Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. So far, the identified defects responsible for NBIA include:
1. pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2;
2. phospholipase A2-associated neurodegeneration (PLAN) due to mutations in PLA2G6;
3. fatty acid hydroxylase-associated neurodegeneration (FAHN) due to mutations in FA2H;
4. mitochondrial membrane protein-associated neurodegeneration (MPAN) due to C19orf12 mutations;
5. an X-linked dominant form due to WDR45 encoding for a protein with a putative role in autophagy.
These genes account for approximately 70% of subjects with NBIA, leaving a significant fraction without an identified genetic defect. Dusi et al. found mutations in COASY, coding for CoA synthase in two unrelated cases with NBIA without mutations in previously associated genes. CoA synthase catalyzes the last two steps in the CoA biosynthetic pathway. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA. Like PANK2, defective in the most common NBIA disorder, CoA synthase is a mitochondrial enzyme. PANK2 is mainly located in the intermembrane space whereas CoA synthase is anchored to the outer mitochondrial membrane or localized within the mitochondrial matrix. It is still unknown how mutations in genes involved in Coenzyme A enzymatic pathway cause neurodegeneration with iron accumulation in specific areas of the brain.
Posted by Nicola Brunetti-Pierri, MD