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Di Meo, I.* ; Anikster, Y.* ; Tiranti, V.* ; Iuso, A.

From common pathway to divergent diseases: Metabolic aspects of inborn errors of CoA biosynthesis.

J. Inherit. Metab. Dis. 49:e70239 (2026)
Verlagsversion DOI PMC
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Coenzyme A (CoA) biosynthesis is a conserved, dynamically regulated pathway essential for mitochondrial energy production, fatty acid oxidation, lipid biosynthesis and protein acylation. Biallelic variants in PANK2, PPCS, PPCDC, and COASY cause rare inborn errors of CoA biosynthesis, associated with markedly different clinical phenotypes: PANK2 and COASY defects predominantly cause neurological disorders within or adjacent to the neurodegeneration with brain iron accumulation (NBIA) spectrum, whereas PPCS and PPCDC deficiencies present mainly as severe early-onset dilated cardiomyopathy. However, COASY variants can also cause pontocerebellar hypoplasia and riboflavin-responsive lipid storage myopathy. This review examines these four disorders from a metabolic perspective, integrating clinical features, experimental models, biochemical data and emerging therapeutic approaches. Current evidence indicates that disease pathogenesis cannot be explained only by global CoA depletion. Total CoA levels may be reduced in PPCS and PPCDC deficiency, but are often preserved under basal conditions in PKAN and COASY-related models. Instead, impaired compartment-specific CoA handling and failure to sustain CoA-dependent flux under increased metabolic demand are emerging as central pathogenic concepts. Perturbation of fatty acid handling, acyl-CoA/acylcarnitine balance, mitochondrial function, iron homeostasis, protein acylation and 4'-phosphopantetheinylation may contribute to tissue-selective vulnerability. Therapeutic strategies are therefore likely to require disease-specific approaches, including precursor bypass or PANK activation where pathway flux can be restored, early pantethine supplementation in cardiomyopathic forms, and downstream or gene-directed strategies for COASY-related disorders. Understanding CoA as a regulator of metabolic adaptability provides a unifying framework for interpreting both shared mechanisms and disease divergence.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Review
Schlagwörter Coasy ; Pank2 ; Ppcdc ; Ppcs ; Coenzyme A (coa) ; Neurodegeneration With Brain Iron Accumulation (nbia); Kinase-associated Neurodegeneration; Coenzyme-a; Pank2; Mutations; Mitochondria; Deficiency; Drosophila; Diagnosis; Synthase
ISSN (print) / ISBN 0141-8955
e-ISSN 1573-2665
Zeitschrift Journal of Inherited Metabolic Disease
Quellenangaben Band: 49, Heft: 5, Seiten: , Artikelnummer: e70239 Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institiute of Neurogenomics (ING)
Förderungen Ricerca Corrente (RRC)