RARE DISEASE
Neurodegeneration with brain iron accumulation
Neurodegeneration with brain iron accumulation
Neurodegeneration with brain iron accumulation
Synonyms: NBIA
Synonyms: NBIA
Synonyms: NBIA
Drug discovery
2
drugs
With orphan designations
Overview
Neurodegeneration with brain iron accumulation (NBIA) encompasses rare inherited disorders marked by iron deposition in the basal ganglia, leading to progressive extrapyramidal symptoms (dystonia, parkinsonism), spasticity, cognitive decline, and retinal degeneration [1][2][15]. Diagnosis relies on MRI showing characteristic iron accumulation (e.g., "eye of the tiger" sign in PKAN) and genetic testing for causative mutations (e.g., PANK2, PLA2G6, CP) [2][6][14]. Most forms lack curative treatments, focusing on symptom management and supportive care [10][12].
Population
Prevalence <1/1,000,000, with onset ranging from infancy to adulthood [15][19]
Autosomal recessive inheritance in 80% of cases (e.g., PKAN, PLAN); X-linked (BPAN) and dominant subtypes (neuroferritinopathy) occur [1][14]
Common subtypes: PKAN (35-50%), PLAN (20%), MPAN (6-10%), and BPAN (1-2%) [18][19]
Burden
Rapid functional decline in childhood-onset cases, often requiring wheelchairs by adolescence [6][7][14]
Reduced life expectancy (10-12 years post-diagnosis) due to dysphagia-related complications [6][7]
High socioeconomic impact from lifelong care needs and limited disease-modifying therapies [14][19]
Therapies
Iron chelation: Deferiprone reduces basal ganglia iron on MRI, but clinical benefits remain uncertain [3][8][12]
Symptomatic control: Baclofen, trihexyphenidyl, botulinum toxin, and deep brain stimulation for dystonia; levodopa for parkinsonism [7][12][14]
Supportive care: Multidisciplinary approach with physical, occupational, and speech therapies [2][12][14]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
297 drug discovery papers about Neurodegeneration with brain iron accumulation, with 2 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
297 drug discovery papers about Neurodegeneration with brain iron accumulation, with 2 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-15 | From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis.
Coenzyme A (CoA) biosynthesis is a conserved, dynamically regulated pathway essential for mitochondrial energy production, fatty acid oxidation, lipid biosynthesis and protein acylation. Biallelic variants in PANK2, PPCS, PPCDC, and COASY cause rare inborn errors of CoA biosynthesis, associated with markedly different clinical phenotypes: PANK2 and COASY defects predominantly cause neurological disorders within or adjacent to the neurodegeneration with brain iron accumulation (NBIA) spectrum, whereas PPCS and PPCDC deficiencies present mainly as severe early-onset dilated cardiomyopathy. However, COASY variants can also cause pontocerebellar hypoplasia and riboflavin-responsive lipid storage myopathy. This review examines these four disorders from a metabolic perspective, integrating clinical features, experimental models, biochemical data and emerging therapeutic approaches. Current evidence indicates that disease pathogenesis cannot be explained only by global CoA depletion. Total CoA levels may be reduced in PPCS and PPCDC deficiency, but are often preserved under basal conditions in PKAN and COASY-related models. Instead, impaired compartment-specific CoA handling and failure to sustain CoA-dependent flux under increased metabolic demand are emerging as central pathogenic concepts. Perturbation of fatty acid handling, acyl-CoA/acylcarnitine balance, mitochondrial function, iron homeostasis, protein acylation and 4'-phosphopantetheinylation may contribute to tissue-selective vulnerability. Therapeutic strategies are therefore likely to require disease-specific approaches, including precursor bypass or PANK activation where pathway flux can be restored, early pantethine supplementation in cardiomyopathic forms, and downstream or gene-directed strategies for COASY-related disorders. Understanding CoA as a regulator of metabolic adaptability provides a unifying framework for interpreting both shared mechanisms and disease divergence.
2026-08-12 | Modelling Ferroptosis in a Human Microglial Line by Sequential Exposure to Iron and GPX4 Inhibition.
Excessive iron accumulation is a pathological feature of several neurodegenerative diseases (NDDs), and a growing body of evidence suggests that ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, is implicated in their pathogenesis. Microglia, the brain's resident immune cells, buffer iron overload but become susceptible to ferroptotic death, exacerbating neuroinflammation and neuronal loss. To uncover the molecular events leading to microglial ferroptosis, we established a human microglial ferroptosis model using the HMC3 cell line. This model recapitulates core features of ferroptosis, including increased reactive oxygen species (ROS) and peroxidation of lipids at the membrane, both rescued by ferrostatin-1 (Fer-1). We used this model to perform integrated multiomic profiling and identified significant dysregulation in lipid species, notably an accumulation of sterols, including oxysterols such as 7-oxo-cholesterol, alongside the oxidation of polyunsaturated fatty acids (PUFAs) that are characteristic of ferroptosis. Transcriptomic and proteomic analyses corroborate these findings, revealing the upregulation of the mevalonate pathway and cholesterol metabolism. Importantly, the increased expression of some of these key metabolic genes was also reversed by Fer-1 treatment, indicating their role in a preferroptotic signature. Our model provides a novel platform for investigating early molecular events in microglia ferroptosis. Integrating these findings into future investigations could uncover new protective mechanisms against microglial ferroptosis to ensure homeostatic regulation of ROS levels and sterol metabolism.
