Journal http://jcn.sagepub.com/ of Child Neurology
Giant Axonal Neuropathy Kadambari Vijaykumar, Parayil Sankaran Bindu, Arun B. Taly, Anita Mahadevan, Rose Dawn Bharath, Narayanappa Gayathri, Madhu Nagappa and Sanjib Sinha J Child Neurol published online 11 September 2014 DOI: 10.1177/0883073814547721 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/09/10/0883073814547721
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Sep 11, 2014 What is This?
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
Article Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814547721 jcn.sagepub.com
Giant Axonal Neuropathy Kadambari Vijaykumar, MBBS1, Parayil Sankaran Bindu, MD, DM1, Arun B. Taly, MD, DM1, Anita Mahadevan, MD2, Rose Dawn Bharath, DM3, Narayanappa Gayathri, PhD2, Madhu Nagappa, MD, DM1, and Sanjib Sinha, MD, DM1
Abstract Giant axonal neuropathy is an autosomal recessive disorder of childhood with distinct morphological features. An 8-year-old boy presented with progressive walking difficulty and recurrent falls. Evaluation showed frizzy hair, characteristic facies, sensory motor neuropathy, and ataxia. Magnetic resonance imaging (MRI) showed bilateral symmetric white matter signal changes in the cerebellum and periventricular regions along with involvement of the posterior limb of the internal capsule. Sural nerve biopsy demonstrated giant axons with neurofilament accumulation. The clinicopathologic manifestations of giant axonal neuropathy are discussed along with the clinical and histologic differential diagnoses. Keywords Giant axonal neuropathy, Frizzy hair, Leukoencephalopathy Received May 01, 2014. Received revised July 23, 2014. Accepted for publication July 25, 2014.
Giant axonal neuropathy (GAN, OMIM #256850) is a rare neurodegenerative disorder of childhood with severe central and peripheral nervous system manifestations.1 It is caused by the recessive mutations in the giant axonal neuropathy gene (GAN) located in chromosome 16q24. The gene encodes gigaxonin, a protein linked to the dynamics of intermediate filaments and cytoskeletal framework.2 The clinicopathologic manifestations of giant axonal neuropathy are discussed with an illustrative example.
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. 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
1
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India 2 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India 3 Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India Corresponding Author: Parayil Sankaran Bindu, MD, DM, Department of Neurology, NIMHANS, Bangalore, Karnataka, India. Email: [email protected]
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
2
Journal of Child Neurology
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)
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 mm in size, but are typically 20 to 30 mm 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 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
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
Vijaykumar et al
3
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 Axonal type of neuropathy; giant axons on Age of onset: infancy to childhood; peripheral peripheral nerve biopsy; mutations in neuropathy presenting with foot deformities, neurofilament light chain gene (NEFL) high-stepping gait, clawing of hand episodic deterioration Demyelinating type of neuropathy; Peripheral neuropathy typically affecting lower Charcot-Marie-Tooth hypomyelination and onion bulbs on sural nerve extremities earlier and more severely than the disease type 4A biopsy; mutations in the ganglioside-induced upper extremities; age of onset: infancy to early (CMT4A) differentiation-associated protein 1 gene childhood; progressive course leading to disability (GDAP1) within the first or second decade Ophthalmoplegia, vocal cord paralysis; facial/bulbar Characterized by myelin outfoldings seen on Charcot-Marie-Tooth nerve biopsy; mutations in myotubularinweakness; scoliosis; proximal/distal weakness; disease type 4B related protein 2 gene (MTMR2); Charcotabnormal auditory evoked potentials (CMT4B) Marie-Tooth type 4B1 gene (CMT4B1) or SET binding factor 2 gene (SBF2) Demyelinating neuropathy with onset in the first or Giant axons and neurofilament accumulation on Charcot-Marie-Tooth nerve biopsy; mutations in SH3 domain and second decade, scoliosis and respiratory disease type 4C tetratricopeptide repeats 2 gene (SH3TC2) compromise (CMT4C) Charcot-Marie-Tooth disease Autosomal recessive severe congenital Giant axons on nerve biopsy; early growth type 4E (CMT4E) hypomyelinating neuropathy response protein 2 gene (EGR2) Charcot-Marie-Tooth disease type 2E (CMT 2E)
Disorders with both peripheral and central nervous system involvement Infantile neuroaxonal dystrophy
Metachromatic leukodystrophy
