2026-07-10 | Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges
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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2026-07-10 | Precision Medicine in Neurodegeneration with Brain Iron Accumulation (NBIA) Disorders: An Update on Emerging Treatments.
Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of heritable, mostly recessive, progressive neurodegenerative diseases characterized by iron deposition in the basal ganglia and brainstem. There are no solid global epidemiological data on prevalence and incidence of NBIA subtypes, but registry data and expert opinion suggest PKAN, BPAN, PLAN, and MPAN are the most common subtypes. NBIA disorders present with a wide spectrum of clinical symptoms, including movement disorders (dystonia, parkinsonism, chorea), pyramidal involvement (eg, spasticity), speech and cognitive deficits, motor and cognitive slowing, and ocular abnormalities. Treatment remains symptomatic, though several new drugs are in development. Following our review published in 2021, this article provides an updated summary of recent developments. We discuss the rationale of new compounds, summarize clinical trials or-in their absence-preclinical studies for NBIA subtypes. The article is divided into two sections: one section on general approaches based on the shared feature of increased iron in the brain; and the second section on tailor-made, mechanistic treatments for the various NBIA subtypes targeting the specific molecular and cellular pathways of the affected enzyme including gene therapy. In summary, randomized controlled trials in NBIA have not yet demonstrated substantial benefit, neither for iron removal, in general, which appears to be clinically ineffective in most subtypes, except aceruloplasminemia; nor for subtype-specific approaches. Several ongoing studies are exploring more dedicated compounds in this exciting field.
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2026-04-30 | Neurodegeneration with Brain Iron Accumulation PANK2 and PLA2G6 Related Disorders
Abstract: Background Neurodegeneration with Brain Iron Accumulation (NBIA) disorders are rare inherited conditions characterized by progressive motor and cognitive decline due to iron deposition in the basal ganglia and cerebellum. Among the eleven genetic subtypes, Pantothenate Kinase-Associated Neurodegeneration (PKAN) and Phospholipase A₂-Associated Neurodegeneration (PLAN) are the best-characterized models linking disrupted iron metabolism to neurodegeneration. This review synthesizes current knowledge on the molecular basis, clinical features, diagnostic challenges, and emerging therapies for PKAN and PLAN. Conclusion PKAN and PLAN result from mutations in PANK2 and PLA2G6, respectively, disrupting coenzyme A synthesis and membrane lipid remodeling. These defects lead to mitochondrial dysfunction, oxidative stress, lipid peroxidation, and ultimately ferroptosis (an iron-dependent cell death pathway). Neuroimaging, particularly the “eye-of-the-tiger” sign in PKAN and cerebellar atrophy with optic atrophy in PLAN, aids diagnosis, though genetic testing remains definitive. Current management is symptomatic, but emerging therapies, including gene therapy, iron chelation, deuterated lipids (RT001), and enzyme activators hold promise for disease modification. A practical diagnostic algorithm is proposed to facilitate early recognition. Integrative longitudinal research is essential to clarify disease progression and optimize treatment timing.
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