.
Demir E, Bomont P, Erdem S, Cavalier L, Demirci M, Kose G, et al.
Giant axonal neuropathy: Clinical and genetic study in six cases. J Neurol Neurosurg Psychiatry 2005;76:825-32.
Ouvrier RA. Giant axonal neuropathy. A review. Brain Dev 1989;11:207-14.
Larbrisseau A, Jasmin G, Hausser C, Brochu P, Geoffroy G. Generalized giant axonal neuropathy-a case with features of Fazio-Londe disease. Neuropadiatrie 1979;10:76-86.
Malandrini A, Dotti MT, Battisti C, Villanova M, Capocchi G, Federico A, et al.
Giant axonal neuropathy with subclinical involvement of the central nervous system: Case report. J Neurol Sci 1998;158:232-5.
Ben Hamida M, Hentati F, Ben Hamida C. Giant axonal neuropathy with inherited multisystem degeneration in a Tunisian kindred. Neurology 1990;40:245-50.
Richen P, Tandan R. Giant axonal neuropathy: Progressive clinical and radiologic CNS involvement. Neurology 1992;42:2220-2.
Ravishankar S, Goel G, Rautenstrauss CP, Nalini A. Spectrum of magnetic resonance imaging findings in a family with giant axonal neuropathy confirmed by genetic studies. Neurol India 2009;57:181-4.
] [Full text]
Brockmann K, Pouwels PJ, Dechent P, Flanigan KM, Frahm J, Hanefeld F, et al.
Cerebral proton magnetic resonance spectroscopy of a patient with giant axonal neuropathy. Brain Dev 2003;25:45-50.
Tazir M, Nouioua S, Magy L, Huehne K, Assami S, Urtizberea A, et al.
Phenotypic variability in giant axonal neuropathy. Neuromuscul Disord 2009;19:270-4.
Tazir M, Vallat JM, Bomont P, Zemmouri R, Sindou P, Assami S, et al.
Genetic heterogeneity in giant axonal neuropathy: An Algerian family not linked to chromosome 16q24.1. Neuromuscul Disord 2002;12:849-52.
Aharoni S, Barwick KE, Straussberg R, Harlalka GV, Nevo Y, Chioza BA, et al.
Novel homozygous missense mutation in GAN associated with charcot-marie-tooth disease type 2 in a large consanguineous family from Israel. BMC Med Genet 2016;17:82.
[Figure 1], [Figure 2]
[Table 1], [Table 2]