Insights into molecular mechanisms of disease in Neurodegeneration with Brain Iron Accumulation; unifying theories.

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterised by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and Ferritin Light Chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis and speculate potential overlap between NBIA subtypes

The down-regulation of pank2 gene in zebrafish as a model of Pantothenate Kinase Associated Neurodegeneration.

open9siThe increased iron deposition is a hallmark of many neurodegenerative diseases, but its pathogenic role is still unclear. A strong link between iron and neurodegeneration is evident in a set of heterogeneous neurological disorders, known as Neurodegeneration with Brain Iron Accumulation (NBIA). The most common form of inherited NBIA is associated with mutations in hPank2 gene (PKAN). Pank2 is the rate limiting enzyme in CoA biosynthesis and its downregulation in mammalian cells leads to perturbation of cellular iron homeostasis. Here we explore Pank2 biological function in Danio rerio, and propose this system as an important new tool for the study of PKAN disease.openZizioli, Daniela; Tiso, Natascia; Busolin, Giorgia; Khatri, Deepak; Giuliani, Roberta; Borsani, Giuseppe; Monti, Eugenio; Argenton, Francesco; Finazzi, DarioZizioli, Daniela; Tiso, Natascia; Busolin, Giorgia; Khatri, Deepak; Giuliani, Roberta; Borsani, Giuseppe; Monti, Eugenio; Argenton, Francesco; Finazzi, Dari

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

Gene co-expression networks shed light into diseases of brain iron accumulation

Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention

Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

International audienceCharacterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3a, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3a was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3a controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3a as a key controller of neuronal and endocrine homeostatic processes

Molekulare Mechanismen isolierter und Syndrom-assoziierter Lipidstoffwechselstörungen

