ORPHA: 401964; DO: 0090069;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q23.2 | ?Giant axonal neuropathy 2, autosomal dominant | 610100 | Autosomal dominant | 3 | DCAF8 | 615820 |
A number sign (#) is used with this entry because of evidence that autosomal dominant giant axonal neuropathy-2 (GAN2) is caused by heterozygous mutation in the DCAF8 gene (615820) on chromosome 1q23. One such family has been reported.
For a discussion of genetic heterogeneity of giant axonal neuropathy, see GAN1 (256850).
Giant axonal neuropathy-2 is an autosomal dominant peripheral axonal neuropathy characterized by onset of distal sensory impairment and lower extremity muscle weakness and atrophy after the second decade. Foot deformities may be present in childhood. More severely affected individuals may develop cardiomyopathy. Sural nerve biopsy shows giant axonal swelling with neurofilament accumulation (summary by Klein et al., 2014).
Vogel et al. (1985) reported a German kinship with clinical features of hereditary motor sensory neuropathy type 2 (HMSN2; see, e.g., CMT2A1; 118210) characterized by axonal swellings with neurofilament accumulations on peripheral nerve biopsy. There were at least 9 affected family members spanning 5 generations; inheritance was autosomal dominant. Clinical features included pes cavus, gait abnormalities, peroneal muscle weakness and atrophy, hand weakness, hyporeflexia or areflexia, and distal sensory loss of tactile and vibratory sensations. EMG showed chronic denervation, and nerve conduction velocities (NCVs) were normal or mildly decreased. Sural nerve biopsy showed mild reduction in myelinated fibers, occasional small onion bulb formations, and swollen axons with neurofilament accumulation. Three of the most severely affected individuals had evidence of a cardiomyopathy. Vogel et al. (1985) distinguished the disorder in this family from autosomal recessive giant axonal neuropathy (GAN1; 256850) by the mode of inheritance, later age at onset, absence of hair abnormalities, and absence of central nervous system involvement. In a follow-up of the family reported by Vogel et al. (1985), Klein et al. (2014) noted that none of the affected individuals had significant progression of the disorder, but 2 had died from cardiomyopathy-related problems.
Lus et al. (2003) reported an Italian family with autosomal dominant inheritance of Charcot-Marie-Tooth disease with giant axons. Clinical features were variable in severity, but included progressive weakness and atrophy of the hands, feet, and legs with a peroneal distribution, generalized hyporeflexia and areflexia, steppage gait, and distal loss of tactile and vibratory sensation. All patients had pes cavus since infancy, but other symptoms developed in adulthood and were slowly progressive. Motor and sensory NCVs were moderately to severely reduced. Sural nerve biopsy of 1 patient showed numerous giant axons with sporadic onion bulb formations. Molecular analysis excluded linkage to known CMT2 loci and mutations in known CMT2 genes, including NEFL (162280) and GAN (605379).
The transmission pattern of the disorder in the families reported by Vogel et al. (1985) and Lus et al. (2003) was consistent with autosomal dominant inheritance.
In affected members of a family with GAN2 reported by Vogel et al. (1985), Klein et al. (2014) identified a heterozygous missense mutation in the DCAF8 gene (R317C; 615820.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. In vitro functional expression assays in HEK293 cells showed that the R317C mutant protein decreased DCAF8 binding to DDB1 (600045), indicating a negative impact on recruitment of the E3 ubiquitin ligase complex. Klein et al. (2014) postulated that the mutation caused a defect in E3 ubiquitin ligase-mediated neurofilament degradation.
Klein, C. J., Wu, Y., Vogel, P., Goebel, H. H., Bonnemann, C., Zukosky, K., Botuyan, M.-V., Duan, X., Middha, S., Atkinson, E. J., Mer, G., Dyck, P. J. Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons. Neurology 82: 873-878, 2014. [PubMed: 24500646] [Full Text: https://doi.org/10.1212/WNL.0000000000000206]
Lus, G., Nelis, E., Jordanova, A., Lofgren, A., Cavallaro, T., Ammendola, A., Melone, M. A. B., Rizzuto, N., Timmerman, V., Cotrufo, R., De Jonghe, P. Charcot-Marie-Tooth disease with giant axons: a clinicopathological and genetic entity. Neurology 61: 988-990, 2003. [PubMed: 14557576] [Full Text: https://doi.org/10.1212/wnl.61.7.988]
Vogel, P., Gabriel, M., Goebel, H. H., Dyck, P. J. Hereditary motor sensory neuropathy type II with neurofilament accumulation: new finding or new disorder? Ann. Neurol. 17: 455-461, 1985. [PubMed: 3859241] [Full Text: https://doi.org/10.1002/ana.410170507]