Neurodegeneration With Brain Iron Accumulation Research Articles

Metabolic impairments in neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) is a broad, heterogeneous group of rare inherited diseases (1–3 patients/1,000,000 people) characterized by progressive symptoms associated with excessive abnormal iron deposition in the brain. Approximately 15,000–20,000 individuals worldwide are estimated to be affected by NBIA. NBIA is usually associated with slowly progressive pyramidal and extrapyramidal symptoms, axonal motor neuropathy, optic nerve atrophy, cognitive impairment and neuropsychiatric disorders. To date, eleven subtypes of NBIA have been described and the most common ones include pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and beta-propeller protein-associated neurodegeneration (BPAN). We present a comprehensive overview of the evidence for disturbed cellular homeostasis and metabolic alterations in NBIA variants, with a careful focus on mitochondrial bioenergetics and lipid metabolism which drives a new perspective in understanding the course of this infrequent malady.

Functional impairments in NBIA patients: Preliminary results.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group (genetically and phenotypically) of genetically determined disorders. Up to date there is no cure for this disease, so the applied treatments focus on symptoms control and palliative care. The main problems are delayed motor development, gait deterioration, postural instability, cognitive dysfunctions, abnormal muscle tone and many others. As gait and balance deficits are predominant features of NBIA patients this study aimed at the use of the objective, instrumented functional tests as well as functional assessment scales to assess their functional impairments. Twenty three NBIA patients recruited for the study underwent objective, instrumented gait analysis, balance assessment, pedobarography and functional evaluation with Gross Motor Function Measure (GMFM-88). The results showed high variability and heterogeneity of NBIA functional status (GMFM from 27.5 to 100.0), but also showed some differences in gait pattern between their types (p < 0.05 at the pelvis, hip and knee). We think that these results could help design objective assessment protocols in future clinical studies.

Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.

Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.

Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?

Iron is an essential metal ion implicated in several cellular processes. However, the reactive nature of iron renders this metal ion potentially dangerous for cells, and its levels need to be tightly controlled. Alterations in the intracellular concentration of iron are associated with different neuropathological conditions, including neurodegeneration with brain iron accumulation (NBIA). As the name suggests, NBIA encompasses a class of rare and still poorly investigated neurodegenerative disorders characterized by an abnormal accumulation of iron in the brain. NBIA is mostly a genetic pathology, and to date, 10 genes have been linked to familial forms of NBIA. In the present review, after the description of the principal mechanisms implicated in iron homeostasis, we summarize the research data concerning the pathological mechanisms underlying the genetic forms of NBIA and discuss the potential involvement of iron in such processes. The picture that emerges is that, while iron overload can contribute to the pathogenesis of NBIA, it does not seem to be the causal factor in most forms of the pathology. The onset of these pathologies is rather caused by a combination of processes involving the interplay between lipid metabolism, mitochondrial functions, and autophagic activity, eventually leading to iron dyshomeostasis.

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.

Distinctive Pattern of Metal Deposition in Neurologic Wilson Disease: Insights From 7T Susceptibility-Weighted Imaging.

Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

Mitochondrial iron deficiency triggers cytosolic iron overload in PKAN hiPS-derived astrocytes

Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and neurodegeneration. We analyzed hiPS-derived astrocytes from PANK2-associated neurodegeneration (PKAN), an NBIA disease characterized by progressive neurodegeneration and high iron accumulation in the globus pallidus. Previous data indicated that PKAN astrocytes exhibit alterations in iron metabolism, general impairment of constitutive endosomal trafficking, mitochondrial dysfunction and acquired neurotoxic features. Here, we performed a more in-depth analysis of the interactions between endocytic vesicles and mitochondria via superresolution microscopy experiments. A significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN cells than in control cells, confirming the impaired intracellular fate of cargo endosomes. The investigation of cytosolic and mitochondrial iron parameters indicated that mitochondrial iron availability was substantially lower in PKAN cells compared to that in the controls. In addition, PKAN astrocytes exhibited defects in tubulin acetylation/phosphorylation, which might be responsible for unregulated vesicular dynamics and inappropriate iron delivery to mitochondria. Thus, the impairment of iron incorporation into these organelles seems to be the cause of cell iron delocalization, resulting in cytosolic iron overload and mitochondrial iron deficiency, triggering mitochondrial dysfunction. Overall, the data elucidate the mechanism of iron accumulation in CoA deficiency, highlighting the importance of mitochondrial iron deficiency in the pathogenesis of disease.

