In honor of rare disease day, I am using my Monday-Friday posts to raise awareness of some of the rare diseases as brief posts. Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease, Sanfilippo syndrome, Krabbe Disease, Niemann-Pick Disease, Batten disease , Hurler Syndrome, Charcot-Marie-Tooth, Fibromuscular dysplasia, Huntington’s disease, and today is the turn of Giant Axonal Neuropathy (GAN).

Yesterday I did the calculation that if I did one of these posts every work day it would take approximately 20 years to cover 7000 rare diseases. I am only planning to do this for 1 month. But this should underline that even then there are still close to 7000 rare diseases to describe, 99.99% of which most people in the general public will ever be aware of. I can bet that GAN would be one of those although, perhaps not based on the visibility this disease has achieved and may expand in the future.

In full disclosure I do consult with a GAN foundation called Hannah’s Hope Fund for GAN, and with Lori Sames, Allison Moore and Jill Wood we have previously written a paper that describes this disease and other rare diseases in which parents are actively seeking a cure. I am using some of our recently written descriptions of the disease and research in the hope that it will inspire others. No matter how rare or small a disease it is possible with the right team and families driving research collaboration, to show that scientific advances can be made.

GAN is a very rare autosomal recessive disorder (incidence unknown), appearing in early childhood and progresses slowly as neuronal injury becomes more severe this leads to progressive nerve death and patients typically become quadriplegics, before dying in the second or third decade. GAN may be underdiagnosed as patients without the characteristic tightly curled hair have been identified with a milder phenotype.

The GAN gene encodes the protein gigaxonin which is an intracellular protein needed for long-term nerve survival. It is a predicted E3 ligase adaptor protein that thought to flag substrates for ubiquination on the proteasome. Recent studies suggest disturbed cytoskeletal regulation likely involving the proteasome degradation pathway is responsible for formation of aggregates of some type 3 and type 4 intermediate filament proteins, which is a morphological characteristic of this disease. GAN patient’s skin fibroblasts have vimentin aggregates and abnormal aggregates of intermediate filaments (IFs) are a hallmark of disease pathology in GAN and many other diseases. Based on histopathological analysis of large axonal swellings, “giant axons” are filled with neurofilament (NF) triplet proteins. The GAN -/- mouse has a similar histological phenotype with increased levels of NF proteins, alpha-internexin, peripherin, as well as vimentin, with mRNA transcription levels remaining normal. Additionally, histological analysis of the GAN -/- mouse brain sections revealed accumulations of NF-H and of alpha-internexin in the cortex (negative for other NF subunits). Using 3 cellular models, Mahammad et al, 2013, were able to show that restoring functional gigaxonin had a direct impact on vimentin, peripherin and NF-L: GAN patient fibroblasts were able to clear the vimentin aggregates by expressing WT gigaxonin. A PC12 cell line stably expressing WT gigaxonin, was able to show the loss of peripherin. A neuroblastoma cell line SH-SY-5Y, that stably expressed WT gigaxonin showed clearance of NF-L protein.

Mussche, Gray et al, 2013, were able to demonstrate proof-of-concept of GAN gene delivery in vitro and in vivo, by clearing IF aggregates. They showed that the restoration of WT gigaxonin with adeno associated virus vector serotype 2 (AAV2) clears vimentin IF aggregates in GAN patient fibroblasts. Using an AAV9 viral vector, GAN mice received an intracisternal injection of an AAV9/GAN vector that globally delivered the GAN gene to the brainstem and spinal cord. The treated mice showed a nearly complete clearance of peripherin IF accumulations at 3 weeks post-injection, demonstrating that gigaxonin gene transfer can reverse the cellular IF aggregate pathology associated with GAN.

The research on GAN is moving rapidly towards the clinic and the pieces likely still needed are validated biomarkers for the disease and potential therapeutics to clear aggregates. The research on GAN could benefit other diseases that share pathological factors which are also hallmarks of Alexander disease (AxD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, neuronal IF inclusion disease (NIFID), diabetic neuropathy, spinal muscular atrophy and some forms of Charcot-Marie-Tooth disease (CMT) such as CMT 2E .