Phenotypic variability in giant axonal neuropathy

Giant axonal neuropathy (GAN), a severe childhood disorder affecting both the peripheral nerves and the central nervous system, is due to mutations in the GAN gene encoding gigaxonin, a protein implicated in the cytoskeletal functions and dynamics. In the majority of the GAN series reported to date, patients had the classical clinical phenotype characterized by a severe axonal neuropathy with kinky hair and early onset CNS involvement including cerebellar and pyramidal signs. We present 12 patients (6 families) with GAN mutations and different clinical phenotypes. Four families were harbouring an identical homozygous nonsense mutation but with different severe clinical phenotypes, one patient had a novel missense homozygous mutation with a peculiar moderate phenotype and prominent skeletal deformations. The last family (4 patients) harbouring a homozygous missense mutation had the mildest form of the disease. In contrast with recent reported series of patients with typical GAN clinical features, the present series demonstrate obvious clinical heterogeneity.     

Giant axonal neuropathy: clinical, electrophysiologic, and neuropathologic features in two siblings

Giant axonal neuropathy is a progressive central-peripheral axonopathy characterized by distention of axons by aggregated neurofilaments. We report two female siblings with giant axonal neuropathy. Both patients developed symptoms of a chronic progressive polyneuropathy at age 3 years. Clinical evidence of central nervous system involvement was present in both cases. Autopsy neuropathologic examination of the older sibling at the age of 11 years revealed numerous giant axons, Rosenthal fibers, and gliosis throughout the brain and spinal cord and typical giant axons in the peripheral nerves. Electrophysiologic studies in the younger sibling indicated brain stem dysfunction, and her sural nerve biopsy revealed enlarged axons packed with neurofilaments. These patients illustrate that neurologic deficits of giant axonal neuropathy result from widespread lesions in the central, as well as peripheral (including autonomic), nervous systems. This occurrence of giant axonal neuropathy in two siblings supports a genetic origin of this disease. This is the first report of autopsy findings in giant axonal neuropathy in an affected sibling.     

Giant axonal neuropathy with inherited multisystem degeneration in a Tunisian kindred

We describe a large kindred of 6 patients with a slowly progressive autosomal recessive form of giant axonal neuropathy (GAN). The propositus presented with progressive infantile onset of distal amyotrophy of 4 limbs, brisk reflexes, diffuse fasciculations, bulbar signs, and deep sensory loss in both lower limbs. The EMG and nerve biopsy showed typical hypertrophic neuritis. In 4 patients, there were giant axons filled with neurofilaments, with normal conduction velocity. In the youngest boy, the neurologic deficit was less severe, and the nerve biopsy revealed only a few unmyelinated axons filled with neurofilaments. These cases appear to represent a different genetic defect from other reported cases of GAN.     

Giant axonal neuropathy: clinical and genetic study in six cases

BACKGROUND: Giant axonal neuropathy (GAN) is a severe recessive disorder characterised by variable combination of progressive sensory motor neuropathy, central nervous system (CNS) involvement, and "frizzly" hair. The disease is caused by GAN gene mutations on chromosome 16q24.1. AIMS: To search for GAN gene mutations in Turkish patients with GAN and characterise the phenotype associated with them. METHODS: Linkage and mutation analyses were performed in six affected patients from three consanguineous families. These patients were also investigated by cranial magnetic resonance imaging (MRI) and electroencephalography (EEG). Electromyography (EMG) was performed in heterozygous carriers from family 1 and family 3. RESULTS: Linkage to 16q24.1 was confirmed by haplotype analysis. GAN mutations were identified in all families. Family 1 had the R293X mutation, previously reported in another Turkish family. Families 2 and 3, originating from close geographical areas, shared a novel mutation, 1502+1G>T, at the donor splice site of exon 9. All patients displayed a common phenotype, including peripheral neuropathy, cerebellar ataxia, and frizzly hair. Cranial MRI showed diffuse white matter abnormalities in two patients from family 1 and the patient from family 3, and minimal white matter involvement in the patient from family 2. EMG of a heterozygous R293X mutation carrier showed signs of mild axonal neuropathy, whereas a 1502+1G>T mutation carrier had normal EMG. EEG abnormalities were found in three patients. CONCLUSION: These findings highlight the association of CNS involvement, in particular white matter abnormalities, with peripheral neuropathy in GAN. The phenotypical consequences of both mutations (when homozygous) were similar.     