Characteristic pathologic feature of axonal Infancy-onset disorder with prominent central and spheroids made of vesiculotubular structures peripheral nervous system involvement resembling and tubular membranous material with clefts on giant axonal neuropathy but without the nerve or skin biopsy; mutations in the characteristic hair changes phospholipase A2 gene group VI (PLA2G6) Deficiency of the lysosomal enzyme arylsulfatase Autosomal recessive lysosomal storage disorder A; characteristic finding of metachromatic with both central and peripheral nervous system deposits on nerve biopsy; bilateral symmetric involvement; late-infantile form presents with white matter signal changes on magnetic clumsiness and gait difficulty; later on complete resonance imaging; molecular testing of the aryl regression of milestones, leading to spasticity; sulfatase A gene (ARSA) juvenile form often has cognitive and behavioral changes; demyelinating peripheral neuropathy characteristically associated
Disorders with same hair abnormalities as giant axonal neuropathy Menkes syndrome
Rare X-linked recessive disorder with prominent Low serum copper and ceruloplasmin; hair central nervous system involvement and short microscopy: pili torti; tortuous blood vessels sparse, coarse twisted often lightly pigmented hair. on magnetic resonance angiography; mutations Often present at the age of 2- 3 mo with loss of in the copper-transporting ATPase gene developmental milestones, hypotonia, and failure to thrive
Disorders with pathologic findings of giant axons Toxic neuropathies
Mixed axonal and demyelinating peripheral neuropathy caused by industrial toxins Charcot-Marie-Tooth disease Same as above type 2E, 4C, and 4E BAG3-associated myofibrillar Rapidly progressive proximal and axial myopathy, myopathy cardiomyopathy, and respiratory compromise along with sensorimotor axonal neuropathy
History of occupational exposure to the toxins Same as above Mutations in Bcl-2-associated athanogene-3 (BAG3); features of myofibrillar myopathy on muscle biopsy
Abbreviation: CMT, Charcot-Marie-Tooth.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
4
Journal of Child Neurology
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.
3. 4.
Author Contributions ABT and PSB conceived the idea of the study, designed the study, supervised the study, interpreted the data, and drafted and revised the manuscript content. KV wrote the first draft. SS and MN were involved in the clinical care of the patient. RDB provided input for the imaging studies, and AM and NG for the pathologic studies. All participated in revisions and editing.
5.
6.
Acknowledgments Authors express sincere gratitude to parents of the patient for giving consent for publication of this information.
7.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
8.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
9.
Ethical Approval The study was approved by the institutional ethics committee, approval number: NIMHANS/68th IEC/2010:10.07).
10.
References
11.
1. Demir E, Bomont P, Erdem S, et al. Giant axonal neuropathy: clinical and genetic study in six cases. J Neurol Neurosurg Psychiatry. 2005;76:825-832. 2. Bomont P, Cavalier L, Blondeau F, et al. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family
12.
is mutated in giant axonal neuropathy. Nat Genet. 2000;26: 370-374. Berg BO, Rosenburg SH, Asbury AK. Giant axonal neuropathy. Pediatrics. 1972;49:894-899. Nalini A, Gayathri N, Yasha TC, et al. Clinical, pathological and molecular findings in two siblings with giant axonal neuropathy (GAN): report from India. Eur J Med Genet. 2008;51: 426-435. Israni A, Chakrabarty B, Gulati S, et al. Giant axonal neuropathy: clinicoradio-pathological diagnosis. Neurology. 2014;82: 816-817. Roth LA, Johnson-Kerner BL, Marra JD, Lamarca NH, Sproule DM. The absence of curly hair is associated with a milder phenotype in giant axonal neuropathy. Neuromuscul Disord. 2014;24:48-55. Carpenter S, Karpati G, Andermann F, Gold R. Giant axonal neuropathy. A clinically and morphologically distinct neurological disease. Ann Neurol. 1974;31:312-316. Bilbao JM, Schmidt R, Hawkins C. Giant axonal neuropathy. In: Love S, Louis D, Ellison DW, eds. Diseases of Peripheral Nerve. Greenfield’s Neuropathology. 8th ed. London: Hodder Arnold; 2008:1647-1648. KuhlenbSˇumer G, Timmerman V, Bomont P. Giant axonal neuropathy. GeneReviewsÔ. January 9, 2003 [updated June 2012]. Wilmshurst JM, Ouvrier R. Hereditary peripheral neuropathies of childhood: an overview for clinicians. Neuromuscul Disord. 2011;21:763-775. Jaffer F, Murphy SM, Scoto M, et al. BAG3 mutations: another cause of giant axonal neuropathy. J Peripher Nerv Syst. 2012; 17:210-216. Alkan A, Kutlu R, Sigirci A, Baysal T, Altinok T, Yakinci C. Giant axonal neuropathy: MRS findings. J Neuroimaging. 2003; 13:371-375.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
Giant Axonal Neuropathy Kadambari Vijaykumar, Parayil Sankaran Bindu, Arun B. Taly, Anita Mahadevan, Rose Dawn Bharath, Narayanappa Gayathri, Madhu Nagappa and Sanjib Sinha J Child Neurol published online 11 September 2014 DOI: 10.1177/0883073814547721 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/09/10/0883073814547721
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Sep 11, 2014 What is This?
