A therapeutic approach to pantothenate kinase associated neurodegeneration: a pilot study.

Autor: Pereira A; Pediatrics Service, Hospital Moinhos de Vento, Porto Alegre, RS, Brazil., Fischinger Moura de Souza C; Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Casa Dos Raros, Porto Alegre, RS, Brazil., Álvarez-Córdoba M; Andalusian Centre for Developmental Biology-CSIC-Pablo de Olavide University, 41013, Seville, Spain., Reche-López D; Andalusian Centre for Developmental Biology-CSIC-Pablo de Olavide University, 41013, Seville, Spain., Sánchez-Alcázar JA; Andalusian Centre for Developmental Biology-CSIC-Pablo de Olavide University, 41013, Seville, Spain. jasanalc@upo.es.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2024 Nov 28; Vol. 19 (1), pp. 442. Date of Electronic Publication: 2024 Nov 28.
DOI: 10.1186/s13023-024-03453-x
Abstrakt: Background: 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.
Methods: In this manuscript, 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.
Trial Registration: CAAE: 58219522.6.0000.5330. Registered 25 May 2022-Retrospectively registered, https://plataformabrasil.saude.gov.br/visao/pesquisador/gerirPesquisa/gerirPesquisaAgrupador.jsf .
Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by The Ethical Committee of Hospital Universitario Virgen del Rocío and Virgen Macarena of Seville, protocol code BRAINCURE16, following the Spanish laws, the principles of the Declaration of Helsinki, and the Guideline for Good Clinical Practices; and by the Ethics Committee of Moinhos de Vento Hospital (CAAE: 58219522.6.0000.5330) and all the parents or legal guardians of subjects signed the written informed consent forms before any procedure was done. Consent for publication: Consent for publication were obtained from all parents or legal guardians. Competing interests: The authors declare that they have no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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