Giant Axonal Neuropathy 1, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that giant axonal neuropathy-1 (GAN1) is caused by homozygous or compound heterozygous mutation in the gigaxonin gene (GAN; 605379) on chromosome 16q23.

Description

Giant axonal neuropathy is a chronic polyneuropathy of childhood that affects both the peripheral and central nervous systems and is accompanied by characteristically kinky hair and unique posture of legs (see illustrations by Berg et al., 1972; Igisu et al., 1975; Carpenter et al., 1974). Axonal loss and the presence of giant axonal swellings filled with neurofilaments on nerve biopsy are the pathologic hallmark of this neurodegenerative disorder (Tazir et al., 2009).

Genetic Heterogeneity of Giant Axonal Neuropathy

See also GAN2 (610100), caused by mutation in the DCAF8 gene (615820) on chromosome 1q23.

Clinical Features

Carpenter et al. (1974) emphasized abnormality of the hair, which was strikingly curly and pale unlike that of his parents. Chemical analysis disclosed a decrease in disulfide bonds and an increase in thiol groups. Curly hair different from that of the parents, with peripheral neuropathy, seemed to suggest the diagnosis, which can be confirmed by specific changes on sural nerve biopsy: greatly enlarged axons packed with neurofilaments. Dooley et al. (1981) described a 17-year-old girl who had been followed for 12 years. Tandan et al. (1987) described a 9-year-old girl with dense, characteristically frizzy scalp hair and long, curly eyelashes. In a 4-year-old girl with clinical and sural nerve biopsy findings typical of GAN, Treiber-Held et al. (1994) found that the hairs showed longitudinal grooves on scanning electron microscopy. This finding had been described in 2 other patients. Treiber-Held et al. (1994) presented a photograph of their patient in comparison with the first reported patient of Berg et al. (1972) and that of Carpenter et al. (1974). They commented on remarkable similarity in facial appearance and head form with prominent high forehead.

In an inbred Tunisian kindred, Ben Hamida et al. (1990) described a form of giant axonal neuropathy without hair abnormalities. Affected individuals showed slow progression and an unusual clinical picture in which the sensorimotor neuropathy was associated with multisystem degeneration including a motor neuron syndrome. Three males and 3 females in 4 sibships were affected. The propositus, a 53-year-old man, presented with progressive infantile onset, distal amyotrophy of 4 limbs, brisk reflexes, diffuse fasciculations, bulbar signs, and deep sensory loss in both lower limbs. Muscle biopsy showed typical hypertrophic neuropathy. In 4 patients, there were giant axons filled with neurofilaments, with normal conduction velocity. The youngest patient, a 4-year-old girl (the abstract states that it was a boy), had mild neurologic deficit, and nerve biopsy showed only a few unmyelinated axons filled with neurofilaments.

Zemmouri et al. (2000) reported a large consanguineous Algerian family in which 4 patients had slowly progressive giant axonal neuropathy. Age at onset ranged from 6 to 10 years. The proband presented with a Charcot-Marie-Tooth type 2 (CMT2; 118210)-like phenotype with foot deformity, distal amyotrophy of the lower limbs, areflexia, and distal sensory loss. The proband developed central nervous system involvement 10 years after onset with mild cerebellar dysarthria and nystagmus; the oldest patient developed spastic paraplegia 16 years after onset. MRI showed cerebellar atrophy in the 2 older patients. Nerve biopsy showed moderate axonal loss with several giant axons filled with neurofilaments. Linkage was found to chromosome 16q. In affected members of the family reported by Zemmouri et al. (2000), Bomont et al. (2000) identified a homozygous mutation in the GAN gene (605379.0006).

Nalini et al. (2008) reported 2 Indian sibs, born of consanguineous parents, with classic features of autosomal recessive GAN. Both had a progressive severe motor and sensory neuropathy, cerebellar dysfunction, thick curly hair, and distended neurofilament-filled axonal swellings on sural nerve biopsy. Skin biopsy also showed characteristic giant axons. One patient had delayed psychomotor development and mental retardation. Both patients were homozygous for a truncation mutation in the GAN gene.

Tazir et al. (2009) reported patients from 5 consanguineous Algerian families with autosomal recessive GAN. The mean age at onset was 5 years (range, 2 to 7). Four of the families had the same homozygous GAN mutation (R477X; 605379.0008). However, the phenotype was variable. Patients from 2 families with this mutation had the classic phenotype with kinky red hair, cerebellar ataxia, and peripheral motor and sensory neuropathy. Mental retardation was variable. A patient from another family had frizzy hair, spastic paraparesis with Babinski sign, facial diplegia, mental retardation, and minor clinical signs of neuropathy and cerebellar ataxia. The patient from the fourth family had a congenital neuropathy with mental retardation and a rapid and severe progression, but without abnormal hair. A patient from the fifth family with a different mutation (E169K; 605379.0009) had onset at age 3 years of weakness of the face and distal and proximal limbs. He also had short stature, foot and hand deformities, scoliosis, and sensory impairment. Mental retardation, spasticity, and kinky hair were not observed. Tazir et al. (2009) noted the clinical variability of giant axonal neuropathy, even among those with the same mutation.