P.047 Survey of caregivers of individuals with NBIAs to identify relevant quality of life outcomes

Background: Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogenous group of disorders with the common theme of iron accumulation in the basal ganglia. These disorders typically present in childhood with progressive neurodegeneration and neuropsychiatric symptoms. Caring for an individual with NBIAs is intensive, however it is unknown what factors impact caregiver well-being and quality of life. Methods: Common themes were obtained via literature review of quality of life surveys in children with neurological and chronic illnesses. Five domains were addressed: Diagnosis, Communication, Symptom Management, Clinical Experience and Resources/Support. The survey was approved by the Family Advisory Committee at the CHEO Research Institute and the CHEO REB. The survey was distributed via the Rare Connect Platform to Canadian caregivers. Results: Survey responses are being analyzed and will be presented at the CNSF. Within each domain, Likert scales will be analyzed. Domains will be ranked according to the caregiver responses. Conclusions: Results of this survey will assist in developing care management guidelines, resources for families and help with future advocacy for patients and families affected by NBIAs. The results will also help guide future NBIA Canada Family Conferences.

Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.

COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders. Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients. These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases.

A c.726C>G (p.Tyr242Ter) nonsense mutation-associated with splicing alteration (NASA) of WDR45 gene underlies β-propeller protein-associated neurodegeneration (BPAN)

Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous disease characterized by increased iron deposition in the basal ganglia and progressive degeneration of the nervous system in adulthood. However, in early childhood, there were no characteristic features to perform early diagnosis. In our study, a female child exhibited global developmental delay, intellectual disability, and febrile seizure without other distinct clinical phenotypes. Through whole exome sequencing (WES), a de novo nonsense mutation (c.726C > G, p. Tyr242Ter) of WDR45 gene was identified in this child. She was finally diagnosed as β‐propeller protein-associated neurodegeneration (BPAN), one of the recently identified subtypes of NBIA. This mutation could act as a premature stop codon (PSC) which rendered the mutated transcripts to be degraded by nonsense-mediated mRNA decay (NMD), leading to decreased levels of PSC-containing mRNAs. Additionally, through mini-gene splicing assays, this mutation could result in an unprecedented novel transcript with the exon 9 of WDR45 excluded by nonsense-associated splicing alteration (NASA). Transcriptome sequencing (RNA-seq) on total RNAs from PBMCs of the trio revealed three types of alternative splicing events in the patient. Further research implied that downregulation of iron transport genes (TFRC, TFR2, SCARA5) might be the underlying mechanism for the iron accumulation in patients with deficient WDR45. This is the first report about NASA happening in WDR45. It implies that nonsense mutations approximal to splicing sites could affect the disease pathogenesis through more than one molecular mechanism and should be taken into consideration when conducting genetic counseling.

Pantothenate kinase-associated neurodegeneration (PKAN) a rare neurodegenerative disease-Two case reports

Neurodegeneration with brain iron accumulation (NBIA) is a subtype of inherited metabolic disorders. It includes pantothenate kinase-associated neurodegeneration (PKAN), which is a rare autosomal recessive disorder caused by the mutation of pantothenate kinase 2-gene (PANK2). It affects the deep grey matter nuclei causing progressive extra pyramidal motor impairment. We present two cases who are presented in our department with walking difficulty, dystonia and dysarthria. MRI of brain (T2) showed- hyper intensity of the basal ganglia with the classic eye-of-the-tiger sign and one child's genetic study revealed mutation in PANK2 gene. We managed them with anti dystonic drugs along with iron chelating agent. J Bangladesh Coll Phys Surg 2024; 42: 209-213

Globus Pallidus Lesion With Iron Deposition and Dopaminergic Denervation in a Patient With a Pathogenic SLC6A1 Variant: A Case Report.

SLC6A1-related disorders encompass heterogeneous neuropsychiatric manifestations through GABAergic dysregulation, without any specific abnormalities on brain MRI, nor evidence of dopaminergic cell loss on I123-FP-β-CIT SPECT. We report here a case of globus pallidus lesions and dopaminergic denervation in a patient with a pathogenic SLC6A1 variant. A 26-year-old female patient with intellectual disability, behavioral, and psychiatric disorders treated by neuroleptics for many years developed a parkinsonian syndrome associated with mild hand dystonia and chorea. A 3T brain MRI and I123-FP-β-CIT SPECT were performed. MRI of the brain found bilateral pallidal lesions consistent with neurodegeneration with iron accumulation. The I123-FP-β-CIT SPECT showed bilateral striatal presynaptic dopaminergic denervation. Whole-genome sequencing revealed a pathogenic SLC6A1 de novo variant. No additional variant was found in any of the genes responsible for Neurodegeneration with Brain Iron Accumulation (NBIA). This is a description of dopaminergic denervation and globus pallidus lesions with iron accumulation related to a SLC6A1 pathogenic variant. These findings expand the phenotype of SLC6A1-related disorder and suggest that it could be considered as a differential diagnosis of NBIA.