2026-08-03 | In Silico Characterization of a Novel Sulfonamide Derivative as a GPX4 Inhibitor: Docking, ADME, and Toxicity Evaluation to Deliver a Translatable Pharmacophore for Wet-Lab Research
Ferroptosis an iron-dependent, regulated form of cell death driven by the lethal accumulation of lipid hydroperoxides within cellular membranes is suppressed principally by glutathione peroxidase 4 (GPX4), a selenoenzyme whose inhibition has emerged as a strategy of growing therapeutic interest in both oncology and neurodegeneration. Despite this promise, the existing GPX4 inhibitor landscape is dominated by covalent electrophiles that carry well-documented pharmacokinetic liabilities, underscoring the need for drug-like, non-covalent alternatives. To address this gap, an integrated computational workflow was applied to a newly designed sulfonamide derivative (hereafter the target compound). Structure-based molecular docking with AutoDock Vina returned a top-ranked binding affinity of −4.67 kcal mol-1; interaction analysis identified a bifurcated hydrogen-bonding network anchoring the ligand to Thr 132 (2.01 Å) and Gln 70 (2.67 Å), complemented by hydrophobic contacts with Phe 71, Asn 102, Ala 126, and Ile 127. Pharmacokinetic profiling via SwissADME confirmed compliance with Lipinski's Rule of Five (MW = 324.37 g mol-1, LogP = 1.63, zero violations), high gastrointestinal absorption, blood–brain barrier (BBB) permeability as assessed by the BOILED-Egg model, zero PAINS alerts, and a synthetic accessibility score of 3.05. Toxicological assessment through ProTox-3.0 estimated an acute oral LD50 of 5000 mg kg-1 (GHS Class 5) with predicted inactivity across hepatotoxicity, cardiotoxicity, nephrotoxicity, mutagenicity, carcinogenicity, and cytotoxicity endpoints. These findings collectively indicate that the target compound satisfies binding, drug-likeness, and safety requirements simultaneously, positioning it as a viable lead candidate for experimental follow-up.
2026-07-29 | Supplementation via DAF-16 and pnk-1 driven pantothenate-coenzyme A flux improves disease related stress resistance in C. elegans.
Metabolic pathways are increasingly recognized as tractable targets in aging and disease. Building on prior work demonstrating that supplementation with low-molecular weight metabolites (amino acids, vitamins, and their intermediates) can extend lifespan in Caenorhabditis elegans, we focused on pantothenate (vitamin B5), which is dysregulated in sarcopenic muscle and in several neurodegenerative and metabolic disorders. Pantothenate is the obligate precursor of coenzyme A through a short, highly conserved biosynthetic pathway in which loss-of-function mutations can cause neurodegeneration with brain iron accumulation. In C. elegans, the longevity curtailing transcription factor DAF-16/FOXO has a conserved binding element in the promoter region of pnk-1, encoding the first enzyme (PNK-1) in the coenzyme A pathway, and pnk-1 is markedly upregulated in long-lived daf-2 (insulin/-like receptor) mutants, implicating coenzyme A metabolism in longevity. Here, we demonstrate that CoA levels naturally increase during early life and decrease towards older age in C. elegans. Dietary pantothenate supplementation increases coenzyme A levels with minimal effects on lifespan but systemic effects on lipid metabolism, mitochondrial dynamics, and muscle structure under basal conditions. Under DAF-16-associated stress conditions, including heat and oxidative stress, pnk-1 expression is upregulated and pantothenate supplementation robustly extends lifespan and improves mobility. Finally, we demonstrate dysregulation of daf-16 and pnk-1 expression in amyotrophic lateral sclerosis (ALS) models, in which pantothenate supplementation confers both lifespan extension and cholinergic neuroprotection.
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.
proteins
2026-04-07 | Clinical Evaluation of Three KRS Families and Cellular Analysis of Distinct ATP13A2 Mutations Reveal Different Levels of Iron Accumulation.
Kufor-Rakeb Syndrome (KRS) is a rare neurodegenerative disease caused by homozygous mutations in the ATP13A2 gene. The ATP13A2 protein, found in lysosomal and late-endosomal membranes, performs cellular functions such as iron-chelating agent transport and intracellular iron homeostasis. Mutations in ATP13A2 can lead to intracellular iron accumulation; however, whether KRS caused by an ATP13A2 mutation falls under Neurodegeneration with Brain Iron Accumulation disorders has long been debated. The most fundamental reason is that magnetic resonance imaging (MRI) cannot identify iron deposits in the basal ganglia in all KRS cases. We hypothesize that analyzing iron deposition at the cellular level could be more sensitive in detecting varying levels of iron accumulation associated with different ATP13A2 mutations, and it may be more useful when conventional MRI fails to detect iron, yields inconclusive results, or cannot be performed. We identified two new ATP13A2 mutations (p.Leu518_Thr519del, and p.Leu939Pro) in this study and comparatively investigated the impacts of three distinct ATP13A2 mutations (p.Pro474fs, p.Leu518_Thr519del, and p.Leu939Pro) using KRS patients' primary fibroblasts and MCF7 cells overexpressing these mutated ATP13A2 proteins to analyze if these different mutations of ATP13A2 can cause differing levels of iron accumulation. Following the detection of iron deposits via Prussian blue staining and inductively coupled plasma mass spectrometry, the cell viability was assessed via MTT assay to ascertain the impact of iron accumulation. Each type of ATP13A2 mutation led to iron accumulation; however, frameshift and deletion mutations resulted in more iron accumulation than the missense mutation. In addition, the transient overexpression of the wild-type ATP13A2 attenuated the cell death caused by iron accumulation. This study demonstrated that different types of ATP13A2 mutations are related to varying levels of iron accumulation and provided an explanation for the inconsistent perspectives on the association of KRS with iron accumulation.
2025-12-17 | Integrating iron and lipid biology in Alzheimer’s disease
Neurons exist at the intersection of two essential yet hazardous metabolic demands: iron-driven bioenergetics and lipid-dependent membrane remodeling. Their reliance on mitochondrial iron for adenosine triphosphate (ATP) generation, combined with the requirement for polyunsaturated fatty acids to sustain synaptic plasticity, creates a biochemical environment primed for ferroptosis. This Perspective examines how the interplay between iron and lipid metabolism defines neuronal vulnerability in neurodegenerative diseases, focusing on apolipoprotein E (ApoE) as a metabolic gatekeeper coordinating those pathways. Beyond its canonical function in lipid transport, ApoE acts as a potent anti-ferroptotic factor by inhibiting ferritinophagy and restraining the release of labile iron, thereby coupling lipid trafficking with iron homeostasis. Dysregulation of this axis in Alzheimer’s disease amplifies lipid peroxidation and compromises antioxidant defenses. Parallel mechanisms are observed in Neurodegeneration with Brain Iron Accumulation disorders, where mutations in lipid-metabolic genes paradoxically lead to brain iron accumulation, underscoring the genetic entanglement of these pathways. Collectively, these findings support a unifying model in which neuronal ferroptosis arises not from isolated iron overload or lipid imbalance, but from the breakdown of a coordinated iron-lipid defense network. We propose that restoring this equilibrium through modulation of ApoE function, preservation of mitochondrial iron utilization, and suppression of lipid peroxidation represents a promising avenue for therapeutic intervention in neurodegenerative disease.
