The reference OMIM entry for this protein is 610100

Giant axonal neuropathy 2, autosomal dominant; gan2

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).

DESCRIPTION

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).

CLINICAL FEATURES

Vogel et al. (1985) reported a German kinship with clinical features of hereditary motor sensory neuropathy type 2 (HMSN2; see, e.g.,

CMT

2A1; 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

CMT

2 loci and mutations in known

CMT

2 genes, including NEFL (162280) and GAN (605379).

INHERITANCE

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.

MOLECULAR GENETICS

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 func ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 610100 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).