Forms Of Neurodegeneration With Brain Iron Accumulation Research Articles

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.

Unusual Presentation of PLA2G6-Related Neurodegeneration with Retinal Vasculitis.

Unusual Presentation of PLA2G6-Related Neurodegeneration with Retinal Vasculitis.

Novel C19orf12 loss-of-function variant leading to neurodegeneration with brain iron accumulation

ABSTRACT Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited disorders characterised by cerebral iron overload mainly in the basal ganglia. Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a form of NBIA caused by pathogenic C19orf12 gene variants. We report on a Romanian patient with MPAN confirmed through exome sequencing, revealing a homozygous nonsense variant in the C19orf12 gene, NM_001031726.3: c.215T>G (p.Leu72*), that co-segregates with disease in tested relatives: the patient`s parents, younger brother and paternal uncle are heterozygous carriers. This is a novel disease-causing variant in the C19orf12 gene and the first reported MPAN case in a Romanian patient.

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA).

The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.

Inborn errors of coenzyme A metabolism and neurodegeneration.

Two inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway. Another very rare but similar disorder, denominated CoPAN, is caused by mutations in coenzyme A synthase gene (COASY) coding for a bi-functional mitochondrial enzyme, which catalyzes the final steps of CoA biosynthesis. It still remains a mystery why dysfunctions in CoA synthesis lead to neurodegeneration and iron accumulation in specific brain regions, but it is now evident that CoA metabolism plays a crucial role in the normal functioning and metabolism of the nervous system.

Anesthesia in patients with NBIA : Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) forms agroup of rare hereditary diseases with rapid neurodegenerative progression due to an abnormal accumulation of iron in the basal ganglia. This causes extrapyramidal symptoms as well as dystonia and mental retardation. The most common form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). There are multiple anesthesiological challenges with great implications for the clinical routine, particularly regarding the preparation for general anesthesia and the premedication visits. As with other orphan diseases, the available recommendations are mainly based on case reports. This article gives ashort overview of complications associated with NBIA pertaining to general anesthesia. This includes anesthesia-relevant clinical symptoms and perioperative management. The published literature and case reports (available on PubMed) were reviewed to extract aset of recommendations. So far only afew reports have included the anesthesia management of NBIA patients. Most of them refer to PKAN as the predominant type (50% of cases). Recommendations were found on www.orphananesthesia.eu and consensus guidelines on PKAN in general. In particular, dystonia-related restrictions in the maxillofacial area can complicate airway management and cause difficulties with respect to intubation. Furthermore, local or regional anesthesia as the sole anesthesia technique is not eligible/viable due to the reduced compliance of the patient. Special attention should be paid to atimely premedication visit and evaluation to ensure sufficient time to safely plan and prepare the anesthetic procedure. The handling of NBIA patients requires good preparation, including an interdisciplinary team and customized time management. In principle, both general anesthesia as abalanced method and total intravenous anesthesia (TIVA) seem to be possible/viable options. The main focus is on airway management. Even after brief sedation in the context of diagnostic measures, the patient should be monitored for longer than usual.

Pantothenate Rescues Iron Accumulation in Pantothenate Kinase-Associated Neurodegeneration Depending on the Type of Mutation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. The most prevalent form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN) associated with mutations in the gene of pantothenate kinase 2 (PANK2), which is essential for coenzyme A (CoA) synthesis. There is no cure for NBIA nor is there a standard course of treatment. In the current work, we describe that fibroblasts derived from patients harbouring PANK2 mutations can reproduce many of the cellular pathological alterations found in the disease, such as intracellular iron and lipofuscin accumulation, increased oxidative stress, and mitochondrial dysfunction. Furthermore, mutant fibroblasts showed a characteristic senescent morphology. Treatment with pantothenate, the PANK2 enzyme substrate, was able to correct all pathological alterations in responder mutant fibroblasts with residual PANK2 enzyme expression. However, pantothenate had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of pantothenate in particular mutations was also confirmed in induced neurons obtained by direct reprograming of mutant fibroblasts. Our results suggest that pantothenate treatment can stabilize the expression levels of PANK2 in selected mutations. These results encourage us to propose our screening model as a quick and easy way to detect pantothenate-responder patients with PANK2 mutations. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of pantothenate.