The shifting landscape of genetic testing for Charcot–Marie–Tooth disease

Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the “giant” axons caused by accumulations of intermediate filaments. The disease is progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot–Marie–Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as “giant axonal neurodegeneration.” Muscle Nerve 50 : 467–476, 2014     

The giant axonal neuropathy--clinical and hisotological aspects, differential diagnosis and a new case

The giant axonal neuropathy (GAN) is morphologically characterized by axonal swellings and accumulations of neurofilaments in giant axons and other cell types. Curly hair is not a constant finding. The clinical course is progressive and mostly starts in early childhood. We report the case of a boy aged 6 years at the time of sural nerve and muscle biopsy. Suralis nerve showed a reduced numerical density of myelinated fibres with a consecutive endoneural fibrosis. Morphometric investigation revealed a pronounced reduction of fibres measuring 8-12 microm in diameter. Giant axons were seen in relatively low number and were not very large with a maximum diameter of 18 microm. They had a relatively thin myelin sheet proved also by the high G ratio in the histogram. Many onion bulb formations of Schwann cells were present. There are only few reports of giant axons with such low maximum diameter in cases with GAN, the lowest maximum diameters being reported in case reports on Japanese children. Up to now, this is the first report of a non-Japanese patient with a low maximum diameter of giant axons of less than 20 microm in peripheral nerve biopsy. Ultrastructurally, typical accumulations of neurofilaments and osmiophilic aggregates were found in giant axons. Other diagnoses with occurrence of giant axons could be excluded in view of the absence of specific findings. Sporadic or familial cases with giant axons are discussed. Sceletal muscle biopsy (M. quadriceps femoris) showed neurogenic affection with presence of small angulated atrophic muscle fibres.     

Charcot-Marie-Tooth 2-like presentation of an Algerian family with giant axonal neuropathy

Giant axonal neuropathy is a rare autosomal recessive childhood disorder characterized by a peripheral neuropathy and features of central nervous system involvement. We describe four patients belonging to a consanguineous Algerian family with late onset (6–10 years) slowly progressive autosomal recessive giant axonal neuropathy. The propositus presented with a Charcot–Marie–Tooth 2-like phenotype with foot deformity, distal amyotrophy of lower limbs, areflexia and distal lower limb hypoesthesia. Central nervous system involvement occurred 10 years later with mild cerebellar dysarthria and nystagmus in the propositus and 16 years after onset, a spastic paraplegia in the oldest patient. The two youngest patients (13 and 8 years old) do not present any signs of central nervous involvement. Magnetic resonance imaging showed cerebellar atrophy in the two older. Nerve biopsy showed moderate axonal loss with several giant axons filled with neurofilaments. Genetic study established a linkage to chromosome 16q locus. This clinical presentation differs from the classical form of giant axonal neuropathy.     

Axonal neurofilamentous accumulations: a comparison between human and canine giant axonal neuropathy and 2,5-HD neuropathy

The neuropathy produced by the hexacarbon 2,5-hexanedione (2,5-HD) resembles human and canine inherited giant axonal neuropathy (GAN) in the presence of giant axonal swellings that contain accumulations of neurofilaments. The accumulations are both paranodal and internodal in GAN and 2,5-HD induced neuropathy. Detailed morphometry on the neurofilaments reveals that the changes in human and canine GAN are closely similar and differ from those of 2,5-HD neuropathy, suggesting that the mechanisms underlying the formation of the axonal neurofilamentous accumulations differ between the two conditions. In both human and canine GAN, the neurofilaments are more closely spaced and are of greater diameter than in 2,5-HD neuropathy. The changes in the NF in GAN may be the consequence of flattening of the side-arms of the neurofilaments against the axis of the filaments     

A case of giant axonal neuropathy showing focal aggregation and hypophosphorylation of intermediate filaments