2024-07-29 | Assessment of the degree of disability of the Polish NBIA-MPAN population based on a patient survey
Neurodegeneration with brain iron accumulation (NBIA) describes a group of extremely rare hereditary disorders with an estimated prevalence of 1–3/1,000,000. Mitochondrial membrane protein associated neurodegeneration (MPAN) is the third most common form of NBIA, accounting for 10% of NBIA cases globally and up to 50% of cases in Poland. This survey was conducted by the Association NBIA Poland to collect data on the functioning of patients with NBIA/MPAN based on self-reported EQ-5D-5L (EuroQoL 5-Dimension 5-Level) scores. A total of 50 patients living in Poland, including 26 patients with NBIA/MPAN, participated in the study. The mean age of NBIA/MPAN patients was 22 years; the mean age at symptom onset is 10 years. At the time of the survey, most patients were disabled and required assistance with daily activities. More than 50% of participants needed help with hygiene or dressing, and 40% were unable to walk on their own. Nearly 50% of patients declared symptoms indicating lowered mood. The survey showed that NBIA/MPAN leads to significant disability within a short period of time after symptom onset. Intensive work is underway to discover the role of the C19orf12 protein and develop therapeutic strategies. Actions are necessary to improve the comfort of everyday life of patients with NBIA/MPAN and to improve access to rehabilitation, including home-based programmes.
2024-02-09 | Nazo, the Drosophila homolog of the NBIA-mutated protein–c19orf12, is required for triglyceride homeostasis
Lipid dyshomeostasis has been implicated in a variety of diseases ranging from obesity to neurodegenerative disorders such as Neurodegeneration with Brain Iron Accumulation (NBIA). Here, we uncover the physiological role of Nazo, the Drosophila melanogaster homolog of the NBIA-mutated protein–c19orf12, whose function has been elusive. Ablation of Drosophila c19orf12 homologs leads to dysregulation of multiple lipid metabolism genes. nazo mutants exhibit markedly reduced gut lipid droplet and whole-body triglyceride contents. Consequently, they are sensitive to starvation and oxidative stress. Nazo is required for maintaining normal levels of Perilipin-2, an inhibitor of the lipase–Brummer. Concurrent knockdown of Brummer or overexpression of Perilipin-2 rescues the nazo phenotype, suggesting that this defect, at least in part, may arise from diminished Perilipin-2 on lipid droplets leading to aberrant Brummer-mediated lipolysis. Our findings potentially provide novel insights into the role of c19orf12 as a possible link between lipid dyshomeostasis and neurodegeneration, particularly in the context of NBIA.
2023-08-07 | The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain.
Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux. The absence of this protein in humans and rodents produces progressive neurodegeneration with brain iron accumulation. Astrocytes express high levels of Cp and iron efflux from these cells has been shown to be central for oligodendrocyte maturation and myelination. To explore the role of astrocytic Cp in brain development and aging we generated a specific conditional KO mouse for Cp in astrocytes (Cp cKO). Deletion of Cp in astrocytes during the first postnatal week induced hypomyelination and a significant delay in oligodendrocyte maturation. This abnormal myelin synthesis was exacerbated throughout the first two postnatal months and accompanied by a reduction in oligodendrocyte iron content, as well as an increase in brain oxidative stress. In contrast to young animals, deletion of astrocytic Cp at 8 months of age engendered iron accumulation in several brain areas and neurodegeneration in cortical regions. Aged Cp cKO mice also showed myelin loss and oxidative stress in oligodendrocytes and neurons, and at 18 months of age, developed abnormal behavioral profiles, including deficits in locomotion and short-term memory. In summary, our results demonstrate that iron efflux-mediated by astrocytic Cp-is essential for both early oligodendrocyte maturation and myelin integrity in the mature brain. Additionally, our data suggest that astrocytic Cp activity is central to prevent iron accumulation and iron-induced oxidative stress in the aging CNS.
gene therapies
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.
2026-06-17 | Pathophysiology, biological models and new therapeutic approaches in β-Propeller Associated Neurodegeneration.
Neurodegeneration with brain iron accumulation (NBIA) encompasses a set of rare disorders that present a diagnostic challenge due to their genetic and clinical diversity, with treatment options currently limited to symptom alleviation. One subtype, β-Propeller Associated Neurodegeneration (BPAN), results from pathogenic variants in the WDR45 gene on the X chromosome. This condition is marked by iron accumulation in the globus pallidus and substantia nigra, alongside early onset developmental delays, seizures, and motor impairments. The WDR45 gene produces the WDR45 protein, which plays a key role in the creation and maturation of autophagosomes-crucial components of the autophagy process, a cellular mechanism vital to the organism's proper function. In BPAN, reduced autophagy correlates with mitochondrial dysfunction, impaired antioxidant defenses, elevated lipid peroxidation, buildup of lipofuscin granules, and disrupted iron metabolism. However, the precise relationships between these pathological issues remain unclear. There is no curative treatment for BPAN, therefore care focuses on palliation and symptom management through a multidisciplinary approach. Nonetheless, research into various therapeutic strategies is ongoing, including gene therapy to correct the genetic anomaly and methods to influence pathological pathways like autophagy deficiency, lipid peroxidation, and iron accumulation. A novel approach has recently been suggested, aimed at reactivating the inactive X chromosome in females with BPAN.
