Journal
MOLECULAR GENETICS AND METABOLISM
Volume 105, Issue 3, Pages 463-471Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2011.12.005
Keywords
PKAN; Coenzyme A; Mitochondria; Metabolomics; Cholesterol
Funding
- Mariani Foundation of Milan [R-10-84]
- Italian Foundation AISNAF (Associazione Italiana Sindromi Neurodegenerative Accumulo di Ferro)
- Italian Minister of Health, Fondi per giovani Ricercatori
- DNA bank [GTB07001]
- Bank for the Diagnosis and Research of Movement Disorders (MDB) of the EuroBiobank
- National Science Foundation [DGE - 0644491]
- Broad Institute Scientific Planning and Allocation of Resources Committee
- Nestle Research Center to the Broad Institute [R01DK081457]
- National Institutes of Health
- Fondazione Telethon Funding Source: Custom
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Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, inborn error of metabolism characterized by iron accumulation in the basal ganglia and by the presence of dystonia, dysarthria, and retinal degeneration. Mutations in pantothenate kinase 2 (PANK2), the rate-limiting enzyme in mitochondrial coenzyme A biosynthesis, represent the most common genetic cause of this disorder. How mutations in this core metabolic enzyme give rise to such a broad clinical spectrum of pathology remains a mystery. To systematically explore its pathogenesis, we performed global metabolic profiling on plasma from a cohort of 14 genetically defined patients and 18 controls. Notably, lactate is elevated in PKAN patients, suggesting dysfunctional mitochondria] metabolism. As predicted, but never previously reported, pantothenate levels are higher in patients with premature stop mutations in PANK2. Global metabolic profiling and follow-up studies in patient-derived fibroblasts also reveal defects in bile acid conjugation and lipid metabolism, pathways that require coenzyme A. These findings raise a novel therapeutic hypothesis, namely, that dietary fats and bile acid supplements may hold potential as disease-modifying interventions. Our study illustrates the value of metabolic profiling as a tool for systematically exploring the biochemical basis of inherited metabolic diseases. (C) 2011 Elsevier Inc. All rights reserved.
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