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Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, or neurodegeneration with brain iron accumulation disorders. Mitochondrial dysfunction, lipofuscin accumulation, autophagy disruption, and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders. Currently, the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear. In this review, we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation, and the effect of iron overload on lipid peroxidation and cellular function. The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration. Therefore, the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration. In addition, we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration, particularly in PLA2G6-associated neurodegeneration, a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the group of neurodegeneration with brain iron accumulation disorders.

Neurodegeneration with brain iron accumulation, beta-propeller protein-associated neurodegeneration, pallido-pyramidal syndrome, WDR45 This case contributes to the expansion of BPAN's clinical phenotype, highlighting the importance of seeking this diagnosis as patients can improve with dopaminergic and botulinum toxin therapy. Keywords: neurodegeneration with brain iron accumulation; beta-propeller protein-associated neurodegeneration; pallido-pyramidal syndrome; WDR45 EN neurodegeneration with brain iron accumulation beta-propeller protein-associated neurodegeneration pallido-pyramidal syndrome WDR45 1211 1214 4 08/29/23 20230801 NES 230801 Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked dominant form of neurodegeneration with brain iron accumulation (NBIA) related to the I WDR45 i gene.[[1], [3]] In most patients, the disease first manifests during infancy or childhood as a global developmental delay, early-onset spastic paraplegia, and epilepsy, with later development of parkinsonism, dystonia, and cognitive decline during adolescence or early adulthood.[[4], [6]] Here we report a late-onset case of BPAN that contributes to the expansion of its clinical phenotype. [Extracted from the article]

Neurodegeneration with brain iron accumulation (NBIA) encompasses a number of heritable disorders affecting children and adults characterized by diverse clinical manifestations and brain iron deposition detected on magnetic resonance imaging (MRI). The most frequent NBIA subtypes are pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, fatty acid-2 hydroxylase-associated neurodegeneration and mitochondrial-membrane proteinassociated neurodegeneration (MPAN). Here, we report a male patient presenting with optic atrophy, progressive cognitive and movement impairment, bilateral hypointensity of the basal ganglia on T2-weighted MRI and proven mutation for MPAN. The NBIA disorders can remain undiagnosed for 3 to 30 years. In children developing optic atrophy, NBIA should be taken into consideration.

Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors. This review analyzes the involvement of each of these pathways in dopamine neuron physiology and function, and discusses how disrupted interplay of dopamine, alpha-synuclein, and iron pathways may synergize to promote pathology and drive the unique vulnerability to disease states. We suggest that elucidating the interactions of dopamine with iron and alpha-synuclein, and the role of dopamine metabolism in driving pathogenic phenotypes will be critical for developing therapeutics to prevent progression in diseases that show degeneration of nigral dopamine neurons such as Parkinson's disease and the rare family of disorders known as Neurodegeneration with Brain Iron Accumulation.

Aim. To analyze current data of scientific literature on the etiology, pathogenesis, approaches to the diagnosis and treatment of rare orphan disease – pantothenate kinase-associated neurodegeneration and to describe the clinical case of this disease. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare inherited autosomal recessive disorder caused by mutations in the PANK2 gene, which is located at the chromosomal locus: 20p13-p12.3. The article presents a literature review and a case report of the diagnosis and treatment of 8-year-old girl with pantothenate kinase-associated neurodegeneration who suffered from progressive motor impairment. Among the dominant clinical manifestations is a growing extrapyramidal motor disorder, the so-called “dystonic storm”, which can range from severe sensorimotor motor deficits in infants and young children to mild parkinsonism in adults. MRI signs in the form of specific changes in the T2-weighted mode, which detects typical areas of hyperintensive signal in globus pallidus, surrounded by a border of hypointensive signal (“tiger’s eye”) are particular important. Neuroimaging data most likely make possible to suspect a correct diagnosis, reducing the time and cost of additional examinations. There is no pathogenetic treatment of this disease now. The main directions of currently available symptomatic drug therapy are described. Clinical trials of detoxifying drugs that reduce iron levels in the body (chelation) and surgical treatments are currently underway. Conclusions. The presented clinical observation once again confirms the complexity of the diagnostic search for orphan diseases of the nervous system. A key place in the diagnosis of pantothenate kinase-associated neurodegeneration belongs to the neuroimaging methods and molecular genetic testing data.