2025-12-12 | Neurodegeneration with Brain Iron Accumulation
Neurodegeneration with brain iron accumulation (NBIA) refers to a heterogeneous group of neurological disorders due to the accumulation of iron in the basal ganglia. NBIA leads to progressive cognitive and motor function degeneration. To date, although 10 different genetic variations of the disease have been reported, this figure is likely to amplify over the coming years. Aceruloplasminemia and neuroferritinopathy are among the various forms of NBIA resulting from iron accumulation and are the primary contributing factors of cellular oxidative damage. NBIA exhibits a wide range of clinical symptoms, which may vary from extrapyramidal symptoms to dystonia, spasms, muscular rigidity, parkinsonism, neuro-psychiatric issues, optic atrophy, and retinal degeneration. The diagnosis of the disease is challenging and hence requires tailored therapeutic interventions, owing to overlapping clinical symptoms with certain non-progressive chronic encephalopathies. Research advances in the field focus on the design and development of novel strategies that could alter 130genetic defects, such as targeted gene therapy, gene editing, and substrate replacement therapies, coupled with monetary benefits and minimal side effects. This chapter highlights the genetic variations of the disease, the underlying molecular mechanisms of NBIA associated with brain iron accumulation, and their possible insights towards future customized targeted therapies.
2025-07-28 | Infantile neuroaxonal dystrophy: Molecular mechanisms and pathogenesis of PLA2G6-associated neurodegeneration.
Infantile neuroaxonal dystrophy (INAD), also known as PLA2G6-associated neurodegeneration (PLAN), is a rare, early-onset, autosomal recessively inherited neurodegenerative disease belonging to the group of neurodegenerations with brain iron accumulation (NBIA). The main cause of this disease is bi-allelic mutations in the PLA2G6 gene, which codes for the enzyme phospholipase A2 type VI. Clinically, it manifests with progressive neurodevelopmental impairment, psychomotor regression, movement disorders, and pyramidal signs. Initially described in the 1950s, the classical form presents in the first two years of life, although later-onset variants are recognized. At the neuropathological level, INAD is characterized by the presence of neuroaxonal spheroids, which are dilations of degenerated axons, located mainly in the white matter, basal ganglia, and cerebellum. INAD is considered a rare or ultra-rare disease, with an estimated prevalence of approximately 1 per million individuals. Diagnosis requires a comprehensive evaluation combining clinical with neuroimaging studies, mainly magnetic resonance imaging (MRI), and genetic analysis. MRI may reveal early cerebellar atrophy and a low-intensity signal in the globus pallidus on iron-sensitive sequences, indicative of iron accumulation. Currently, there is no curative treatment for INAD, so management focuses on providing palliative care and symptom control using a multidisciplinary approach. However, various therapeutic strategies are being investigated, including gene therapy to correct the genetic defect, as well as approaches to modulate pathological pathways such as lipid peroxidation and iron accumulation.
2025-02-21 | AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.
Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the WDR45 gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. WDR45 encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of WDR45 can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human WDR45 transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that WDR45 gene transfer can be a promising therapeutic strategy for BPAN.
cell therapies
2025-11-05 | Exosome-based modulation of ferroptosis in neurological disorders: mechanisms, therapeutic potential, and translational challenges.
Neurological disorders, including acute insults such as stroke and traumatic brain injury and chronic neurodegenerative diseases like Alzheimer's disease and Parkinson's disease, exert a profound global health burden. Ferroptosis, a distinct form of regulated cell death driven by iron accumulation, lipid peroxidation, and oxidative stress, has emerged as a central pathological mechanism across these conditions. Exosomes, nanoscale extracellular vesicles capable of crossing the blood-brain barrier and delivering functional cargos such as microRNAs, long non-coding RNAs, and proteins, have demonstrated remarkable potential in modulating ferroptotic signaling. Through regulation of the GPX4-GSH axis, ferritinophagy, iron homeostasis, and antioxidant pathways, exosome-based interventions offer neuroprotective benefits in diverse models of neurological injury. This review synthesizes current advances in the mechanistic understanding of ferroptosis and highlights emerging strategies leveraging exosomes as precision delivery platforms for ferroptosis-targeted therapy. We also discuss the translational challenges and future directions necessary to realize exosome-guided neuroprotection as a viable clinical paradigm.
2016-02-10 | Globus pallidus neuronal firing rates relate to dystonia aetiology and outcome from Deep Brain Stimulation (DBS) in children
To compare neuronal firing rates from the Globus Pallidus interna (GPi) and externa (GPe) in children undergoing DBS for different types of dystonia and to relate findings to outcome. Microelectrode data were obtained to guide electrode position in 44 children with dystonia (14 Primary, 22 Secondary Static, 8 Secondary Progressive due to Neurodegeneration and Brain Iron Accumulation (NBIA); age 3.3–18.1 years). Digitised spike trains were analysed off-line, blind to clinical data. We identified 267 GPi and 87 GPe cells. Median GPi firing frequency was higher in Primary (13.5 Hz) than Secondary Static dystonia (9.6 Hz) (p = 0.002) and higher in NBIA (25 Hz) than either Primary (p = 0.006) or Secondary Static dystonia (p = 0.00004). Median GPe firing frequency was higher in NBIA (15.9 Hz) than Secondary Static dystonia (7 Hz) (p = 0.013). The proportion of regular versus irregularly firing cells also varied significantly across groups (p < 0.001). GPi firing frequency showed a positive correlation with 1-year outcome from DBS (percentage improvement in Burke–Fahn–Marsden Dystonia Rating Scale motor score), for the group overall (p = 0.040) and particularly for the non-progressive patients (p = 0.006). Pallidal firing rates differ with dystonia type and correlate with DBS outcome. This information could guide future target selection in a more individualized approach to neuromodulation.
other
2026-01-04 | Inflammation and oligoclonal bands in cerebrospinal fluid in neurodegeneration associated with C19orf12 mutations.