We report here the clinicopathological features of a typical case of giant axonal neuropathy (GAN). Scanning electron microscopy of the hair of this case revealed an extraordinarily irregular cuticle. Focal accumulation of intermediate filaments in axons, Schwann cells, muscle fibers and skin fibroblasts were also found under an electron microscopy. When examined immunocytochemically, muscle fibers exhibited local disruption of the filamentous network in the subsarcolemmal space and in the central cytoplasm accompanied by focal accumulation of desmin. The intracellular network of vimentin was also disrupted, exhibiting global accumulation in some of the cultured skin fibroblasts. Decreased interneurofilament spacing was found in enlarged axons, suggesting the presence of hypophosphorylation of neurofilaments in this patient. These findings suggest general disorganization, abnormal distribution and possible defective phosphorylation of intermediate filaments in GAN.     

Genetic heterogeneity in giant axonal neuropathy: an Algerian family not linked to chromosome 16q24.1

Giant axonal neuropathy is a rare severe autosomal recessive childhood disorder affecting both the peripheral nerves and the central nervous system. Peripheral nerves characteristically show giant axonal swellings filled with neurofilaments. The giant axonal neuropathy gene was localised by homozygosity mapping to chromosome 16q24.1 and identified as encoding a novel, ubiquitously expressed cytoskeletal protein named gigaxonin.We describe a consanguineous Algerian family with three affected sibs aged 16, 14 and 12 years who present a mild demyelinating sensory motor neuropathy, hypoacousia and kyphoscoliosis which was moderate in the two elder patients, severe in the third one, with no sign of central nervous system involvement and normal cerebral magnetic resonance imaging. This clinical picture is different from the classical severe form, with kinky hairs and early onset of central nervous system involvement and from the less severe form, with protracted course and late involvement of central nervous system. Nerve biopsy showed a moderate loss of myelinated fibers and several giant axons with thin or absent myelin, filled with neurofilaments. This neuropathological aspect is similar to the previously described families linked to the gigaxonin gene. Genetic study in this family showed absence of linkage to chromosome 16q24.1, indicating for the first time, a genetic heterogeneity in giant axonal neuropathy. We propose to call this form of giant axonal neuropathy giant axonal neuropathy 2, and to use the name of giant axonal neuropathy 1 for the form linked to 16q24.1.     

A novel homozygous nonsense mutation in NEFL causes autosomal recessive Charcot–Marie–Tooth disease

The neurofilament light polypeptide (NEFL) gene mutations cause mainly autosomal dominant Charcot–Marie–Tooth disease (CMT) and rarely the recessive forms of CMT. We describe a 13-year-old girl born of consanguineous parents. She presented an early onset of gait disturbance with weakness in lower extremities during the first decade. Nerve conduction velocity of median nerve was 24 m/s and amplitude of compound muscle action potential was 2.2 mV. Sensory nerve action potential was not recordable. Sural nerve biopsy showed severe loss of the large myelinated fibers. Electron microscopy revealed absence of neurofilaments in both myelinated and unmyelinated axons. Genetic analysis identified a novel homozygous nonsense mutation in NEFL c.487G>T (p.Glu163*) as the potential causative mutation in this patient. Our study expands the mutation spectrum of NEFL-related neuropathy.     

Clinicogenetical features of a Japanese patient with giant axonal neuropathy

Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder that affects both the peripheral nerves and central nervous system. Since the discovery in 2000 of the gigaxonin gene on chromosome 16q24.1 to be causative, more than 40 GAN mutations have been reported from different racial backgrounds. We report the clinicogenetic findings of a 24-year-old Japanese man with GAN. He had consanguineous parents and showed the phenotype of classical severe GAN. We found a novel homozygous nonsense mutation (p.R162X) in the GAN gene. This is the first genetically-determined Japanese case of GAN, with a follow-up period of more than 15 years. In addition, this mutation is novel. We also reviewed previous reports of GAN to see whether there is any genotype-phenotype correlation.     