Metabolische Erkrankungen sind ein Hauptfaktor für die Entstehung von Atherosklerose und das damit einhergehende Risiko für das Auftreten von akuten Myokardinfarkten. Sie stellen somit einen der wichtigsten Faktoren für die erhöhte Morbidität und Mortalität in der westlichen Population dar. Im Rahmen der vorliegenden Arbeit sollten neue genetische Faktoren und molekulare Mechanismen identifiziert werden, die zu einer Hypercholesterinämie sowie zwei ausgewählten, angeborenen Syndromen führen, die bekanntermaßen mit metabolischen Störungen assoziiert sind. Wir initiierten molekulargenetische Untersuchungen bei 200 Patienten der deutschen LIANCO Kohorte mit diagnostizierter Hypercholesterinämie. Die Bestimmung des Mutationsspektrums in den bekannten Genen für familiäre Hypercholesterinämie (FH) führte zur Identifizierung von insgesamt 30 unterschiedlichen, heterozygoten LDLR-Mutationen bei 20 % der Patienten und zeigt die hohe Prävalenz von LDLR-Mutationen in Patientenkohorten ohne beschriebene positive Familienanamnese für Hypercholesterinämie. Die europäische APOB-Gründermutation p.R3500Q konnte nur bei einem Patienten detektiert werden. In PCSK9 wurde keine Mutation gefunden. Bei etwa 50 % der nachgewiesenen LDLR-Mutationen handelte es sich um Missense-Mutationen, die anderen 50 % umfassten Nonsense-Mutationen, Spleißmutationen, kleinere Deletionen und Duplikationen sowie größere Deletionen, die mittels MLPA detektiert wurden. Untersuchungen möglicher modifizierender genetischer Faktoren der Cholesterin-Konzentration bei Patienten mit LDLR Mutation, zeigten keine statistisch signifikanten Ergebnisse für eine Assoziation von Nonsense-SNPs in ABCA10, APOL3 und LPL. Bei einem Patienten konnten wir die heterozygote Nukleotidsubstitution c.-188C>T in der konservierten, GC-reichen SP1-Bindungsstelle im repeat 1 der LDLR-Promotorregion identifizieren. Ein Luciferase Reporter Assay zeigte, dass es infolge einer verminderten SP1-Bindungsfähigkeit an den Promotor in vitro zu einer signifikanten Reduktion der transkriptionellen Aktivität des mutanten Promotors um 80 % kommt. Diese Ergebnisse wiesen auf die große Bedeutung von transkriptionellen Veränderungen der LDLR-Expression in der Pathogenese der Hypercholesterinämie hin. Basierend auf dieser Erkenntnis führten wir bei Mutations-negativen Patienten der LIANCO Kohorte Mutationsanalysen in SREBP1 und SREBP2 durch, zwei Transkriptionsfaktoren, die eine zentrale Rolle in der Cholesterinhomöostase spielen, indem sie unter anderem die Regulation der LDLR-Expression kontrollieren. Wir konnten bei einem Patienten die heterozygote Missense-Mutation p.R812Q im SREBP1-Gen identifizieren und bei einem zweiten Patienten die heterozygote Missense-Mutation p.G852R in SREBP2. Nach genetischer Bestätigung der kausalen Rolle dieser Mutationen konnten wir mittels einer in vitro-Interaktionsstudie zeigen, dass beide Mutationen die konstitutive Wechselwirkung zwischen der regulatorischen, C-terminalen Domäne der SREBP-Vorläuferproteine und der cytoplasmatischen WD-Domäne von SCAP in der Membran des endoplasmatischen Retikulums beeinträchtigen. Infolgedessen kommt es zu einer verminderten Freisetzung des N-terminalen, transkriptionell aktiven Teils von SREBPs und dadurch zu einer reduzierten Expression von LDLR, was mittels Luciferase Reporter Assay nachgewiesen wurde. Die resultierende LDL-Rezeptordefizienz an der Zelloberfläche bietet eine Erklärung für die Akkumulation von LDL-Partikeln im Plasma der Patienten, die Diagnose Hypercholesterinämie und identifiziert zwei neue ursächliche Gene für Hypercholesterinämie. Mittels eines zweiten Ansatzes, bei dem große Familien mit diagnostizierter FH für Kopplungsanalysen verwendet wurden, ließen sich keine neuen FH-Gene identifizieren. In einer großen türkischen Familie mit neun betroffenen Individuen stellten wir fest, das das Auftreten von Phänokopien bei häufigen Erkrankungen die experimentellen Daten sehr beeinflussen kann und konnten zeigen, wie sich das Problem durch die Verwendung einer nicht Modell-basierten, nicht-parametrischen Kopplungsanalyse bewältigen lässt. Nachfolgend wurde die p.C222R LDLR-Mutation bei sieben von neun betroffenen Familienmitgliedern gefunden. Die Identifizierung von neuen genetischen Faktoren und molekularen Mechanismen der Hypercholesterinämie bei Patienten der LIANCO Kohorte kann entscheidend dazu beitragen, künftig eine präzisere genetische Beratung anzubieten, individuelle Risikoabschätzungen zu treffen und hoffentlich neue therapeutische Strategien zu entwickeln. Des Weiteren führten Studien über zwei angeborene, autosomal-rezessiv vererbte Syndrome, die mit metabolischen Störungen assoziiert sind, zur Identifizierung von neuen krankheitsverursachenden Mutationen und zur Aufklärung der molekularen Pathogenese dieser Erkrankungen. Nach genomweiter Kopplungsanalyse in einer Familie, die klinisch durch Hypogonadismus, Diabetes, Alopezie und mentale Retardierung charakterisiert ist, fanden wir eine krankheitsverursachende Mutation, c.1091+1G>A, im C2orf37-Gen, welches in einer großen homozygoten Region auf Chromosom 2q31.1 lokalisiert war. Während unserer Analysen wurde C2orf37 als kausales Gen für das autosomal-rezessive Woodhouse-Sakati Syndrom beschrieben, das überlappende Symptome mit unseren Familien aufweist. Zusätzlich identifizierten wir loss-of-function Mutationen in C2orf37 in zwei weiteren Familien mit diagnostizierten Syndromen, die überlappende Phänotypen zeigen, was die Vermutung nahelegte, dass diese zum Spektrum von Woodhouse-Sakati-ähnlichen Phänotypen gehören. Modifizierende genetische Faktoren sind vermutlich verantwortlich für die inter- und intrafamiliäre klinische Variabilität. Letztendlich ist es im Rahmen dieser Arbeit gelungen, mittels Exom-Sequenzierung, einer neuen High-End-Technologie, bei einem Patienten mit diagnostiziertem Wiedemann-Rautenstrauch Syndrom (WRS) die kausale homozygote Missense-Mutation p.G206R im PYCR1-Gen zu identifizieren. WRS ist ein seltenes, rezessives, neonatales Progerie Syndrom mit frühzeitig auftretenden endokrinen und metabolischen Störungen. Aufgrund der rezessiven Vererbung und der elterlichen Konsanguinität erwies es sich als äußerst effizient, die gewonnenen Exom-Daten mittels Analyse auf homozygote Bereiche zu filtern und so die Anzahl der detektierten potentiell pathogenen Varianten zu minimieren. PYCR1-Mutationen wurden bereits für ein Spektrum an Erkrankungen beschrieben, zu dem die Gerodermia Osteodysplastika, das Wrinkly Skin Syndrom und das de Barsy Syndrom gehören. Die klinische Re-Evaluierung unseres Patienten ergab Überlappungen mit diesen Erkrankungen und zeigte, dass der Phänotyp unseres Patienten eine schwere Form am Ende des Spektrums darstellt. Die gestörte PYCR1-Funktion beeinflusst den Prolin-Metabolismus und könnte sowohl die mitochondriale Funktion als auch die Produktionsmenge von freien Radikalen beeinträchtigen. Der pathogene Mechanismus muss in Zukunft zwar erst noch aufgeklärt werden, eine mitochondriale Fehlfunktion liefert jedoch bereits jetzt eine höchst schlüssige Arbeitshypothese für die bei unserem Patienten beobachtete beschleunigte Alterung und die aufgetretenen endokrinen und metabolischen Störungen