Analysis of cerebrospinal fluid examination can provide valuable information about the ongoing pathological processes in the central nervous system. To demonstrate chronic inflammation, oligoclonal bands (OCB) are detected and are typical of chronic demyelinating disease-multiple sclerosis (MS). This study aimed to detect OCB and white matter hyperintensities in patients with C19orf12 mutations. Thirteen patients with C19orf12 mutations causing mitochondrial membrane protein-associated neurodegeneration (MPAN) were examined. Eight patients exhibited oligoclonal bands, with 6 having type 3 and 2 having type 2. All patients with OCB and 3 without OCB showed myelin loss. Our findings, which reveal chronic inflammation in NBIA-MPAN alongside myelin loss, provide new insights into disease pathology and promote discussion of anti-inflammatory treatments in C19orf12 carriers.
2024-04-15 | Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy.
Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin's E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.
2024-02-26 | Acetylated oligopeptide and N-acetylcysteine protect against iron overload-induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO-1 and downregulation of MMP-9/TIMP-1 and GFAP.
Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.
small molecules
2026-08-15 | From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis.
Coenzyme A (CoA) biosynthesis is a conserved, dynamically regulated pathway essential for mitochondrial energy production, fatty acid oxidation, lipid biosynthesis and protein acylation. Biallelic variants in PANK2, PPCS, PPCDC, and COASY cause rare inborn errors of CoA biosynthesis, associated with markedly different clinical phenotypes: PANK2 and COASY defects predominantly cause neurological disorders within or adjacent to the neurodegeneration with brain iron accumulation (NBIA) spectrum, whereas PPCS and PPCDC deficiencies present mainly as severe early-onset dilated cardiomyopathy. However, COASY variants can also cause pontocerebellar hypoplasia and riboflavin-responsive lipid storage myopathy. This review examines these four disorders from a metabolic perspective, integrating clinical features, experimental models, biochemical data and emerging therapeutic approaches. Current evidence indicates that disease pathogenesis cannot be explained only by global CoA depletion. Total CoA levels may be reduced in PPCS and PPCDC deficiency, but are often preserved under basal conditions in PKAN and COASY-related models. Instead, impaired compartment-specific CoA handling and failure to sustain CoA-dependent flux under increased metabolic demand are emerging as central pathogenic concepts. Perturbation of fatty acid handling, acyl-CoA/acylcarnitine balance, mitochondrial function, iron homeostasis, protein acylation and 4'-phosphopantetheinylation may contribute to tissue-selective vulnerability. Therapeutic strategies are therefore likely to require disease-specific approaches, including precursor bypass or PANK activation where pathway flux can be restored, early pantethine supplementation in cardiomyopathic forms, and downstream or gene-directed strategies for COASY-related disorders. Understanding CoA as a regulator of metabolic adaptability provides a unifying framework for interpreting both shared mechanisms and disease divergence.
2026-08-12 | Modelling Ferroptosis in a Human Microglial Line by Sequential Exposure to Iron and GPX4 Inhibition.
Excessive iron accumulation is a pathological feature of several neurodegenerative diseases (NDDs), and a growing body of evidence suggests that ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, is implicated in their pathogenesis. Microglia, the brain's resident immune cells, buffer iron overload but become susceptible to ferroptotic death, exacerbating neuroinflammation and neuronal loss. To uncover the molecular events leading to microglial ferroptosis, we established a human microglial ferroptosis model using the HMC3 cell line. This model recapitulates core features of ferroptosis, including increased reactive oxygen species (ROS) and peroxidation of lipids at the membrane, both rescued by ferrostatin-1 (Fer-1). We used this model to perform integrated multiomic profiling and identified significant dysregulation in lipid species, notably an accumulation of sterols, including oxysterols such as 7-oxo-cholesterol, alongside the oxidation of polyunsaturated fatty acids (PUFAs) that are characteristic of ferroptosis. Transcriptomic and proteomic analyses corroborate these findings, revealing the upregulation of the mevalonate pathway and cholesterol metabolism. Importantly, the increased expression of some of these key metabolic genes was also reversed by Fer-1 treatment, indicating their role in a preferroptotic signature. Our model provides a novel platform for investigating early molecular events in microglia ferroptosis. Integrating these findings into future investigations could uncover new protective mechanisms against microglial ferroptosis to ensure homeostatic regulation of ROS levels and sterol metabolism.
2026-08-03 | In Silico Characterization of a Novel Sulfonamide Derivative as a GPX4 Inhibitor: Docking, ADME, and Toxicity Evaluation to Deliver a Translatable Pharmacophore for Wet-Lab Research
Ferroptosis an iron-dependent, regulated form of cell death driven by the lethal accumulation of lipid hydroperoxides within cellular membranes is suppressed principally by glutathione peroxidase 4 (GPX4), a selenoenzyme whose inhibition has emerged as a strategy of growing therapeutic interest in both oncology and neurodegeneration. Despite this promise, the existing GPX4 inhibitor landscape is dominated by covalent electrophiles that carry well-documented pharmacokinetic liabilities, underscoring the need for drug-like, non-covalent alternatives. To address this gap, an integrated computational workflow was applied to a newly designed sulfonamide derivative (hereafter the target compound). Structure-based molecular docking with AutoDock Vina returned a top-ranked binding affinity of −4.67 kcal mol-1; interaction analysis identified a bifurcated hydrogen-bonding network anchoring the ligand to Thr 132 (2.01 Å) and Gln 70 (2.67 Å), complemented by hydrophobic contacts with Phe 71, Asn 102, Ala 126, and Ile 127. Pharmacokinetic profiling via SwissADME confirmed compliance with Lipinski's Rule of Five (MW = 324.37 g mol-1, LogP = 1.63, zero violations), high gastrointestinal absorption, blood–brain barrier (BBB) permeability as assessed by the BOILED-Egg model, zero PAINS alerts, and a synthetic accessibility score of 3.05. Toxicological assessment through ProTox-3.0 estimated an acute oral LD50 of 5000 mg kg-1 (GHS Class 5) with predicted inactivity across hepatotoxicity, cardiotoxicity, nephrotoxicity, mutagenicity, carcinogenicity, and cytotoxicity endpoints. These findings collectively indicate that the target compound satisfies binding, drug-likeness, and safety requirements simultaneously, positioning it as a viable lead candidate for experimental follow-up.