Systemic Biomarkers Show Elevated Oxidative Stress and Chronic Inflammation in Two Disorders of Neurodegeneration with Brain Iron Accumulation (NBIA)

Background: Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of rare genetic disorders characterized by progressive degenerative motor symptoms and the accumulation of iron in the basal ganglia. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of NBIA caused by a mutation in the PANK2 gene leading to a deficiency in pantothenate kinase. Phospholipase A2G6-Associated Neurodegeneration (PLAN) is caused by a mutation in the PLA2G6 gene resulting in impaired phospholipase activity. Current understanding of systemic changes in NBIA disorders is limited, leaving no clear diagnostic biomarkers. Monitoring the systemic changes could identify candidate biomarkers for assessing disease severity and evaluating the efficacy of new therapies.Previous studies of Parkinson's disease (PD) have found a systemic burden of increased oxidative stress and chronic inflammation accompanies the neurological symptoms of the disease. Similarly, abnormal systemic iron regulation associated with brain iron accumulation as well as damage associated with neuromuscular degeneration could lead to increased oxidative stress and a state of chronic inflammation in NBIA. Our initial investigation of a patient with PLAN1, revealed elevated levels of systemic oxidative stress. We investigated a group of PKAN patients as well as continued our investigation of a patient with PLAN to evaluate the possibility of abnormal iron trafficking, increased oxidative stress and chronic inflammation in NBIA. Our aim was to expand our investigation of circulating levels of inflammatory cytokines, oxidative stress markers and iron regulatory and metabolic proteins in NBIA patients to include a group of patients with PKAN.Methods: Plasma samples from 15 PKAN patients were collected at the UCSF Benioff Children's Hospital in Oakland, California. Similarly, a plasma sample from a patient with PLAN was collected in Campbell River, British Columbia. Plasma samples from a matched group of 15 healthy controls were also collected at the University of Victoria. All patients provided informed consent to the study.The pro-inflammatory cytokines IL-6 and TNFα as well as the anti-inflammatory cytokine IL-10 were measured by ELISA. Total levels of the lipid peroxidation product malondialdehyde (MDA) were measured using N-Methyl-Phenyl-Indole (NMPI). Free, acutely generated, MDA not bound to proteins, was measured by removing plasma proteins via a 10KD spin filtration then measuring the MDA content of resulting filtrate using NMPI.Results: The levels of MDA and Free MDA were significantly elevated in PKAN patients at baseline in comparison to controls (p = 0.05, p = 0.03). IL-6 and TNFα were slightly, but not significantly elevated at baseline compared to controls. We previously demonstrated, similar elevations of oxidative stress in our case study of an NBIA patient with PLAN1. Additionally, all three inflammatory cytokines measured for this study expansion in PLAN were higher than average levels observed in the PKAN and control groups (S ee Table 1). Further analysis of systemic biomarkers in NBIA including proteomic analysis of 30 systemic blood proteins, including iron trafficking proteins is ongoing.Conclusions: We expand previous findings of elevated levels of systemic oxidative stress in other neurodegenerative diseases such as PD to include NBIA patients with PKAN and PLAN. We provide novel evidence of elevated levels of Free MDA; representative of an acute oxidative stress burden in NBIA in addition to the previously noted elevation in total MDA levels. We provide preliminary signs that of an accompanying inflammatory burden in NBIA, but a larger sample group may be needed to determine its significance.

A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging.

Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.

Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation

ABSTRACTThe PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia parkinsonism, collectively known as PLA2G6-associated neurodegeneration (PLAN). Recently Kinghorn et al. demonstrated in Drosophila and PLA2G6 mutant fibroblasts that loss of normal PLA2G6 activity is associated with mitochondrial dysfunction and mitochondrial lipid peroxidation. Furthermore, they were able to show the beneficial effects of deuterated polyunsaturated fatty acids (D-PUFAs), which reduce lipid peroxidation. D-PUFAs were able to rescue the locomotor deficits of flies lacking the fly ortholog of PLA2G6 (iPLA2-VIA), as well as the mitochondrial abnormalities in PLA2G6 mutant fibroblasts. This work demonstrated that the iPLA2-VIA knockout fly is a useful organism to dissect the mechanisms of pathogenesis of PLAN, and that further investigation is required to determine the therapeutic potential of D-PUFAs in patients with PLA2G6 mutations. The fruit fly has also been used to study some of the other genetic causes of NBIA, and here we also describe what is known about the mechanisms of pathogenesis of these NBIA variants. Mitochondrial dysfunction, defects in lipid metabolism, as well as defective Coenzyme A (CoA) biosynthesis, have all been implicated in some genetic forms of NBIA, including PANK2, CoASY, C12orf19 and FA2H.

Missions of <italic>Journal of Movement Disorders</italic>

Rapid advances in communication and information technologies have made available the clinical data of diverse ethnic and cultural populations around the world, lending them clinical relevance in neurology practice. Despite the growing need to understand clinical and epidemiological differences among various populations, competition among journals to increase citation and impact factor has hindered the publication of diverse regional data, which usually lags behind the publication of novel findings. As its aim and scope, the Journal of Movement Disorders is interested in publishing clinical studies of Parkinson’s disease and other movement and neurodegenerative disorders in Asian-Oceanian populations. It is our mission to serve as a platform to broaden the knowledge of these fields and to enhance patient care by sharing clinical and epidemiological data from various regions with the global health care community. An article reporting the genotypes and phenotypes of Korean patients affected by neurodegeneration with brain iron accumulation (NBIA), published in the current issue, is of interest in this regard. NBIA is a group of inherited disorders that share clinical features such as extrapyramidal movement disorders, varying degrees of intellectual disability, and abnormal iron deposition in the basal ganglia [1]. At present, causative genes for ten forms of NBIA have been identified. Lee et al. [2] analyzed genetically confirmed cases of NBIA from 12 referral hospitals in Korea and reported clinical findings for patients with atypical pantothenate kinase-associated neurodegeneration (PKAN). The data of Korean patients with atypical PKAN differ from those of the Caucasian population in terms of clinical manifestations and mutation hot spots. These researchers found considerable phenotypic heterogeneity ranging from isolated freezing of the gait to generalized dystonia with concurrent parkinsonism. The age of onset tended to affect the presentation of extrapyramidal symptoms in atypical PKAN. Translational research transfers knowledge from basic research to clinical research, and transfers findings from clinical studies or clinical trials to practice settings and communities, with the goal of improving health [3]. In this issue, Journal of Movement Disorders is launching a new section entitled “Translational Research Review”. This section will cover current translational research on interesting topics in Parkinson’s disease and neurodegenerative disorders. Diverse new disciplines in clinical neurology and neuroscience such as molecular neuroimaging, magnetic resonance imaging techniques, bioinformatics, and systems biology will also be covered. In this issue, Lee and Lee [4] provide an article entitled “The mechanism of anti-α-synuclein immunotherapy”. This article provides up-to-date information regarding our pathogenic and therapeutic understanding of α-synuclein. Over the past two years, the editorial team at Journal of Movement Disorders has tried improve the quality and stature of the publication. One of our missions is to make our articles readily available worldwide free of charge. Pursuing this mission has been expedited by indexing the Journal of Movement Disorders in PubMed Central. As a result, the citation of articles published in our journal has been on the rise. Moreover, our policy of maintaining an open access journal without article processing fees or page charges will facilitate the dissemination of knowledge published in the Journal of Movement Disorders. Our efforts to index the Journal of Movement Disorders in other journal databases, such as SCOPUS and Web of Science, are ongoing. We would like to thank our sponsoring organization, the Korean Movement Disorders Society, for providing financial support to continue pursuing our mission. We hope that readers of the Journal of Movement Disorders find our articles informative and valuable.

