Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges.

Overview

1. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy; (F.C.); (G.G.); (V.T.)

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic movement disorders characterized by progressive neurological deterioration, dystonia, parkinsonism, spasticity, and abnormal iron deposition in the basal ganglia. Although iron accumulation is the shared neuroradiological hallmark, most NBIA genes do not directly regulate iron metabolism. Instead, major NBIA forms arise from disruption of distinct but converging cellular pathways, including coenzyme A (CoA) biosynthesis, lipid metabolism, mitochondrial function, and autophagy. This narrative review aims to examine the pathogenic mechanisms of major NBIA disorders, namely pantothenate kinase-associated neurodegeneration (PKAN), COASY protein-associated neurodegeneration (CoPAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), and beta-propeller protein-associated neurodegeneration (BPAN), and how these insights are guiding therapeutic development. Preclinical strategies aimed at restoring CoA metabolism, improving mitochondrial function, limiting lipid peroxidation, modulating autophagy, or correcting the underlying genetic defect have shown encouraging results, although none have yet reached robust clinical validation. Clinical translation remains limited by disease rarity, clinical heterogeneity, absence of validated biomarkers, and preclinical models that only partially recapitulate human pathology. Advancing the field will depend on earlier molecular diagnosis, biomarkers capable of tracking disease stage, and trial designs suited to ultra-rare populations. NBIA thus offers a paradigm for how mechanistic classification of a genetically defined disease group can redirect therapeutic strategy away from a shared radiological feature and toward pathway-specific intervention.

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Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 9 keywords, 1 funder, 179 references.

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This paper

Cascone, F., Gasparini, G., Tiranti, V., & Di Meo, I. (2026). Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges. Neurology international, 18(7), 133. https://doi.org/10.3390/neurolint18070133

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