Copyright of Turkish Journal of Neurology / Turk Noroloji Dergisi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Young onset dementias present significant diagnostic challenges. We present the case of a 35-year-old Kuwaiti man with social withdrawal, drowsiness, irritability, anxiety, aphasia, memory loss, hypereflexia, and Parkinsonism. Brain MRI showed bilateral symmetric gradient echo hypointensities in the globi pallidi and substantiae nigrae. Left cortical hypometabolism was seen on brain fluorodeoxyglucose positron emission tomography. A cortical brain biopsy revealed a high Lewy body burden. Genetic testing revealed a homozygous p.T11M mutation in the C19orf12 gene consistent with mitochondrial membrane protein-associated neurodegeneration. This is the oldest onset age of MPAN reported.

Clinical Vignette: A 23-year-old woman with pantothenate kinase-associated neurodegeneration (PKAN) presented with medication-refractory generalized dystonia and an associated gait impairment., Clinical Dilemma: Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) can be an effective treatment for dystonia. However, outcomes for PKAN DBS have been variable and there are no standardized criteria for patient selection., Clinical Solution: Bilateral GPi DBS implantation resulted in improvement in dystonia and gait. The benefit has persisted over one year after implantation., Gap in Knowledge: PKAN is a rare neurodegenerative disorder and evidence supporting the use of PKAN DBS has been largely limited to case reports and case series. Consequently, there is a paucity of long-term data, especially on gait-related outcomes., Expert Commentary: The clinical characteristics of dystonia that respond to DBS tend to respond in PKAN. Clinicians counselling patients about the effects of DBS for PKAN should thoughtfully discuss gait and postural instability as important aspects to consider, especially as the disease will progress post-DBS., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

A disturbed iron metabolism may damage brain and trigger disorders known as neurodegeneration with brain iron accumulation (NBIA). NBIAs are rare, inherited disorders in which responsible mutations affect the function of proteins that participate in tissue iron homeostasis. Accumulated iron, which may be recognized as a low signal intensity on T2-weighted MRI images, oftentimes points to a diagnosis. Recent genetic discoveries confirm that NBIA is not a homogenous group of diseases. Fifteen different NBIAs have been described to date; among these, autosomal recessive inheritance was reported in 13, and autosmal dominant and X-linked dominant inheritance in one disease, respectively. Among NBIAs, the most common is pantothenate kinase-associated neurodegeneration (PKAN-NBIA 1) (30%-50% of all NBIA cases), that occurrs as a consequence of the autosomal recessive mutation in PANK2 gene, followed by phospholipase 2-associated neurodegeneration (PLAN, NBIA 2), due to mutation in PLA2G6 gene, and mitochondrial membrane protein-associated neurodegeneration (MPAN) with the underlying C19orf12 mutation [Table 1]. NBIAs are characterized by complex motor presentations from early-onset degeneration and premature fatality to adult-onset parkinsonism and dystonia. Epileptic seizures, pyramidal signs, visual disorders, and cognitive deterioration can develop. NBIAs are often refractory to therapeutical strategies, although certain interventions may provide significant symptomatic relief in selected patients. In this review, we discuss the expanding clinical spectrum of these complex and rare syndromes, their genetic and imaging features, and potential therapeutical targets and strategies. [ABSTRACT FROM AUTHOR]

Introduction. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare, recessively inherited disorder caused by mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20p13. The objective of this report is to present a patient with atypical PKAN with the novel heterozygous PANK2 mutation. Case outline. We present a 32-year-old female who had disease onset at the age 20 (depression, speech, chewing problems and backward falls) with progressive course. Neurological examination revealed hypomimia, risus sardonicus, dysphagia, tachylalia and severe dystonic dysarthria, moderate arms, legs, and jaw-opening dystonia, postural instability, urge incontinence, and decreased visual acuity. Brain magnetic resonance imaging revealed iron accumulation in the bilateral globus pallidus and putamen (“eye-of-the-tiger”), a radiological finding pathognomonic for PKAN. Genetic analysis revealed known mutation p.T528M (c.1583C>T) in exon 6, and novel p.Y405D (c.1213T>G) in exon 3 of the PANK2 gene. In silico analyses strongly suggested this mutation to be pathogenic. Conclusion. We report a patient with PKAN, and novel substitution p.Y405D (c.1213T>G) in PANK2 that has not been previously described in PKAN patients.

Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4′-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4′-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage.

Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4′-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4′-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage. [ABSTRACT FROM AUTHOR]

Mitochondrial membrane Protein Associated Neurodegeneration (MPAN) is a rare genetic disorder due to mutations in C19orf12 gene. In most cases, the disorder is transmitted as an autosomal recessive trait and the main clinical features are progressive spastic para/tetraparesis, dystonia, motor axonal neuropathy, parkinsonisms, psychiatric symptoms, and optic atrophy. Besides iron accumulation in the globus pallidus and substantia nigra, the neuropathology shows features also observed in Parkinson’s Disease brains, such as α-synuclein-positive Lewy bodies and hyperphosphorylated tau. Mutations in the gene have been found in other neurodegenerative disorders, including PD, hereditary spastic paraplegia, pallido-pyramidal syndrome, and amyotrophic lateral sclerosis. The biological function of C19orf12 gene is poorly defined. In humans, it codes for two protein isoforms: the longer one is present in mitochondria, endoplasmic reticulum, and contact regions between mitochondria and ER. Mutations in the gene appear to be linked to defects in mitochondrial activity, lipid metabolism and autophagy/mitophagy. To increase the available tools for the investigation of MPAN pathogenesis, we generated a new animal model in zebrafish embryos. The zebrafish genome contains four co-orthologs of human C19orf12. One of them, located on chromosome 18, is expressed at higher levels at early stages of development. We downregulated its expression by microinjecting embryos with a specific ATG-blocking morpholino, and we analyzed embryonal development. Most embryos showed morphological defects such as unsettled brain morphology, with smaller head and eyes, reduced yolk extension, tilted and thinner tail. The severity of the defects progressively increased and all injected embryos died within 7 days post fertilization. Appropriate controls confirmed the specificity of the observed phenotype. Changes in the expression and distribution of neural markers documented a defective neuronal development, particularly evident in the eyes, the optic tectum, the midbrain-hindbrain boundary; Rohon Beard and dorsal root ganglia neurons were also affected. Phalloidin staining evidenced a significant perturbation of musculature formation that was associated with defective locomotor behavior. These data are consistent with the clinical features of MPAN and support the validity of the model to investigate the pathogenesis of the disease and evaluate molecules with potential therapeutic effect.

Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.

We present a case of beta-propeller protein-associated neurodegeneration, a form of neurodegeneration with brain iron accumulation. The patient harbored a novel mutation in the WDR45 gene. A detailed video and description of her clinical condition are provided. Her movement disorder phenomenology was characterized primarily by limb stereotypies and gait dyspraxia. The patient’s disability was advanced by the time iron-chelating therapy with deferiprone was initiated, and no clinical response in terms of cognitive function, behavior, speech, or movements were observed after one year of treatment.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Background: Specific phenomenology and pattern of involvement in movement disorders point toward a probable clinical diagnosis. For example, forehead chorea usually suggests Huntington’s disease; feeding dystonia suggests neuroacanthocytosis and risus sardonicus is commonly seen in Wilson’s disease. Dystonic opisthotonus has been described as a characteristic feature of neurodegeneration with brain iron accumulation (NBIA) related to PANK2 and PLA2G6 mutations. Case report: We describe two additional patients in their 30s with severe extensor truncal dystonia causing opisthotonic posturing in whom evaluation revealed the diagnosis of NBIA confirmed by genetic testing. Discussion: Dystonic opisthotonus may be more common in NBIA than it is reported and its presence especially in a young patient should alert the neurologists to a possibility of probable NBIA.