Update in Neurodegeneration with Brain Iron Accumulation: Advances in Molecular Diagnosis and Treatment Strategies

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term used to clinically describe a group of neurologic conditions associated with high brain iron. To date, there are 10 genetic subtypes described, which share several common clinical features. Novel technologies such as improved magnetic resonance imaging techniques and whole exome sequencing have provided new clinical and genetic insight into these disorders, thereby improving clinical diagnosis for patients. Indeed, precise diagnosis is now possible for approximately 60% of patients with NBIA. Despite these genetic advances, little is known about the exact underlying disease pathways governing many forms of NBIA. In fact, for most subtypes, the causative genes and affected proteins are not directly related to iron homeostasis. Management for all subtypes remains mainly supportive and based on a multidisciplinary approach, but there are promising advances in the development of novel therapeutic strategies. Focusing mainly on the newly described NBIA subtypes, we summarize the clinical phenotypes, genetic basis, and postulated pathophysiological disease mechanisms, and propose an NBIA diagnostic pathway to guide clinical testing and genetic councelling.

PP15.15 – 2688: NBIA Alliance – The impact of the international NBIA patient advocacy on NBIA research and vice versa

Objective Neurodegeneration with Brain Iron Accumulation (NBIA) is a group of very rare and mostly hereditary neurological movement disorders characterized by high iron levels in the basal ganglia and a progressive degeneration of the nervous system. Currently, there is no cure or proven therapy for any of the NBIA forms. Given the lack of treatment options, the international consortium TIRCON (Treat–Iron–Related–Childhood–Onset–Neurodegeneration), funded by the EU under FP7, is dedicated to the investigation of NBIA. 13 partners from eight countries are conducting a clinical therapy study and set up a patient registry/biobank in order to improve the infrastructure for NBIA research and care. We present the latest development, goals, recent and upcoming activities of the NBIA lay advocacy, thus demonstrating the rising impact of the growing NBIA Alliance and its member groups in interrelationship to the TIRCON consortium and to further NBIA research groups. Methods The lay advocacy groups, NBIA Disorders Association (NBIADA, USA) and Hoffnungsbaum e.V. (HoBa, Germany), are full partners in TIRCON. Based upon their experience in such collaborative projects, NBIADA and HoBa have been promoting the creation of further patient groups worldwide. The NBIA Alliance, launched under the patronage of TIRCON in 2012, is the only international umbrella association for NBIA lay advocacy groups. Currently, eight NBIA patient organizations are involved in the Alliance. The groups share the common goals of helping families cope with NBIA disorders, promoting improved health care in NBIA, and supporting research to find more effective treatments for these disorders. Results Current efforts include developing a strategic plan to support these common goals and expand the Alliance to other countries. Conclusion We will underline the mutual empowerment of the NBIA patients' movement and the NBIA research and care community.

Mitochondria: A crossroads for lipid metabolism defect in neurodegeneration with brain iron accumulation diseases

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Exact pathologic mechanism of iron deposition in NBIA remains unknown. However, it is becoming increasingly evident that many neurodegenerative diseases are hallmarked by metabolic dysfunction that often involves altered lipid profile. Among the identified disease genes, four encode for proteins localized in mitochondria, which are directly or indirectly implicated in lipid metabolism: PANK2, CoASY, PLA2G6 and C19orf12. Mutations in PANK2 and CoASY, both implicated in CoA biosynthesis that acts as a fatty acyl carrier, lead, respectively, to PKAN and CoPAN forms of NBIA. Mutations in PLA2G6, which plays a key role in the biosynthesis and remodeling of membrane phospholipids including cardiolipin, lead to PLAN. Mutations in C19orf12 lead to MPAN, a syndrome similar to that caused by mutations in PANK2 and PLA2G6. Although the function of C19orf12 is largely unknown, experimental data suggest its implication in mitochondrial homeostasis and lipid metabolism. Altogether, the identified mutated proteins localized in mitochondria and associated with different NBIA forms support the concept that dysfunctions in mitochondria and lipid metabolism play a crucial role in the pathogenesis of NBIA.This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.

Beta-Propeller-Protein-Associated Neurodegeneration: A Case of Mutation in WDR45.

