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Orphanet Journal of Rare Diseases
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Open Access 01-12-2024 | Research

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

Authors: Alessandra Pereira, Carolina Fischinger Moura de Souza, Mónica Álvarez-Córdoba, Diana Reche-López, José Antonio Sánchez-Alcázar

Published in: Orphanet Journal of Rare Diseases | Issue 1/2024

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Abstract

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/​gerirPesquisaAgr​upador.​jsf.
Appendix
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Metadata
Title
A therapeutic approach to pantothenate kinase associated neurodegeneration: a pilot study
Authors
Alessandra Pereira
Carolina Fischinger Moura de Souza
Mónica Álvarez-Córdoba
Diana Reche-López
José Antonio Sánchez-Alcázar
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2024
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-024-03453-x

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