2026-07-29 | Supplementation via DAF-16 and pnk-1 driven pantothenate-coenzyme A flux improves disease related stress resistance in C. elegans.
Metabolic pathways are increasingly recognized as tractable targets in aging and disease. Building on prior work demonstrating that supplementation with low-molecular weight metabolites (amino acids, vitamins, and their intermediates) can extend lifespan in Caenorhabditis elegans, we focused on pantothenate (vitamin B5), which is dysregulated in sarcopenic muscle and in several neurodegenerative and metabolic disorders. Pantothenate is the obligate precursor of coenzyme A through a short, highly conserved biosynthetic pathway in which loss-of-function mutations can cause neurodegeneration with brain iron accumulation. In C. elegans, the longevity curtailing transcription factor DAF-16/FOXO has a conserved binding element in the promoter region of pnk-1, encoding the first enzyme (PNK-1) in the coenzyme A pathway, and pnk-1 is markedly upregulated in long-lived daf-2 (insulin/-like receptor) mutants, implicating coenzyme A metabolism in longevity. Here, we demonstrate that CoA levels naturally increase during early life and decrease towards older age in C. elegans. Dietary pantothenate supplementation increases coenzyme A levels with minimal effects on lifespan but systemic effects on lipid metabolism, mitochondrial dynamics, and muscle structure under basal conditions. Under DAF-16-associated stress conditions, including heat and oxidative stress, pnk-1 expression is upregulated and pantothenate supplementation robustly extends lifespan and improves mobility. Finally, we demonstrate dysregulation of daf-16 and pnk-1 expression in amyotrophic lateral sclerosis (ALS) models, in which pantothenate supplementation confers both lifespan extension and cholinergic neuroprotection.
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.
proteins
2026-04-07 | Clinical Evaluation of Three KRS Families and Cellular Analysis of Distinct ATP13A2 Mutations Reveal Different Levels of Iron Accumulation.
Kufor-Rakeb Syndrome (KRS) is a rare neurodegenerative disease caused by homozygous mutations in the ATP13A2 gene. The ATP13A2 protein, found in lysosomal and late-endosomal membranes, performs cellular functions such as iron-chelating agent transport and intracellular iron homeostasis. Mutations in ATP13A2 can lead to intracellular iron accumulation; however, whether KRS caused by an ATP13A2 mutation falls under Neurodegeneration with Brain Iron Accumulation disorders has long been debated. The most fundamental reason is that magnetic resonance imaging (MRI) cannot identify iron deposits in the basal ganglia in all KRS cases. We hypothesize that analyzing iron deposition at the cellular level could be more sensitive in detecting varying levels of iron accumulation associated with different ATP13A2 mutations, and it may be more useful when conventional MRI fails to detect iron, yields inconclusive results, or cannot be performed. We identified two new ATP13A2 mutations (p.Leu518_Thr519del, and p.Leu939Pro) in this study and comparatively investigated the impacts of three distinct ATP13A2 mutations (p.Pro474fs, p.Leu518_Thr519del, and p.Leu939Pro) using KRS patients' primary fibroblasts and MCF7 cells overexpressing these mutated ATP13A2 proteins to analyze if these different mutations of ATP13A2 can cause differing levels of iron accumulation. Following the detection of iron deposits via Prussian blue staining and inductively coupled plasma mass spectrometry, the cell viability was assessed via MTT assay to ascertain the impact of iron accumulation. Each type of ATP13A2 mutation led to iron accumulation; however, frameshift and deletion mutations resulted in more iron accumulation than the missense mutation. In addition, the transient overexpression of the wild-type ATP13A2 attenuated the cell death caused by iron accumulation. This study demonstrated that different types of ATP13A2 mutations are related to varying levels of iron accumulation and provided an explanation for the inconsistent perspectives on the association of KRS with iron accumulation.
2025-12-17 | Integrating iron and lipid biology in Alzheimer’s disease
Neurons exist at the intersection of two essential yet hazardous metabolic demands: iron-driven bioenergetics and lipid-dependent membrane remodeling. Their reliance on mitochondrial iron for adenosine triphosphate (ATP) generation, combined with the requirement for polyunsaturated fatty acids to sustain synaptic plasticity, creates a biochemical environment primed for ferroptosis. This Perspective examines how the interplay between iron and lipid metabolism defines neuronal vulnerability in neurodegenerative diseases, focusing on apolipoprotein E (ApoE) as a metabolic gatekeeper coordinating those pathways. Beyond its canonical function in lipid transport, ApoE acts as a potent anti-ferroptotic factor by inhibiting ferritinophagy and restraining the release of labile iron, thereby coupling lipid trafficking with iron homeostasis. Dysregulation of this axis in Alzheimer’s disease amplifies lipid peroxidation and compromises antioxidant defenses. Parallel mechanisms are observed in Neurodegeneration with Brain Iron Accumulation disorders, where mutations in lipid-metabolic genes paradoxically lead to brain iron accumulation, underscoring the genetic entanglement of these pathways. Collectively, these findings support a unifying model in which neuronal ferroptosis arises not from isolated iron overload or lipid imbalance, but from the breakdown of a coordinated iron-lipid defense network. We propose that restoring this equilibrium through modulation of ApoE function, preservation of mitochondrial iron utilization, and suppression of lipid peroxidation represents a promising avenue for therapeutic intervention in neurodegenerative disease.