Clinical, neuroimaging and genetic findings in Brazilian patients with neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) encompasses a clinically and genetically heterogeneous group of rare disorders. Here, we report clinical, neuroimaging and genetic studies in twenty three Brazilian NBIA patients. In thirteen subjects, deleterious variants were detected in known NBIA-causing genes (PANK2, PLA2G6, C9ORF12, WDR45 and FA2H), including previously unreported variants in PANK2 and PLA2G6. Two patients carried rare, likely pathogenic variants in genes not previously associated with NBIA: KMT2A c.11785A > C (p.Ile3929Leu), and TIMM8A c.127T > C (p.Cys43Arg), suggesting an expansion of their associated phenotypes to include NBIA. In eight patients the etiology remains unsolved, suggesting variants undetectable by the adopted methods, or the existence of additional NBIA-causing genes.

Genetic Targets and Applications of Iron Chelators for Neurodegeneration with Brain Iron Accumulation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative diseases that are typically caused by a monogenetic mutation, leading to development of disordered movement symptoms such as dystonia, hyperreflexia, etc. Brain iron accumulation can be diagnosed through MRI imaging and is hypothesized to be the cause of oxidative stress, leading to the degeneration of brain tissue. There are four main types of NBIA: pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MKAN), and beta-propeller protein-associated neurodegeneration (BPAN). There are no causative therapies for these diseases, but iron chelators have been shown to have potential toward treating NBIA. Three chelators are investigated in this Review: deferoxamine (DFO), desferasirox (DFS), and deferiprone (DFP). DFO has been investigated to treat neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD); however, dose-related toxicity in these studies, as well as in PKAN studies, have shown that the drug still requires more development before it can be applied toward NBIA cases. Iron chelation therapies other than the ones currently in clinical use have not yet reached clinical studies, but they may possess characteristics that would allow them to access the brain in ways that current chelators cannot. Intranasal formulations are an attractive dosage form to study for chelation therapy, as this method of delivery can bypass the blood-brain barrier and access the CNS. Gene therapy differs from iron chelation therapy as it is a causal treatment of the disease, whereas iron chelators only target the disease progression of NBIA. Because the pathophysiology of NBIA diseases is still unclear, future courses of action should be focused on causative treatment; however, iron chelation therapy is the current best course of action.

Ferritinophagy: Assessing the Selective Degradation of Iron by Autophagy in Human Fibroblasts.

Mutations in the autophagy gene WDR45/WIPI4 are the cause of beta-propeller-associated neurodegeneration (BPAN), a subtype of human diseases known as neurodegeneration with brain iron accumulation (NBIA) due to the presence of iron deposits in the brains of patients. Intracellular iron levels are tightly regulated by a number of cellular mechanisms, including the critical mechanism of ferritinophagy. This paper describes how ferritinophagy can be assessed in primary, skin-derived human fibroblasts. In this protocol, we use iron-modulating conditions for inducing or inhibiting ferritinophagy at the cellular level, such as the administration of bafilomycin A1 to inhibit lysosome function and ferric ammonium citrate (FAC) or deferasiox (DFX) treatments to overload or deplete iron, respectively. Such treated fibroblasts are then subjected to high-throughput imaging and CellProfiler-based quantitative localization analysis of endogenous ferritin and autophagosomal/lysosomal markers, here LAMP2. Based on the level of autophagosomal/lysosomal ferritin, conclusions can be drawn regarding the level of ferritinophagy. This protocol can be used to assess ferritinophagy in BPAN patient-derived primary fibroblasts or other types of mammalian cells.

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.

Neurodegeneration with Brain Iron Accumulation Disorders and Retinal Neurovascular Structure.