Dear Editor, Neurodegeneration with brain iron accumulation (NBIA) constitutes a group of genetic disorders characterized by iron deposition in the brain, and in particular the basal ganglia. These disorders are genetically heterogeneous, and their clinical features include cognitive impairment, psychiatric abnormality, and movement disorders such as parkinsonism and dystonia.1,2 Brain magnetic resonance imaging (MRI) is used to investigate iron accumulation in the basal ganglia. In addition to the several known NBIA genes, beta-propeller protein-associated neurodegeneration (BPAN) was recently identified with heterozygous mutation in the WD repeat-containing protein 45 (WDR45) on the X-chromosome.3,4 While BPAN shares clinical and laboratory features with other NBIA disorders with respect to its X-linked inheritance pattern, it differs from all other previously identified genes for NBIA disorders, which are autosomal recessive or dominant traits. In this report we describe the case of a 43-year-old female with developmental retardation, chorea, and parkinsonism who was diagnosed with BPAN following genetic analysis of WDR45. A 38-year-old female visited the neurologic department of our hospital due to sensations of slowness in her right upper and lower extremities of 20 years duration. The patient was born at full term via a normal delivery and without perinatal complications. There was no familial or medical history to account for her condition. She had a masked face with chorea on the forehead. Her speech was monotone, and there was no tremor movement during either resting posture or action states. There was marked joint rigidity of her wrists and knees. The patient stood upright without a stooped posture, and walked slowly without bilateral arm swing; however, there was no festination or propulsion. Laboratory testing included a complete blood count, blood chemistry, thyroid function test, parathyroid function test, HIV antibody, antistreptolysin O antibody, ferritin, serum copper level, ceruloplasmin, and peripheral blood smear test; all test results were within normal ranges. Conventional MRI using a 1.5-T magnetic resonance scanner (Gyroscan, Philips, Best, The Netherlands) revealed bilateral linear lesions in the substantia nigra surrounded by a hypertense 'halo' on the T1-weighted image. The corresponding lesions also appeared hypointense without linear signal abnormality on the T2-weighted and gradient-echo images. Bilateral hypointense lesions in the globus pallidus were evident in the T2-weighted and gradient-echo images, while there was no abnormal signal change on the T1-weighted image (Fig. 1). Fig. 1 Magnetic resonance imaging reveals bilateral hypointense lesions in the substantial nigra surrounded by a hyperintense 'halo' on the T1-weighted image (A). The corresponding lesions appear hypointense on the T2-weighted (B) and gradient-echo (C) images ... The patient's WDR45 status was analyzed. All exons and exon-intron boundaries of WDR45 were amplified by the polymerase chain reaction and Sanger sequenced directly. Primer design and amplification were performed as reported previously.4 Genomic DNA and complementary DNA sequencing revealed a novel mutation, c.345-1G>A, which resulted in deletion of exon 7 and the introduction of a premature stop codon in exon 8, r.345_439del. WDR45 mutation on the X-chromosome is associated with defective autophagy, which plays an important role in the cellular processing of abnormal protein degradation.5 In summary, this is the first published case of WDR45-related BPAN in Korea. The patient had phenotypically clinical features of BPAN with the development of movement disorders. In addition to clinical manifestations, a distinct pattern of iron deposition in the globus pallidus and substantia nigra revealed by MRI, could be a useful clue for distinguishing different forms of NBIA.

Neurodegeneration with brain iron accumulation: diagnosis and management.

Neurodegeneration with brain iron accumulation (NBIA) encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.

Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron.

Neurodegeneration with brain iron accumulation (NBIA) is a group of devastating and life threatening rare diseases. Adult and early-onset NBIA syndromes are inherited as X-chromosomal, autosomal dominant or recessive traits and several genes have been identified as responsible for these disorders. Among the identified disease genes, only two code for proteins directly involved in iron metabolism while the remaining NBIA genes encode proteins with a wide variety of functions ranging from fatty acid metabolism and autophagy to still unknown activities. It is becoming increasingly evident that many neurodegenerative diseases are associated with metabolic dysfunction that often involves altered lipid metabolism. This is not surprising since neurons have a peculiar and heterogeneous lipid composition critical for the development and correct functioning of the nervous system. This review will focus on specific NBIA forms, namely PKAN, CoPAN, PLAN, FAHN and MPAN, which display an interesting link between neurodegeneration and alteration of phospholipids and sphingolipids metabolism, mitochondrial morphology and membrane remodelling.