Uma orientação diagnóstica para neurodegeneração com acúmulo cerebral de ferro: aspectos clínicos, genéticos e de neuroimagem

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.A neurodegeneração com acúmulo cerebral de ferro (sigla em inglês NBIA) representa um grupo heterogêneo e complexo de doenças neurodegenerativas hereditárias, caracterizada pelo acúmulo cerebral de ferro, especialmente nos núcleos da base. O quadro clínico das NBIAs em geral inclui distúrbios do movimento, particularmente parkinsonismo e distonia, disfunção cognitiva, sinais piramidais e anormalidades da retina. As formas de NBIA descritas até o momento incluem neurodegeneração associada a pantothenase kinase (PKAN), neurodegeneração associada a phospholipase A2 (PLAN), neuroferritinopatia, aceruloplasminemia, neurodegeneração associada a beta-propeller protein (BPAN), síndrome de Kufor-Rakeb, neurodegeneração associada a mitochondrial membrane protein (MPAN), neurodegeneração associada a “fatty acid hydroxylase” (FAHN), neurodegeneração associada a coenzyme A synthase protein (CoPAN) e síndrome de Woodhouse-Sakati. Esta revisão é uma orientação para o diagnóstico das NBIAs, partindo das características clínicas e achados de neuroimagem, até a etiologia genética

An international registry for neurodegeneration with brain iron accumulation

We report the development of an international registry for Neurodegeneration with Brain Iron Accumulation (NBIA), in the context of TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration), an EU-FP7-funded project. This registry aims to combine scattered resources, integrate clinical and scientific knowledge, and generate a rich source for future research studies. This paper describes the content, architecture and future utility of the registry with the intent to capture as many NBIA patients as possible and to offer comprehensive information to the international scientific community

From biology to genes and back again: Gene discovery for monogenic forms of beta cell dysfunction in diabetes

