A therapeutic approach to pantothenate kinase associated neurodegeneration
Published in Biomedical Research
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Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic neurological disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA disorders. The diagnosis of PKAN is established with clinical features and the "eye of the tiger" sign identified on brain MRI and the identification of biallelic pantothenate kinase 2 (PANK2) pathogenic variants on molecular genetic testing. PANK2 catalyzes the first reaction of coenzyme A (CoA) biosynthesis, thus, altered PANK2 activity is expected to induce CoA deficiency as well as low levels of essential metabolic intermediates such as 4'-phosphopantetheine which is a necessary cofactor for critical proteins involved in cytosolic and mitochondrial pathways such as fatty acid biosynthesis, mitochondrial respiratory complex I assembly and lysine and tetrahydrofolate metabolism, among other metabolic processes.
In this work, we examined the effect of a multitarget complex supplements (pantothenate, pantethine, omega-3 and vitamin E) on in vitro patient-derived cellular models and the clinical outcome of the adjuvant supplements in combination with the baseline neurological medication in three PKAN patients.
Results: Multitarget complex supplements significantly reduced iron accumulation and increased PANK2 and ACP expression levels in the cellular models derived from all three PKAN patients. In addition, the adjunct treatment to the standard neurological medication improved or stabilized the clinical symptoms of patients.
Conclusions: Our results suggest that multitarget complex supplements can be clinically useful as augmentation therapy for PKAN patients harboring pathogenic variants with residual enzyme levels.
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Precision Personalized Medicine for Rare diseases:
Mitochondrial diseases
Neurodegenerative diseases
Congenital Myopathies
Genetic susceptibility to cancer
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Orphanet Journal of Rare Diseases
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In this manuscript we provide evidence that the complementation of the baseline neurological medication of PKAN patients with pantothenate, pantethine (aiming to increase PANK2 and mtACP levels) and omega 3 and vitamin E (targeting oxidative stress and lipid peroxidation) could help in improving or delaying the progression of motor dysfunction. Novel targeted treatments are extremely needed to retard or stop disease progression and to optimize the quality of life in PKAN.