The unique neurovascular structure of the retina has provided an opportunity to observe brain pathology in many neurological disorders. However, such studies on neurodegeneration with brain iron accumulation (NBIA) disorders are lacking. To investigate NBIA's neurological and ophthalmological manifestations. This cross-sectional study was conducted on genetically confirmed NBIA patients and an age-gender-matched control group. The thickness of retinal layers, central choroidal thickness (CCT), and capillary plexus densities were measured by spectral domain-optical coherence tomography (SD-OCT) and OCT angiography, respectively. The patients also underwent funduscopy, electroretinography (ERG), visual evoked potential (VEP), and neurological examination (Pantothenate-Kinase Associated Neurodegeneration-Disease Rating Scale [PKAN-DRS]). The generalized estimating equation model was used to consider inter-eye correlations. Seventy-four patients' and 80 controls' eyes were analyzed. Patients had significantly decreased visual acuity, reduced inner or outer sectors of almost all evaluated layers, increased CCT, and decreased vessel densities, with abnormal VEP and ERG in 32.4% and 45.9%, respectively. There were correlations between visual acuity and temporal peripapillary nerve fiber layer (positive) and between PKAN-DRS score and disease duration (negative), and scotopic b-wave amplitudes (positive). When considering only the PKAN eyes, ONL was among the significantly decreased retinal layers, with no differences in retinal vessel densities. Evidence of pachychoroid was only seen in patients with Kufor Rakeb syndrome. Observing pathologic structural and functional neurovascular changes in NBIA patients may provide an opportunity to elucidate the underlying mechanisms and differential retinal biomarkers in NBIA subtypes in further investigations. © 2023 International Parkinson and Movement Disorder Society.

Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of neurodegeneration with brain iron accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression and to estimate sample sizes for clinical trials. We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites. Linear mixed-effect modelling (LMEM) was used to calculate annual progression rates for the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia (BAD) scale, Schwab and England Activities of Daily Living (SE-ADL) scale and the Pediatric Quality of Life Inventory (PedsQL). We investigated 85 MPAN patients cross-sectionally, with functional outcome data collected in 45. Median age at onset was 9 years and the median diagnostic delay was 5 years. The most common findings were gait disturbance (99%), pyramidal involvement (95%), dysarthria (90%), vision disturbances (82%), with all but dysarthria presenting early in the disease course. After 16 years with the disease, 50% of patients were wheelchair dependent. LMEM showed an annual progression rate of 4.5 points in total UPDRS. The total BAD scale score showed no significant progression over time. The SE-ADL scale and the patient- and parent-reported PedsQL showed a decline of 3.9%, 2.14 and 2.05 points, respectively. No patient subpopulations were identified based on longitudinal trajectories. Our cross-sectional results define the order of onset and frequency of symptoms in MPAN, which will inform the diagnostic process, help to shorten diagnostic delay and aid in counselling patients, parents and caregivers. Our longitudinal findings define the natural history of MPAN, reveal the most responsive outcomes and highlight the need for an MPAN-specific rating approach. Our sample size estimations inform the design of upcoming clinical trials.

Diagnosis and Treatment of Pantothenate Kinase-Associated Neurodegeneration (PKAN): A Systematic Review.

A specific type of neurodegeneration with brain iron accumulation (NBIA) falls under the omit phenotypic continuum-early childhood development of progressive pantothenate kinase-associated neurodegeneration (PKAN). Classic PKAN is distinguished from atypical PKAN by stiffness, dystonia, dysarthria, and choreoathetosis. Pigmentary retinal degeneration is a widespread cause of classic PKAN. Atypical PKAN is distinguished by a later onset (>10 years), noticeable speech abnormalities, psychological disorders, and slower disease development. Studies designed to support various PKANtherapeutic strategies have highlighted the intricacy of coenzyme A (CoA) metabolism and the limitations of our present understanding of disease causation. Therefore, improvements in our knowledge of the causes and therapy of PKAN may have ramifications for our comprehension of other, more prevalent diseases. They may also shed fresh light on the physiological significance of CoA, a cofactor essential for the operation of several cellular metabolic processes. The existence of low but considerable PANK2 expression, which can be elevated in some mutations, provides necessary information that can justify using a hefty dose of pantothenate as a treatment. A more effective therapeutic approach can be achieved by comparing the effects of various currently available pharmacological alternatives on the pathophysiological alterations in fibroblasts and neuronal cells obtained from PKAN patients. The objective of this study is to educate and inform people about PKAN disease conditions such as treatment, diagnosis, and complications. These cell models will also help evaluate the effectiveness of future medicinal innovations. This review discusses the neurodegeneration generated by pantothenate kinase in cellular models, iron/lipofuscin in pantothenate kinase-related neurodegeneration, and treatment and diagnosis of PKAN.

Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.