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive neurodegenerative disease caused by mutations in the pantothenate kinase 2 (PANK2) gene and associated with iron deposition in basal ganglia. Pantothenate kinase isoforms catalyze the first step in coenzyme A (CoA) biosynthesis. Since PANK2 is the only isoform in erythrocytes, these cells are an excellent ex vivo model to study the effect of PANK2 point mutations on expression/stability and activity of the protein as well as on the downstream molecular consequences. PKAN erythrocytes containing the T528M PANK2 mutant had residual enzyme activities but variable PANK2 abundances indicating an impaired regulation of the protein. Patients with G521R/G521R, G521R/G262R, and R264N/L275fs PANK2 mutants had no residual enzyme activity and strongly reduced PANK2 abundance. G521R inactivates the catalytic activity of the enzyme, whereas G262R and the R264N point mutations impair the switch from the inactive to the active conformation of the PANK2 dimer. Metabolites in cytosolic extracts were analyzed by gas chromatography–mass spectrometry and multivariate analytic methods revealing changes in the carboxylate metabolism of erythrocytes from PKAN patients as compared to that of the carrier and healthy control. Assuming low/absent CoA levels in PKAN erythrocytes, changes are consistent with a model of altered citrate channeling where citrate is preferentially converted to α-ketoglutarate and α-hydroxyglutarate instead of being used for de novo acetyl-CoA generation. This finding hints at the importance of carboxylate metabolism in PKAN pathology with potential links to reduced cytoplasmic acetyl-CoA levels in neurons and to aberrant brain iron regulation.

Abstract Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin‐knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin‐treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin‐treated CpKO mice share a similar pattern with wild‐type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.

We report the case of a 27-year-old man presenting with slowly progressive extrapyramidal dysfunction and learning disability considered to have a syndromic intellectual disability. The re-evaluation of the clinical features and the investigations performed led to the diagnosis of atypical pantothenate kinase-associated neurodegeneration (PKAN).

Abstract Background Mitochondrial membrane protein‐associated neurodegeneration (MPAN) is caused by pathogenic sequence variants in C19orf12. Autosomal recessive inheritance has been demonstrated. We present evidence of autosomal dominant MPAN and propose a mechanism to explain these cases. Methods Two large families with apparently dominant MPAN were investigated; additional singleton cases of MPAN were identified. Gene sequencing and multiplex ligation‐dependent probe amplification were used to characterize the causative sequence variants in C19orf12. Post‐mortem brain from affected subjects was examined. Results In two multi‐generation non‐consanguineous families, we identified different nonsense sequence variations in C19orf12 that segregate with the MPAN phenotype. Brain pathology was similar to that of autosomal recessive MPAN. We additionally identified a preponderance of cases with single heterozygous pathogenic sequence variants, including two with de novo changes. Conclusions We present three lines of clinical evidence to demonstrate that MPAN can manifest as a result of only one pathogenic C19orf12 sequence variant. We propose that truncated C19orf12 proteins, resulting from nonsense variants in the final exon in our autosomal dominant cohort, impair function of the normal protein produced from the non‐mutated allele via a dominant negative mechanism and cause loss of function. These findings impact the clinical diagnostic evaluation and counseling.

Aceruloplasminemia (ACP) is a rare, adult-onset, autosomal recessive disorder, characterized by systemic iron overload due to mutations in the Ceruloplasmin gene (CP), which in turn lead to absence or strong reduction of CP activity. CP is a ferroxidase that plays a key role in iron export from various cells, especially in the brain, where it maintains the appropriate iron homeostasis with neuroprotective effects. Brain iron accumulation makes ACP unique among systemic iron overload syndromes, e.g., various types of genetic hemochromatosis. The main clinical features of fully expressed ACP include diabetes, retinopathy, liver disease, and progressive neurological symptoms reflecting iron deposition in target organs. However, biochemical signs of the disease, namely a mild anemia mimicking iron deficiency anemia because of microcytosis and low transferrin saturation, but with “paradoxical” hyperferritinemia, usually precedes the onset of clinical symptoms of many years and sometimes decades. Prompt diagnosis and therapy are crucial to prevent neurological complications of the disease, as they are usually irreversible once established. In this mini-review we discuss some major issues about this rare disorder, pointing out the early clues to the right diagnosis, instrumental to reduce significant disability burden of affected patients.