Alteration of the coenzyme A biosynthetic pathway in neurodegeneration with brain iron accumulation syndromes

NBIA (neurodegeneration with brain iron accumulation) comprises a heterogeneous group of neurodegenerative diseases having as a common denominator, iron overload in specific brain areas, mainly basal ganglia and globus pallidus. In the past decade a bunch of disease genes have been identified, but NBIA pathomechanisms are still not completely clear. PKAN (pantothenate kinase-associated neurodegeneration), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA. It is caused by mutations in the PANK2 (pantothenate kinase 2) gene, coding for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the CoA (coenzyme A) biosynthetic pathway. A distinct form of NBIA, denominated CoPAN (CoA synthase protein-associated neurodegeneration), is caused by mutations in the CoASY (CoA synthase) gene coding for a bifunctional mitochondrial enzyme, which catalyses the final steps of CoA biosynthesis. These two inborn errors of CoA metabolism further support the concept that dysfunctions in CoA synthesis may play a crucial role in the pathogenesis of NBIA.

Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms.

Perturbation of iron distribution is observed in many neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, but the comprehension of the metal role in the development and progression of such disorders is still very limited. The combination of more powerful brain imaging techniques and faster genomic DNA sequencing procedures has allowed the description of a set of genetic disorders characterized by a constant and often early accumulation of iron in specific brain regions and the identification of the associated genes; these disorders are now collectively included in the category of neurodegeneration with brain iron accumulation (NBIA). So far 10 different genetic forms have been described but this number is likely to increase in short time. Two forms are linked to mutations in genes directly involved in iron metabolism: neuroferritinopathy, associated to mutations in the FTL gene and aceruloplasminemia, where the ceruloplasmin gene product is defective. In the other forms the connection with iron metabolism is not evident at all and the genetic data let infer the involvement of other pathways: Pank2, Pla2G6, C19orf12, COASY, and FA2H genes seem to be related to lipid metabolism and to mitochondria functioning, WDR45 and ATP13A2 genes are implicated in lysosomal and autophagosome activity, while the C2orf37 gene encodes a nucleolar protein of unknown function. There is much hope in the scientific community that the study of the NBIA forms may provide important insight as to the link between brain iron metabolism and neurodegenerative mechanisms and eventually pave the way for new therapeutic avenues also for the more common neurodegenerative disorders. In this work, we will review the most recent findings in the molecular mechanisms underlining the most common forms of NBIA and analyze their possible link with brain iron metabolism.

Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: Novel mutations and neuropsychiatric phenotype in three adult patients

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare neuropsychiatric syndromes characterized by iron accumulation in the basal ganglia. The pantothenate kinase-associated neurodegeneration (PKAN) was the first NBIA form to be genetically identified almost 15 years ago. Nowadays, eight types can be genetically distinguished. More recently, a novel NBIA was delineated and termed Static Encephalopathy of childhood with Neurodegeneration in Adulthood (SENDA), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with an onset in the second to third decade. Very recently, mutations in the WD repeat-containing protein 45 (WDR45) gene located on Xp11.23 were shown to be the causal factor. The protein encoded by WDR45 propels protein interaction important for autophagy. This form was therefore retermed Beta-propeller Protein Associated Neurodegeneration (BPAN). Here, the first three Dutch patients with genetically proven BPAN are comprehensively described with respect to course and neurological as well as neuropsychiatric phenotypes. All three showed a characteristic delayed progression of neurological symptoms with parkinsonism and prominent dystonia. Treatment with levodopa/carbidopa had limited effects only. Neuropsychiatric symptoms within the autistic and affective spectrum were present in the early phase of the disease. The specific course and prognosis should implicate restrained psychopharmacological interventions.The clinical picture and imaging hallmarks are often highly suggestive and should lead to suspect this specific disorder. However, the identification of a WDR45 mutation is needed for a definite diagnosis of BPAN.