Buysse et al. (2010) reported a boy, born of nonconsanguineous parents, with GAN. Delayed motor development was noted in the second half of the first year of life. He began to walk at age 24 months, but showed an awkward and unstable gait with areflexia. He had a large head and frizzy hair. EMG showed low action potential amplitudes, but nerve conduction velocities were normal. At age 3 years, brain MRI showed relatively large lateral ventricles, and he showed mild cognitive delay with a total IQ of 71. Skeletal muscle and skin biopsy performed at age 6 years showed dense intraaxonal accumulations of neurofilaments in some abnormally large myelinated axons and intermediate filament accumulations in some dermal fibroblasts. Array CGH identified an intragenic deletion in the GAN gene inherited from the mother and a point mutation in the GAN gene (E486K; 605379.0001) inherited from the father. Buysse et al. (2010) noted that the deletion was found using high-resolution array CGH, and that the patient was initially erroneously thought to be homozygous for the point mutation. The findings illustrated the use of array CGH for proper molecular characterization and in the unmasking of a deletion as a recessive allele.

Inheritance

Giant axonal neuropathy is an autosomal recessive disorder. Parental consanguinity was noted by Ouvrier et al. (1974), Igisu et al. (1975), and Gambarelli et al. (1977). Affected sibs were described by Takebe et al. (1979) and by Jones et al. (1979). Donaghy et al. (1988) described an affected Iranian boy whose parents were consanguineous. The authors stated that this was the 19th reported case and that 6 patients, including theirs, had resulted from consanguineous marriages.

Mapping

Flanigan et al. (1998) pursued a genomewide search for regions of homozygosity by descent in 5 consanguineous families with giant axonal neuropathy. They found a 5.3-cM region of homozygosity, shared in all 5 families, on 16q24. Linkage was established to this locus with a lod score of 4.18 at theta = 0.00 for the most tightly linked marker, D16S3098.

By homozygosity mapping, Ben Hamida et al. (1997) demonstrated that the GAN1 locus is situated on 16q24.1 between D16S3073 and D16S505 in 3 unrelated Tunisian families. One of the families had been reported by Ben Hamida et al. (1990). Two-point lod score calculation between the linked haplotype and the disease locus was 14.2 at theta = 0.0. The patients shared a slow course of the disease. The observation of kinky or curly hair was not a consistent finding. Differences in the course of the disease between Tunisian and non-Tunisian patients suggested possible genetic heterogeneity; for that reason, Ben Hamida et al. (1997) referred to the linkage in the locus identified in the Tunisian cases as GAN1.

Cavalier et al. (2000) refined the GAN1 locus to a less than 590-kb region by analysis of 12 unrelated affected families, 3 of which had been reported by Ben Hamida et al. (1997). Two Tunisian families shared a common haplotype, suggesting a founder effect.

Pathogenesis

The histopathology of peripheral nerves in GAN as well as changes in other tissues implies that the underlying defect is one of generalized intermediate filament (IF) organization, with neurofilaments predominantly affected (Flanigan et al., 1998). Nerve fibers are distorted by giant axonal swellings filled with densely packed bundles of neurofilaments (the primary intermediate filament in neurons), with segregation of other axoplasmic organelles. In addition to disorganized neurofilaments in nerve, disorganization of other members of the IF family of proteins is seen in other tissues; these include vimentin (VIM; 193060) in endothelial cells, Schwann cells, and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP; 137780) in astrocytes (Prineas et al., 1976; Pena, 1982; Bousquet et al., 1996). Keratin intermediate filaments also seem to be altered, as most patients present characteristic curly or kinky hairs (Treiber-Held et al., 1994).

Bomont and Koenig (2003) showed that vimentin aggregation in primary fibroblasts from patients with giant axonal neuropathy demonstrated great variation on prolonged culture at confluence and in low serum conditions. While neither the microfilament nor the microtubule networks were perturbed by vimentin destabilization, the aggregates were in close proximity to the microtubule organizing centers. Microtubule depolymerization induced a total vimentin aggregation in GAN fibroblasts. Bomont and Koenig (2003) proposed that gigaxonin may play an important role in the crosstalk between the cytoplasmic intermediate filament and microtubule networks.

Molecular Genetics

In patients with giant axonal neuropathy, Bomont et al. (2000) identified frameshift, nonsense, and missense mutations in the GAN gene (see, e.g., 605379.0001-605379.0003; 605379.0006- 605379.0007). Some of the families had been reported by Ben Hamida et al. (1990), Ben Hamida et al. (1997), Cavalier et al. (2000), and Zemmouri et al. (2000).

Animal Model

Duncan et al. (1981) described a possibly homologous disorder in German shepherd dogs. Unusually tight curly hair may be a feature as in the human disorder. The canine disorder is autosomal recessive.