2024-07-29 | Assessment of the degree of disability of the Polish NBIA-MPAN population based on a patient survey
Neurodegeneration with brain iron accumulation (NBIA) describes a group of extremely rare hereditary disorders with an estimated prevalence of 1–3/1,000,000. Mitochondrial membrane protein associated neurodegeneration (MPAN) is the third most common form of NBIA, accounting for 10% of NBIA cases globally and up to 50% of cases in Poland. This survey was conducted by the Association NBIA Poland to collect data on the functioning of patients with NBIA/MPAN based on self-reported EQ-5D-5L (EuroQoL 5-Dimension 5-Level) scores. A total of 50 patients living in Poland, including 26 patients with NBIA/MPAN, participated in the study. The mean age of NBIA/MPAN patients was 22 years; the mean age at symptom onset is 10 years. At the time of the survey, most patients were disabled and required assistance with daily activities. More than 50% of participants needed help with hygiene or dressing, and 40% were unable to walk on their own. Nearly 50% of patients declared symptoms indicating lowered mood. The survey showed that NBIA/MPAN leads to significant disability within a short period of time after symptom onset. Intensive work is underway to discover the role of the C19orf12 protein and develop therapeutic strategies. Actions are necessary to improve the comfort of everyday life of patients with NBIA/MPAN and to improve access to rehabilitation, including home-based programmes.
2024-02-09 | Nazo, the Drosophila homolog of the NBIA-mutated protein–c19orf12, is required for triglyceride homeostasis
Lipid dyshomeostasis has been implicated in a variety of diseases ranging from obesity to neurodegenerative disorders such as Neurodegeneration with Brain Iron Accumulation (NBIA). Here, we uncover the physiological role of Nazo, the Drosophila melanogaster homolog of the NBIA-mutated protein–c19orf12, whose function has been elusive. Ablation of Drosophila c19orf12 homologs leads to dysregulation of multiple lipid metabolism genes. nazo mutants exhibit markedly reduced gut lipid droplet and whole-body triglyceride contents. Consequently, they are sensitive to starvation and oxidative stress. Nazo is required for maintaining normal levels of Perilipin-2, an inhibitor of the lipase–Brummer. Concurrent knockdown of Brummer or overexpression of Perilipin-2 rescues the nazo phenotype, suggesting that this defect, at least in part, may arise from diminished Perilipin-2 on lipid droplets leading to aberrant Brummer-mediated lipolysis. Our findings potentially provide novel insights into the role of c19orf12 as a possible link between lipid dyshomeostasis and neurodegeneration, particularly in the context of NBIA.
2023-08-07 | The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain.
Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux. The absence of this protein in humans and rodents produces progressive neurodegeneration with brain iron accumulation. Astrocytes express high levels of Cp and iron efflux from these cells has been shown to be central for oligodendrocyte maturation and myelination. To explore the role of astrocytic Cp in brain development and aging we generated a specific conditional KO mouse for Cp in astrocytes (Cp cKO). Deletion of Cp in astrocytes during the first postnatal week induced hypomyelination and a significant delay in oligodendrocyte maturation. This abnormal myelin synthesis was exacerbated throughout the first two postnatal months and accompanied by a reduction in oligodendrocyte iron content, as well as an increase in brain oxidative stress. In contrast to young animals, deletion of astrocytic Cp at 8 months of age engendered iron accumulation in several brain areas and neurodegeneration in cortical regions. Aged Cp cKO mice also showed myelin loss and oxidative stress in oligodendrocytes and neurons, and at 18 months of age, developed abnormal behavioral profiles, including deficits in locomotion and short-term memory. In summary, our results demonstrate that iron efflux-mediated by astrocytic Cp-is essential for both early oligodendrocyte maturation and myelin integrity in the mature brain. Additionally, our data suggest that astrocytic Cp activity is central to prevent iron accumulation and iron-induced oxidative stress in the aging CNS.
gene therapies
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.
2026-06-17 | Pathophysiology, biological models and new therapeutic approaches in β-Propeller Associated Neurodegeneration.
Neurodegeneration with brain iron accumulation (NBIA) encompasses a set of rare disorders that present a diagnostic challenge due to their genetic and clinical diversity, with treatment options currently limited to symptom alleviation. One subtype, β-Propeller Associated Neurodegeneration (BPAN), results from pathogenic variants in the WDR45 gene on the X chromosome. This condition is marked by iron accumulation in the globus pallidus and substantia nigra, alongside early onset developmental delays, seizures, and motor impairments. The WDR45 gene produces the WDR45 protein, which plays a key role in the creation and maturation of autophagosomes-crucial components of the autophagy process, a cellular mechanism vital to the organism's proper function. In BPAN, reduced autophagy correlates with mitochondrial dysfunction, impaired antioxidant defenses, elevated lipid peroxidation, buildup of lipofuscin granules, and disrupted iron metabolism. However, the precise relationships between these pathological issues remain unclear. There is no curative treatment for BPAN, therefore care focuses on palliation and symptom management through a multidisciplinary approach. Nonetheless, research into various therapeutic strategies is ongoing, including gene therapy to correct the genetic anomaly and methods to influence pathological pathways like autophagy deficiency, lipid peroxidation, and iron accumulation. A novel approach has recently been suggested, aimed at reactivating the inactive X chromosome in females with BPAN.
2025-12-12 | Neurodegeneration with Brain Iron Accumulation
Neurodegeneration with brain iron accumulation (NBIA) refers to a heterogeneous group of neurological disorders due to the accumulation of iron in the basal ganglia. NBIA leads to progressive cognitive and motor function degeneration. To date, although 10 different genetic variations of the disease have been reported, this figure is likely to amplify over the coming years. Aceruloplasminemia and neuroferritinopathy are among the various forms of NBIA resulting from iron accumulation and are the primary contributing factors of cellular oxidative damage. NBIA exhibits a wide range of clinical symptoms, which may vary from extrapyramidal symptoms to dystonia, spasms, muscular rigidity, parkinsonism, neuro-psychiatric issues, optic atrophy, and retinal degeneration. The diagnosis of the disease is challenging and hence requires tailored therapeutic interventions, owing to overlapping clinical symptoms with certain non-progressive chronic encephalopathies. Research advances in the field focus on the design and development of novel strategies that could alter 130genetic defects, such as targeted gene therapy, gene editing, and substrate replacement therapies, coupled with monetary benefits and minimal side effects. This chapter highlights the genetic variations of the disease, the underlying molecular mechanisms of NBIA associated with brain iron accumulation, and their possible insights towards future customized targeted therapies.