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
Article Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814547721 jcn.sagepub.com
Giant Axonal Neuropathy Kadambari Vijaykumar, MBBS1, Parayil Sankaran Bindu, MD, DM1, Arun B. Taly, MD, DM1, Anita Mahadevan, MD2, Rose Dawn Bharath, DM3, Narayanappa Gayathri, PhD2, Madhu Nagappa, MD, DM1, and Sanjib Sinha, MD, DM1
Abstract Giant axonal neuropathy is an autosomal recessive disorder of childhood with distinct morphological features. An 8-year-old boy presented with progressive walking difficulty and recurrent falls. Evaluation showed frizzy hair, characteristic facies, sensory motor neuropathy, and ataxia. Magnetic resonance imaging (MRI) showed bilateral symmetric white matter signal changes in the cerebellum and periventricular regions along with involvement of the posterior limb of the internal capsule. Sural nerve biopsy demonstrated giant axons with neurofilament accumulation. The clinicopathologic manifestations of giant axonal neuropathy are discussed along with the clinical and histologic differential diagnoses. Keywords Giant axonal neuropathy, Frizzy hair, Leukoencephalopathy Received May 01, 2014. Received revised July 23, 2014. Accepted for publication July 25, 2014.
Giant axonal neuropathy (GAN, OMIM #256850) is a rare neurodegenerative disorder of childhood with severe central and peripheral nervous system manifestations.1 It is caused by the recessive mutations in the giant axonal neuropathy gene (GAN) located in chromosome 16q24. The gene encodes gigaxonin, a protein linked to the dynamics of intermediate filaments and cytoskeletal framework.2 The clinicopathologic manifestations of giant axonal neuropathy are discussed with an illustrative example.
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. 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
1
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India 2 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India 3 Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India Corresponding Author: Parayil Sankaran Bindu, MD, DM, Department of Neurology, NIMHANS, Bangalore, Karnataka, India. Email: [email protected]
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
2
Journal of Child Neurology
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)
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 mm in size, but are typically 20 to 30 mm 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 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
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
Vijaykumar et al
3
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 Axonal type of neuropathy; giant axons on Age of onset: infancy to childhood; peripheral peripheral nerve biopsy; mutations in neuropathy presenting with foot deformities, neurofilament light chain gene (NEFL) high-stepping gait, clawing of hand episodic deterioration Demyelinating type of neuropathy; Peripheral neuropathy typically affecting lower Charcot-Marie-Tooth hypomyelination and onion bulbs on sural nerve extremities earlier and more severely than the disease type 4A biopsy; mutations in the ganglioside-induced upper extremities; age of onset: infancy to early (CMT4A) differentiation-associated protein 1 gene childhood; progressive course leading to disability (GDAP1) within the first or second decade Ophthalmoplegia, vocal cord paralysis; facial/bulbar Characterized by myelin outfoldings seen on Charcot-Marie-Tooth nerve biopsy; mutations in myotubularinweakness; scoliosis; proximal/distal weakness; disease type 4B related protein 2 gene (MTMR2); Charcotabnormal auditory evoked potentials (CMT4B) Marie-Tooth type 4B1 gene (CMT4B1) or SET binding factor 2 gene (SBF2) Demyelinating neuropathy with onset in the first or Giant axons and neurofilament accumulation on Charcot-Marie-Tooth nerve biopsy; mutations in SH3 domain and second decade, scoliosis and respiratory disease type 4C tetratricopeptide repeats 2 gene (SH3TC2) compromise (CMT4C) Charcot-Marie-Tooth disease Autosomal recessive severe congenital Giant axons on nerve biopsy; early growth type 4E (CMT4E) hypomyelinating neuropathy response protein 2 gene (EGR2) Charcot-Marie-Tooth disease type 2E (CMT 2E)
Disorders with both peripheral and central nervous system involvement Infantile neuroaxonal dystrophy
Metachromatic leukodystrophy