View Supplementary Video 1 View Supplementary Video 2 [ABSTRACT FROM AUTHOR]

Iron homeostasis is an essential prerequisite for metabolic and neurological functions throughout the healthy human life, with a dynamic interplay between intracellular and systemic iron metabolism. The development of different neurodegenerative diseases is associated with alterations of the intracellular transport of iron and heavy metals, principally mediated by Divalent Metal Transporter 1 (DMT1), responsible for Non-Transferrin Bound Iron transport (NTBI). In addition, DMT1 regulation and its compartmentalization in specific brain regions play important roles during aging. This review highlights the contribution of DMT1 to the physiological exchange and distribution of body iron and heavy metals during aging and neurodegenerative diseases. DMT1 also mediates the crosstalk between central nervous system and peripheral tissues, by systemic diffusion through the Blood Brain Barrier (BBB), with the involvement of peripheral iron homeostasis in association with inflammation. In conclusion, a survey about the role of DMT1 and iron will illustrate the complex panel of interrelationship with aging, neurodegeneration and neuroinflammation. [ABSTRACT FROM AUTHOR]

Aceruloplasminemia (ACP) is a rare, adult-onset, autosomal recessive disorder, characterized by systemic iron overload due to mutations in the Ceruloplasmin gene (CP), which in turn lead to absence or strong reduction of CP activity. CP is a ferroxidase that plays a key role in iron export from various cells, especially in the brain, where it maintains the appropriate iron homeostasis with neuroprotective effects. Brain iron accumulation makes ACP unique among systemic iron overload syndromes, e.g., various types of genetic hemochromatosis. The main clinical features of fully expressed ACP include diabetes, retinopathy, liver disease, and progressive neurological symptoms reflecting iron deposition in target organs. However, biochemical signs of the disease, namely a mild anemia mimicking iron deficiency anemia because of microcytosis and low transferrin saturation, but with "paradoxical" hyperferritinemia, usually precedes the onset of clinical symptoms of many years and sometimes decades. Prompt diagnosis and therapy are crucial to prevent neurological complications of the disease, as they are usually irreversible once established. In this mini-review we discuss some major issues about this rare disorder, pointing out the early clues to the right diagnosis, instrumental to reduce significant disability burden of affected patients. [ABSTRACT FROM AUTHOR]

Keywords: parkinsonian disorders; neurodegeneration with brain iron accumulation; group VI phospholipases A2; akinetic mutism EN parkinsonian disorders neurodegeneration with brain iron accumulation group VI phospholipases A2 akinetic mutism 794 796 3 07/21/21 20210701 NES 210701 The phospholipase A2 group VI ( I PLA2G6 i ) gene is associated with several neurodegenerative diseases with diverse clinical presentations.1 Nearly 200 variants of I PLA2G6 i have been reported in 3 gene variant databases (ClinVar, Human Gene Mutation Database (HMGD), and Leiden Open Variation Database (LOVD)). It has been reported in populations, including Chinese, Indian, and Pakistanis.3,10 Here we describe the first report of the NBIA/DYT/PARK- I PLA2G6 i phenotype in a Brazilian patient, without consanguinity or a family history of similar cases. Lack of functional improvement despite the presence of dyskinesias after brief exposure to levodopa has also been described in other patients with the same condition.4 Brain MRI findings in patients with NBIA/DYT/PARK- I PLA2G6 i are nonspecific. [Extracted from the article]

Neurodegeneration with brain iron accumulation (NBIA) is aclinically and genetically heterogeneous group of hereditary (predominantlyautosomal recessive) progressive disorders of the CNSwith a common feature of iron accumulation in basal ganglia andcharacteristic MRI image. By now, nine genes responsible for differentNBIA are known, and some of these genes cause the developmentof several allelic phenotypes. In the review, current data onNBIA clinical and molecular genetic aspects, particularly onrecently discovered forms and atypical clinical variants, are summarized.

Neurodegeneration with brain iron accumulation (Hallervorden-Spatz Disease) is a rare, slowly progressing disorder characterized by progressive extrapyramidal dysfunction resulting in dementia, dystonia, torticollis, ataxia, kyphoscoliosis, and seizures. In chronic cases, muscle contractures, bony changes, temporomandibular joint, and cervical spine immobility may occur. Due to chronic malnutrition, there is increased the tendency for pathological fractures. Any noxious stimulus (anxiety, pain, light plane of anesthesia) intensifies dystonia. Significant speech disturbances, confusion, disorientation, mental retardation, dementia, and visual loss make communication with these patients a problem. Managing anesthesia in such patients is quite challenging as there is difficulty in positioning, intravenous cannulation, and airway management. We present a case report of a 14-year-old male patient with neurodegeneration with brain iron accumulation who was administered anesthesia for the stem-cell therapy.