2025-07-28 | Infantile neuroaxonal dystrophy: Molecular mechanisms and pathogenesis of PLA2G6-associated neurodegeneration.
Infantile neuroaxonal dystrophy (INAD), also known as PLA2G6-associated neurodegeneration (PLAN), is a rare, early-onset, autosomal recessively inherited neurodegenerative disease belonging to the group of neurodegenerations with brain iron accumulation (NBIA). The main cause of this disease is bi-allelic mutations in the PLA2G6 gene, which codes for the enzyme phospholipase A2 type VI. Clinically, it manifests with progressive neurodevelopmental impairment, psychomotor regression, movement disorders, and pyramidal signs. Initially described in the 1950s, the classical form presents in the first two years of life, although later-onset variants are recognized. At the neuropathological level, INAD is characterized by the presence of neuroaxonal spheroids, which are dilations of degenerated axons, located mainly in the white matter, basal ganglia, and cerebellum. INAD is considered a rare or ultra-rare disease, with an estimated prevalence of approximately 1 per million individuals. Diagnosis requires a comprehensive evaluation combining clinical with neuroimaging studies, mainly magnetic resonance imaging (MRI), and genetic analysis. MRI may reveal early cerebellar atrophy and a low-intensity signal in the globus pallidus on iron-sensitive sequences, indicative of iron accumulation. Currently, there is no curative treatment for INAD, so management focuses on providing palliative care and symptom control using a multidisciplinary approach. However, various therapeutic strategies are being investigated, including gene therapy to correct the genetic defect, as well as approaches to modulate pathological pathways such as lipid peroxidation and iron accumulation.
2025-02-21 | AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.
Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the WDR45 gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. WDR45 encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of WDR45 can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human WDR45 transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that WDR45 gene transfer can be a promising therapeutic strategy for BPAN.
cell therapies
2025-11-05 | Exosome-based modulation of ferroptosis in neurological disorders: mechanisms, therapeutic potential, and translational challenges.
Neurological disorders, including acute insults such as stroke and traumatic brain injury and chronic neurodegenerative diseases like Alzheimer's disease and Parkinson's disease, exert a profound global health burden. Ferroptosis, a distinct form of regulated cell death driven by iron accumulation, lipid peroxidation, and oxidative stress, has emerged as a central pathological mechanism across these conditions. Exosomes, nanoscale extracellular vesicles capable of crossing the blood-brain barrier and delivering functional cargos such as microRNAs, long non-coding RNAs, and proteins, have demonstrated remarkable potential in modulating ferroptotic signaling. Through regulation of the GPX4-GSH axis, ferritinophagy, iron homeostasis, and antioxidant pathways, exosome-based interventions offer neuroprotective benefits in diverse models of neurological injury. This review synthesizes current advances in the mechanistic understanding of ferroptosis and highlights emerging strategies leveraging exosomes as precision delivery platforms for ferroptosis-targeted therapy. We also discuss the translational challenges and future directions necessary to realize exosome-guided neuroprotection as a viable clinical paradigm.
2016-02-10 | Globus pallidus neuronal firing rates relate to dystonia aetiology and outcome from Deep Brain Stimulation (DBS) in children
To compare neuronal firing rates from the Globus Pallidus interna (GPi) and externa (GPe) in children undergoing DBS for different types of dystonia and to relate findings to outcome. Microelectrode data were obtained to guide electrode position in 44 children with dystonia (14 Primary, 22 Secondary Static, 8 Secondary Progressive due to Neurodegeneration and Brain Iron Accumulation (NBIA); age 3.3–18.1 years). Digitised spike trains were analysed off-line, blind to clinical data. We identified 267 GPi and 87 GPe cells. Median GPi firing frequency was higher in Primary (13.5 Hz) than Secondary Static dystonia (9.6 Hz) (p = 0.002) and higher in NBIA (25 Hz) than either Primary (p = 0.006) or Secondary Static dystonia (p = 0.00004). Median GPe firing frequency was higher in NBIA (15.9 Hz) than Secondary Static dystonia (7 Hz) (p = 0.013). The proportion of regular versus irregularly firing cells also varied significantly across groups (p < 0.001). GPi firing frequency showed a positive correlation with 1-year outcome from DBS (percentage improvement in Burke–Fahn–Marsden Dystonia Rating Scale motor score), for the group overall (p = 0.040) and particularly for the non-progressive patients (p = 0.006). Pallidal firing rates differ with dystonia type and correlate with DBS outcome. This information could guide future target selection in a more individualized approach to neuromodulation.
other
2026-01-04 | Inflammation and oligoclonal bands in cerebrospinal fluid in neurodegeneration associated with C19orf12 mutations.
Analysis of cerebrospinal fluid examination can provide valuable information about the ongoing pathological processes in the central nervous system. To demonstrate chronic inflammation, oligoclonal bands (OCB) are detected and are typical of chronic demyelinating disease-multiple sclerosis (MS). This study aimed to detect OCB and white matter hyperintensities in patients with C19orf12 mutations. Thirteen patients with C19orf12 mutations causing mitochondrial membrane protein-associated neurodegeneration (MPAN) were examined. Eight patients exhibited oligoclonal bands, with 6 having type 3 and 2 having type 2. All patients with OCB and 3 without OCB showed myelin loss. Our findings, which reveal chronic inflammation in NBIA-MPAN alongside myelin loss, provide new insights into disease pathology and promote discussion of anti-inflammatory treatments in C19orf12 carriers.
2024-04-15 | Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy.
Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin's E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.
2024-02-26 | Acetylated oligopeptide and N-acetylcysteine protect against iron overload-induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO-1 and downregulation of MMP-9/TIMP-1 and GFAP.
Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.
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Drug Discovery Landscape
2 orphan drug designations for Neurodegeneration with brain iron accumulation.
2 orphan drug designations for Neurodegeneration with brain iron accumulation.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Deferiprone | small molecules | EMA | 2018-06-27 | — | Chiesi Farmaceutici S.p.A. |
deferiprone | small molecules | FDA | 2017-06-15 | — | Chiesi USA, Inc. |
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