Infantile Neuroaxonal Dystrophy - Pathophysiology

Pathophysiology

Mutations in the PLA2G6 gene have been identified in most individuals with infantile neuroaxonal dystrophy. The PLA2G6 gene provides instructions for making an enzyme called an A2 phospholipase. This enzyme family is involved in metabolizing phospholipids. Phospholipid metabolism is important for many body processes, including helping to keep the cell membrane intact and functioning properly. Specifically, the A2 phospholipase produced from the PLA2G6 gene, sometimes called PLA2 group VI, helps to regulate the levels of a compound called phosphatidylcholine, which is abundant in the cell membrane.

Mutations in the PLA2G6 gene impair the function of the PLA2 group VI enzyme. This impairment of enzyme function may disrupt cell membrane maintenance and contribute to the development of spheroid bodies in the nerve axons. Although it is unknown how changes in this enzyme's function lead to the signs and symptoms of infantile neuroaxonal dystrophy, phospholipid metabolism problems have been seen in both this disorder and a related disorder called pantothenate kinase-associated neurodegeneration. These disorders, as well as the more common Alzheimer disease and Parkinson disease, also are associated with changes in brain iron metabolism. Researchers are studying the links between phospholipid defects, brain iron, and damage to nerve cells, but have not determined how the iron accumulation that occurs in some individuals with infantile neuroaxonal dystrophy may contribute to the features of this disorder.

A few individuals with infantile neuroaxonal dystrophy have not been found to have mutations in the PLA2G6 gene. The genetic cause of the condition in these cases is unknown; there is evidence that at least one other gene may be involved.

Mutations in the NAGA gene, resulting in alpha-N-acetylgalactosaminidase deficiency, cause an infantile neuroaxonal dystrophy known as Schindler disease.