Rare diseases are those that have a low prevalence in the population (less than 5 individuals per 10,000 inhabitants). However, infrequent pathologies affect a large number of people, since according to the World Health Organization (WHO), there are about 7000 rare diseases that affect 7% of the world’s population. Many patients with rare diseases have suffered the consequences of what is called the diagnostic odyssey, that is, extensive and prolonged serial tests and clinical visits, sometimes for many years, all with the hope of identifying the etiology of their disease. For patients with rare diseases, obtaining the genetic diagnosis can mean the end of the diagnostic odyssey, and the beginning of another, the therapeutic odyssey. This scenario is especially challenging for the scientific community, since more than 90% of rare diseases do not currently have an effective treatment. This therapeutic failure in rare diseases means that new approaches are necessary. Our research group proposes that the use of precision or personalized medicine techniques can be an alternative to find potential therapies in these diseases. To this end, we propose that patients’ own cells can be used to carry out personalized pharmacological screening for the identification of potential treatments.

A 13-year-old girl with infantile-onset self-resolving epilepsy and developmental delay had an unremarkable workup, including normal brain magnetic resonance imaging (MRI) and chromosomal microarray. During adolescence, she presented with features of early-onset parkinsonism: gait dyspraxia, freezing during walking, cogwheel rigidity in both upper extremities, and left arm dystonia. Repeat brain MRI showed iron deposition on the substantia nigra (SN) and basal ganglia, with hyperintense halo sign around a central linear hypointensity within the SN on the T1 imaging sequence. Whole-exome sequencing with trio revealed de novo heterozygote mutation in WDR45 to confirm the diagnosis of beta-propeller protein-associated neurodegeneration (BPAN). BPAN is a rare neurodegenerative with brain iron accumulation disorder with the pathognomonic halo sign. Preferential iron deposition over the SN compared to globus pallidus can distinguish this condition from other iron storage disorders. BPAN does not cause the radiologic eye of the tiger sign seen in other forms of iron storage disorders. Other types of childhood-onset parkinsonian disorders, such as PINK1-related Parkinson disease and Parkin-type Parkinson disease, do not have iron storage in the brain. This report describes a case of early-onset parkinsonism secondary to a mutation in WDR45. It underscores the importance of brain MRI to differentiate this condition from other childhood-onset parkinsonism and also other brain iron accumulation disorders. This report also shows iron deposition over the pituitary as a novel site of iron deposition in BPAN and emphasizes the presence of peri-dentate white matter volume loss and hyperintensity, which is another key radiologic abnormality associated with BPAN. [ABSTRACT FROM AUTHOR]

Background and Methods: Mutations in WDR45 cause β‐propeller protein‐associated neurodegeneration (BPAN), a type of neurodegeneration with brain iron accumulation (NBIA). We reviewed clinical and MRI findings in 4 patients with de novo WDR45 mutations. Results: Psychomotor delay and movement disorders were present in all cases; early‐onset epileptic encephalopathy was present in 3. In all cases, first MRI showed: prominent bilateral SN enlargement, bilateral dentate nuclei T2‐hyperintensity, and corpus callosum thinning. Iron deposition in the SN and globus pallidus (GP) only became evident later. Diffuse cerebral atrophy was present in 3 cases. Conclusions: In this series, SN swelling and dentate nucleus T2 hyperintensity were early signs of BPAN, later followed by progressive iron deposition in the SN and GP. When clinical suspicion is raised, MRI is crucial for identifying early features suggesting this type of NBIA. [ABSTRACT FROM AUTHOR]

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next‐generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine. [ABSTRACT FROM AUTHOR]

Abstract: View Supplementary Video1 View Supplementary Video2 View Supplementary Video3 View Supplementary Video4 View Supplementary Video5 Background: Kufor‐Rakeb syndrome (KRS) is a rare autosomal recessive neurologic disease with diverse phenotypic features. Herein we report an Iranian KRS family with seizure and action myoclonus in addition to other typical manifestations of this syndrome. Method: All family members underwent careful neurologic examination. Exome sequencing was performed and ATP13A2 variation genotyped in all family members. Results: Cognitive deficits, hypokinesia, rigidity, spasticity, brisk deep tendon reflexes, upward gaze palsy, tremor, and facial‐faucial‐finger mini‐myoclonus were the common manifestations of all affected siblings. Two cases had seizure and the most severely affected sibling demonstrated severe action myoclonus. Exome sequencing identified a homozygous nonsense mutation c.2455C>T;p.Arg819* in ATP13A2 gene. Conclusions: We reported five KRS affected siblings who manifested myoclonus and seizure. The most severely affected one demonstrated action myoclonus, which has not been reported so far. [ABSTRACT FROM AUTHOR]