Neuropathologic and morphometric studies in hereditary motor and sensory neuropathy type II with neurofilament accumulation

Histological, electron microscopic and morphometric data on sural nerve, muscle, and skin biopsies of three patients affected by autosomal dominant hereditary motor and sensory neuropathy type II with neurofilament accumulation, whose neurological, cardiological and electrophysiological data have been provided in a previous paper disclosed focally enlarged myelinated axons, due to aggregation of neurofilaments in sural nerves of all 3 biopsied patients, as well as densely packed clusters of filaments in occasional non-myelinated axons without axonal enlargement, in several fibroblasts and endothelial cells in muscle and particularly in skin. This accumulation of filaments was less pronounced in our patients' tissues than in autosomal-recessive GAN. No ultrastructural differences concerning the accumulated filaments appear to exist between the affected cells of our patients and GAN. Taken together, these findings best fit a hereditary motor and sensory neuropathy type II with focal accumulation of intra-axonal neurofilaments. This paper was in part presented at the 59^th Annual Meeting of the American Association of Neuropathologists St. Louis/MO, June 9–12, 1983.     

Clinical and molecular findings in patients with giant axonal neuropathy (GAN)

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder of early onset, clinically characterized by a progressive involvement of both peripheral and CNS. The diagnosis is based on the presence of characteristic giant axons, filled with neurofilaments, on nerve biopsy. Recently, the defective protein, gigaxonin, has been identified and different pathogenic mutations in the gigaxonin gene have been reported as the underlying genetic defect. Gigaxonin, a member of the BTB/kelch superfamily proteins, seems to play a crucial role in the cross talk between the intermediate filaments and the membrane network. The authors report clinical and molecular findings in five Italian patients with GAN. This study shows the allelic heterogeneity of GAN and expands the spectrum of mutations in the GAN gene. The frequent occurrence of private mutations stresses the importance of a complete gene analysis.     

Giant axonal neuropathy: normal protein composition of neurofilaments.

A 14-year-old boy had progressive weakness and ataxia since two years of age with tightly curled hair, facial diplegia, distal weakness and hypaesthesia, cerebellar syndrome and normal intelligence. He also had distal renal tubular acidosis manifested by metabolic acidosis. Sural nerve ultrastructure showed numerous giant axons packed with neurofilaments. The neurofilament major proteins of 68 000, 160 000 and 210 000 daltons found in normal sural nerve were also present in the diseased nerve indicating that the protein composition of neurofilaments which accumulates in this disorder has not been appreciably altered. The amount of 68 000 dalton neurofilament protein was two times higher in giant axonal neuropathy nerve than in the control nerve. Our results suggest that the neurofibrillary pathology in giant axonal neuropathy is due to a build-up of normal neurofilaments.     

Giant axonal neuropathy

Summary Giant axonal neuropathy (GAN) is a disease characterized by a slowly progressive neuropathy and signs of central involvement, manifested by visual impairment, corticospinal tract dysfunction, ataxia, and dementia. Pathological hallmarks of the disease include axonal swellings packed with neurofilaments in both peripheral and central nervous systems, and accumulations of intermediate filaments in Schwann cells, fibroblasts, melanocytes, endothelial, and Langerhans cells. Rosenthal fibers, sometimes appearing in masses and mimicking Alexander's disease, emerge as a conspicuous characteristic in longstanding GAN.Supported by a grant from the National Institutes of Health (NS 22786)     