Characteristic pathologic feature of axonal Infancy-onset disorder with prominent central and spheroids made of vesiculotubular structures peripheral nervous system involvement resembling and tubular membranous material with clefts on giant axonal neuropathy but without the nerve or skin biopsy; mutations in the characteristic hair changes phospholipase A2 gene group VI (PLA2G6) Deficiency of the lysosomal enzyme arylsulfatase Autosomal recessive lysosomal storage disorder A; characteristic finding of metachromatic with both central and peripheral nervous system deposits on nerve biopsy; bilateral symmetric involvement; late-infantile form presents with white matter signal changes on magnetic clumsiness and gait difficulty; later on complete resonance imaging; molecular testing of the aryl regression of milestones, leading to spasticity; sulfatase A gene (ARSA) juvenile form often has cognitive and behavioral changes; demyelinating peripheral neuropathy characteristically associated
Disorders with same hair abnormalities as giant axonal neuropathy Menkes syndrome
Rare X-linked recessive disorder with prominent Low serum copper and ceruloplasmin; hair central nervous system involvement and short microscopy: pili torti; tortuous blood vessels sparse, coarse twisted often lightly pigmented hair. on magnetic resonance angiography; mutations Often present at the age of 2- 3 mo with loss of in the copper-transporting ATPase gene developmental milestones, hypotonia, and failure to thrive
Disorders with pathologic findings of giant axons Toxic neuropathies
Mixed axonal and demyelinating peripheral neuropathy caused by industrial toxins Charcot-Marie-Tooth disease Same as above type 2E, 4C, and 4E BAG3-associated myofibrillar Rapidly progressive proximal and axial myopathy, myopathy cardiomyopathy, and respiratory compromise along with sensorimotor axonal neuropathy
History of occupational exposure to the toxins Same as above Mutations in Bcl-2-associated athanogene-3 (BAG3); features of myofibrillar myopathy on muscle biopsy
Abbreviation: CMT, Charcot-Marie-Tooth.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
4
Journal of Child Neurology
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.
3. 4.
Author Contributions ABT and PSB conceived the idea of the study, designed the study, supervised the study, interpreted the data, and drafted and revised the manuscript content. KV wrote the first draft. SS and MN were involved in the clinical care of the patient. RDB provided input for the imaging studies, and AM and NG for the pathologic studies. All participated in revisions and editing.
5.
6.
Acknowledgments Authors express sincere gratitude to parents of the patient for giving consent for publication of this information.
7.
Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
8.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
9.
Ethical Approval The study was approved by the institutional ethics committee, approval number: NIMHANS/68th IEC/2010:10.07).
10.
References
11.
1. Demir E, Bomont P, Erdem S, et al. Giant axonal neuropathy: clinical and genetic study in six cases. J Neurol Neurosurg Psychiatry. 2005;76:825-832. 2. Bomont P, Cavalier L, Blondeau F, et al. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family
12.
is mutated in giant axonal neuropathy. Nat Genet. 2000;26: 370-374. Berg BO, Rosenburg SH, Asbury AK. Giant axonal neuropathy. Pediatrics. 1972;49:894-899. Nalini A, Gayathri N, Yasha TC, et al. Clinical, pathological and molecular findings in two siblings with giant axonal neuropathy (GAN): report from India. Eur J Med Genet. 2008;51: 426-435. Israni A, Chakrabarty B, Gulati S, et al. Giant axonal neuropathy: clinicoradio-pathological diagnosis. Neurology. 2014;82: 816-817. Roth LA, Johnson-Kerner BL, Marra JD, Lamarca NH, Sproule DM. The absence of curly hair is associated with a milder phenotype in giant axonal neuropathy. Neuromuscul Disord. 2014;24:48-55. Carpenter S, Karpati G, Andermann F, Gold R. Giant axonal neuropathy. A clinically and morphologically distinct neurological disease. Ann Neurol. 1974;31:312-316. Bilbao JM, Schmidt R, Hawkins C. Giant axonal neuropathy. In: Love S, Louis D, Ellison DW, eds. Diseases of Peripheral Nerve. Greenfield’s Neuropathology. 8th ed. London: Hodder Arnold; 2008:1647-1648. KuhlenbSˇumer G, Timmerman V, Bomont P. Giant axonal neuropathy. GeneReviewsÔ. January 9, 2003 [updated June 2012]. Wilmshurst JM, Ouvrier R. Hereditary peripheral neuropathies of childhood: an overview for clinicians. Neuromuscul Disord. 2011;21:763-775. Jaffer F, Murphy SM, Scoto M, et al. BAG3 mutations: another cause of giant axonal neuropathy. J Peripher Nerv Syst. 2012; 17:210-216. Alkan A, Kutlu R, Sigirci A, Baysal T, Altinok T, Yakinci C. Giant axonal neuropathy: MRS findings. J Neuroimaging. 2003; 13:371-375.
Downloaded from jcn.sagepub.com at CAMBRIDGE UNIV LIBRARY on October 21, 2014