Pantothenate kinase-associated neurodegeneration (PKAN) is the most common form of neurodegeneration with brain iron accumulation, it is an autosomal recessive disease due to mutation in PANK 2 on chromosome 20, which causes the accumulation of iron in basal ganglia and production of free radicals that cause degeneration of the cells. Deferiprone is an iron chelator that was used in treatment of thalassemia patients, it can cross the blood-brain barrier and reverse the iron deposition in the brain. Five patients with genetically confirmed PKAN received 15 mg/kg deferiprone twice daily. All patients were examined at baseline, 12 and 18 months and magnetic resonance imaging (MRI) was done at the baseline and after 18 months. In our study qualitative evaluation of MRI showed that deferiprone was able to reduce the iron load in globus pallidus of all the patients and the results of clinical rating scales show that in four patients, there is an improvement in the first 12 months. The results of our paper show that deferiprone can prevent the progression of the disease.

The prevalence of autism spectrum disorder (ASD) is high, yet the etiology of this disorder is still uncertain. Advancements in genetic analysis have provided the ability to identify potential genetic changes that may contribute to ASD. Interestingly, several genetic syndromes have been linked to metabolic dysfunction, suggesting an avenue for treatment. In this case study, we report siblings with ASD who had similar initial phenotypic presentations. Whole exome sequencing (WES) revealed a novel c.795delT mutation in the WDR45 gene affecting the girl, which was consistent with her eventual progression to a Rett-like syndrome phenotype including seizures along with a stereotypical cyclic breathing pattern. Interestingly, WES identified that the brother harbored a novel heterozygous Y1546H variant in the DEP domain-containing protein 5 (DEPDC5) gene, consistent with his presentation. Both siblings underwent a metabolic workup that demonstrated different patterns of mitochondrial dysfunction. The girl demonstrated statistically significant elevations in mitochondrial activity of complex I + III in both muscle and fibroblasts and increased respiration in peripheral blood mononuclear cells (PBMCs) on Seahorse Extracellular Flux analysis. The boy demonstrates a statistically significant decrease in complex IV activity in buccal epithelium and decreased respiration in PBMCs. These cases highlight the differences in genetic abnormalities even in siblings with ASD phenotypes as well as highlights the individual role of novel mutations in the WDR45 and DEPDC5 genes. These cases demonstrate the importance of advanced genetic testing combined with metabolic evaluations in the workup of children with ASD.

Key Clinical Message: Beta‐propeller protein‐associated neurodegeneration (BPAN) is a rare disorder, which is increasingly recognized thanks to next‐generation sequencing. Due to a highly variable phenotype, patients may present to pediatrics, neurology, psychiatry, or internal medicine. It is therefore essential that physicians of different specialties are familiar with this severe and debilitating condition. [ABSTRACT FROM AUTHOR]

Abstract: Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin‐knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin‐treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin‐treated CpKO mice share a similar pattern with wild‐type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia. [ABSTRACT FROM AUTHOR]

Mutations in WDR45 are responsible for beta-propeller protein-associated neurodegeneration (BPAN), which is an X-linked form of neurodegeneration with brain iron accumulation. BPAN mainly affects females and is characterized by seizures and developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. However, rare male patients have recently been reported with hemizygous germline mutations in WDR45 and severe clinical manifestations, such as epileptic encephalopathies. We report here a 4-year-old boy presenting with profound developmental delay, non-syndromic epileptic encephalopathy, and early brain atrophy. The level of serum neuron specific enolase (NSE) was elevated, but the level of serum phosphorylated neurofilament heavy chain was not detectable. Targeted next-generation sequencing identified a de novo hemizygous splice donor site mutation, c.830+1G > A in WDR45 , which resulted in a splicing defect evidenced by reverse transcriptase-PCR. Mutations in WDR45 should be considered as a cause for epileptic encephalopathies in males with profound developmental delay and brain atrophy. Furthermore, elevation of serum NSE may contribute to early diagnosis of BPAN. [ABSTRACT FROM AUTHOR]