Giant axonal neuropathy in two siblings: clinical histopathological findings

OBJECTIVE: Giant axonal neuropathy is a rare, severe autosomal-recessive neurologic disease affecting both the peripheral and the central nervous system. In this article, we describe a detailed clinicopathological report of two affected sibs from a consanguineous Turkish family. PATIENTS: The index patient was a 6.5-year-old girl. Her intellectual development was normal. At the age of 3, her parents noticed progressive lack of balance and deterioration of motor skills. On examination, she had paresis and sensory loss more marked distally. Her mental status was normal. Her older brother had similar findings. RESULTS: Electrophysiological studies of young patients showed decreased median and ulnar nerve conduction velocities, absent peroneal motor potential, absent sensory nerve potentials and an EMG suggesting a neurogenic pattern. MRI showed mild cerebral and cerebellar atrophy. The nerve biopsy showed moderate myelinated nerve fibres loss, several regenerative clusters and multiple giant axons. Focal demyelination, hypertrophic "onion pulp" changes and endoneural fibrosis were also seen. Immunohistochemically, neurofilament protein accumulation was detectable in giant axons. CONCLUSIONS: This consanguineous family with two affected siblings and healthy parents complies with autosomal-recessive inheritance in GAN. In the majority of reported GAN cases, CNS involvement is described early in the course of the disease, but these patients did not present any sign of CNS involvement. GAN is a rare genetic disease of childhood involving the central and peripheral nervous systems. The diagnosis is easy with clinical, electrophysiological, and histopathological features, if it has been done. Early diagnosis is important, because of possible prenatal diagnosis.     

Homozygosity mapping of giant axonal neuropathy gene to chromosome 16q24.1

Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder described as a symmetrical distal neuropathy, with peripheral axons dilated by accumulation of 10 nm neurofilaments (NF) and a severe course of disease. The observation of kinky or curly hairs is not a constant finding. The GAN1 locus was localized by homozygosity mapping to chromosome 16 q24.1 in a 3 (4) cM interval flanked by the markers D16S3073 and D16S505 (D16S511) in three non-related Tunisian families, showing a genetic homogeneity in these families. Two point lod-score calculation between the linked haplotype and the disease locus was 14.2 at θ_max = 0. The patients share a slow course of the disease. The differences in the course of the disease between Tunisian and non-Tunisian patients suggest a possible genetic heterogeneity, which is why the present linkage has been referred to as GAN1. The biochemical defect in GAN1 should help to understand the mechanisms involved in NF accumulations as in other neurological diseases (ALS, SMA). Received June 30, 1997; Revised and Accepted July 1, 1997     

Infantile neuroaxonal dystrophy and giant axonal neuropathy--overlap diseases of neuronal cytoskeletal elements in childhood?

Giant axonal neuropathy (GAN) and infantile neuroaxonal dystrophy (INAD) are two progressive neurodegenerative disorders of childhood that have considerable clinical as well as histological overlap but are believed to be ultrastructurally distinct. The clinicopathological and ultrastructural features of three cases of INAD, two of whom are siblings and one case of GAN are described. The sural nerve biopsies in all four cases were essentially similar on light microscopy revealing giant axons. On electron microscopy, the findings in the case of GAN were typical with dense accumulation of neurofilaments within the giant axons. In the three cases of INAD, too, in addition to accumulation of mitochondria and organelles with vesiculotubular profiles, a similar increase in neurofilaments was evident. We, therefore, believe that these two disorders may represent a spectrum in evolution of intermediate filament pathology with various organelles participating in the temporal evolution of the disease process.     

Giant axonal neuropathy (GAN): an immunohistochemical and ultrastructural study report of a Latin American case

Summary Giant axonal neuropathy (GAN), a progressive childhood disorder of intermediate filaments (IF), is characterized by a peripheral neuropathy and central nervous system involvement. Twenty-eight cases have been reported while several pathogenic hypotheses have been proposed. Sural nerve biopsy of a 10-year-old Argentinian girl showed a reduced number of myelinated fibers as well as several enlarged axons up to 30 m in diameter, thinly myelinated or devoid of myelin sheath, displaying accumulation of neurofilaments (NF), but few microtubules (MT) beneath the axolemmal membrane. There was IF accumulation in Schwann and perineural cells as well as in melanocytes, fibroblasts, pericytes, endothelial and epithelial cells in both nerve and skin biopsy. Our findings strongly support GAN as a generalized IF disorder with MT segregation from NF in giant axons. Abnormal NF phosphorylation is suggested by heavy immunostaining of enlarged axons by a monoclonal antibody to NF phosphorylated determinants (SMI 31-Sternberger's) and lack of reaction with a monoclonal antibody with different phosphoepitopes affinity (SMI 34-Sternberger's).Part of this work has been presented at the meeting of the American Association of Neuropathologists Charleston 1988