Giant Axonal Neuropathy – a neurodegenerative disorder – a novel mutation in the GAN-Gen

Introduction: Giant Axonal Neuropathy (GAN) is a rare, autosomal recessive, neurodegenerative disorder with usual onset in infancy. Mutations of the GAN-Gen, encoding for the BTB/kelch protein gigaxonin, are responsible for an abnormal accumulation of intermediate filaments in different cell types. Neurofilaments increase in the neurons resulting in cell degeneration and symptoms of peripheral and central nervous system .

Case report: A now 12 year old girl was presented for the first time at the age of 4 years with pes cavus and unstable gait. Tendon reflexes were absent and she had tight curly hair. The motor nerve conduction velocity of N. peronaeus was reduced (35 m/s). A sural nerve biopsy showed extremely thickened axons due to abnormal accumulation of neurofilamentes which assured the diagnosis of GAN. In the following years the girl got wheelchair bound, a leukodystrophy in MR with mental retardation and epileptic seizures developed as well as optic atrophy. Molecular genetic investigation revealed a novel unpublished mutation in the GAN gen.

Discussion: In GAN the abnormal storage of neurofilamentes, which are important for the cytoskeletton, results in a peripheral neuropathy. In most cases the CNS is affected as well with deficient myelinisation and cranial nerve involvement. In this constellation GAN should be considered as differential diagnosis. The typical feature curly hair can be an important hint. In our patient we found a novel IVS+97 G>T mutation. This mutation leads to a direct alteration of a splice site, which is necessary for synthesis of a intact GAN mRNA.