Giant axonal neuropathy (Giant axonal neuropathy) - Gen GAN
Giant axonal neuropathy is a rare inherited disease characterized by abnormally large and dysfunctional axons, called giant axons. Axons are specialized extensions of neurons that transmit nerve impulses. The giant axons occur in the peripheral nervous system, which connects the central nervous system to the muscles and sensory cells that detect sensation like touch, pain, heat and sound. Axons in the central nervous system may also be affected.
Signs and symptoms of giant axonal neuropathy usually begin in early childhood and progress over time. Most affected individuals suffer first trouble walking. Later they may lose sensitivity, strength and reflexes in their limbs and suffer from ataxia. In addition, there are frequent visual problems. Many affected individuals have frizzy hair, compared to other family members. As the disease progresses and the central nervous system is affected, they can manifest paralysis, convulsions and dementia. Most people with giant axonal neuropathy do not survive beyond 30 years.
This process is due to mutations in the GAN (gigaxonin) gene, located on the long arm of chromosome 16 (16q24.1), which encodes the protein gigaxonina. The gigaxonina is part of the ubiquitin proteasome system, a process that identifies and removes excess proteins or damaged proteins inside cells. In particular, the gigaxonina plays a role in the degradation of neurofilament, which provide the structural framework that sets the size and shape of axons, essential for the transmission of nerve impulses.
They have been described at least 51 mutations in the GAN in people with giant axonal neuropathy. These mutations correspond to: missense mutations (37), and cutting mutations -splicing- binding (5), small deletions (2), small insertions (1), larger deletions (4), insertions / higher duplications (1) and complex rearrangements (1). GAN genetic mutations lead to an unstable protein gigaxonina easily decomposes, thereby significantly reducing the amount of gigaxonina cells. In neurons, reducing gigaxonina results in the accumulation of neurofilament that should have been eliminated by the ubiquitin-proteasome system. Neurofilament become dense in the giant axons of people with giant axonal neuropathy. These abnormal axons transmit signals properly and eventually deteriorate, leading to serious problems in the peripheral nervous system and the central nervous system.
This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with giant axonal neuropathy, by complete PCR amplification of exons GAN gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).