Inborn errors of coenzyme A metabolism and neurodegeneration
Two inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway. Another very rare but similar disorder, denominated CoPAN, is caused by mutations in coenzyme A synthase gene (COASY) coding for a bi-functional mitochondrial enzyme, which catalyzes the final steps of CoA biosynthesis. It still remains a mystery why dysfunctions in CoA synthesis lead to neurodegeneration and iron accumulation in specific brain regions, but it is now evident that CoA metabolism plays a crucial role in the normal functioning and metabolism of the nervous system.
The support of Telethon GGP16234 to VT and of Mariani Foundation of Milan is gratefully acknowledged.
IDM: Drafting of the manuscript; VT: Conception and design; MC revising the clinical description; IDM, MC and VT: Revising of the manuscript.
Compliance with ethics guidelines
Conflict of interest
Ivano Di Meo declares that he has no conflict of interest.
Miryam Carecchio declares she has no conflict of interest.
Valeria Tiranti declares that she has no conflict of interest.
- Almannai M, Alsamri A, Alqasmi A et al (2018) Expanding the phenotype of SLC25A42-associated mitochondrial encephalomyopathy. Clin Genet. https://doi.org/10.1111/cge.13210
- Aoun M, Corsetto PA, Nugue G et al (2017) Changes in red blood cell membrane lipid composition: a new perspective into the pathogenesis of PKAN. Mol Genet Metab. https://doi.org/10.1016/j.ymgme.2017.04.006
- Evers C, Seitz A, Assmann B et al (2017) Diagnosis of CoPAN by whole exome sequencing: waking up a sleeping tiger’s eye. Am J Med Genet A. https://doi.org/10.1002/ajmg.a.38252
- Gregory A, Hayflick S (2014) Neurodegeneration with brain iron accumulation disorders overview. In Adam MP, Ardinger HH, Pagon RA et al, eds. GeneReviews. University of Washington, Seattle; 1993–2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK121988/
- Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM-Y (2005) Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci 25:689–698. https://doi.org/10.1523/JNEUROSCI.4265-04.2005 CrossRefPubMedGoogle Scholar
- Leoni V, Strittmatter L, Zorzi G et al (2012) Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Mol Genet Metab 105:463–71Google Scholar
- Prohl C, Pelzer W, Diekert K et al (2001) The yeast mitochondrial carrier Leu5p and its human homologue Graves’ disease protein are required for accumulation of coenzyme A in the matrix. Mol Cell Biol 21:1089–1097. https://doi.org/10.1128/MCB.21.4.1089-1097.2001 CrossRefPubMedPubMedCentralGoogle Scholar
- Santambrogio P, Dusi S, Guaraldo M et al (2015) Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients. Neurobiol Dis 81:144–153. https://doi.org/10.1016/j.nbd.2015.02.030 CrossRefPubMedPubMedCentralGoogle Scholar
- Siudeja K, Srinivasan B, Xu L et al (2011) Impaired coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration. EMBO Mol Med 3:755–766. https://doi.org/10.1002/emmm.201100180 CrossRefPubMedPubMedCentralGoogle Scholar
- Zizioli D, Tiso N, Guglielmi A et al (2016) Knock-down of pantothenate kinase 2 severely affects the development of the nervous and vascular system in zebrafish, providing new insights into PKAN disease. Neurobiol Dis 85:35–48. https://doi.org/10.1016/j.nbd.2015.10.010 CrossRefPubMedPubMedCentralGoogle Scholar
- Zorzi G, Nardocci N (2013) Therapeutic advances in neurodegeneration with brain iron accumulation. Int Rev Neurobiol 110:153–164. https://doi.org/10.1016/B978-0-12-410502-7.00008-9 CrossRefPubMedGoogle Scholar