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordThis review focusses on gene discovery strategies used to identify monogenic forms of diabetes caused by reduced pancreatic beta cell number (due to destruction or defective development) or impaired beta cell function. Gene discovery efforts in monogenic diabetes have identifi ed 36 genes so far. These genetic causes have been identified using four main approaches: linkage analysis, candidate gene sequencing and most recently, exome and genome sequencing. The advent of next-generation sequencing has allowed researchers to move away from linkage analysis (relying on large pedigrees and/or multiple families with the same genetic condition) and candidate gene (relying on previous knowledge on the gene’s role) strategies to use a gene agnostic approach, utilising genetic evidence (such as variant frequency, predicted variant effect on protein function, and predicted mode of inheritance) to identify the causative mutation. This approach led to the identification of 7 novel genetic causes of monogenic diabetes, 6 by exome sequencing and one by genome sequencing. In many of these cases, the disease-causing gene was not known to be important for beta cell function prior of the gene discovery study. These novel findings highlight a new role for gene discovery studies in furthering our understanding of beta cell function and dysfunction in diabetes. Whilst many gene discovery studies in the past were led by knowledge in the field (through the candidate gene strategy) now they often lead the scientific advances in the field by identifying new important biological players to be further characterised by in vitro and in vivo studies.EFSD Rising Star Fellowshi

Neurodegeneration with Brain Iron Accumulation: An Overview

How to Cite This Article: Tonekaboni SH, Mollamohammadi M. Neurodegeneration with Brain Iron Accumulation: An Overview. Iran J Child Neurol. 2014 Autumn;8(4): 1-8.AbstractObjectiveNeurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative disorder with deposition of iron in the brain (mainly Basal Ganglia) leading to a progressive Parkinsonism, spasticity, dystonia, retinal degeneration, optic atrophy often accompanied by psychiatric manifestations and cognitive decline. 8 of the 10 genetically defined NBIA types are inherited as autosomal recessive and the remaining two by autosomal dominant and X-linked dominant manner. Brain MRI findings are almost specific and show abnormal brain iron deposition in basal ganglia some other related anatomicallocations. In some types of NBIA cerebellar atrophy is the major finding in MRI.ReferencesShevel M. Racial hygiene, activeeuthanasia, and Julius Hallervorden. Neurology 1992;42:2214-2219.HayflickSJ. Neurodegeneration with brain Iron accumulation: from genes to pathogenesis.Semin Pediatr Neurol 2006;13:182-185.Zhou B, Westawy SK, Levinson B, et al. A novel pantothenate kinase gene(PANK2) is defective in Hallervorden-Spatzsyndrome. Nat Genet 2001;28:345- 349.www.ncbi.nlm.nihgov/NBK111Y/university of Washington, seattle. Allison Gregory and Susan Hayflick.Paisan-Ruiz C, Li A, Schneider SA, et al. Widesread Levy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2012;33:814-823.Dick KJ, Eckhardt M, Paison-Ruiz C, et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia(SPG 35). Hum Mutat 31: E1251-E1260.Edvardson S, Hama H, Shaag A, et al. Mutation in the fatty acid 2-Hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am I Hum Genet 2008;83:647-648.Schneider SA, Aggarwal A, Bhatt m, et al. Severe tongue protrusion dystonia: clinical syndromes and possible treatment. Neurology 2006;67: 940-943.Egan RA, Weleber RG, Hogarth P. et al. Neuroopthamologic and electroreinographic finding in pantothenate kinase associated neurodegeneration. Am J ophtalmol 2005;140:167-274.Kruer MC, Boddaert N. Adiadnostic Algorithm. Semin Pediatrn Neurol  2012;19: 67-74.Dezfouli MA, Alavi A, Rohani M, Rezvani M, Nekuie T, Klotzle B, Tonekaboni SH, Shahidi GA, Elahi E. PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation. Mov Disord 2013 Feb;28(2):228-32. doi: 10.1002/mds.25271.Epub 2012 Nov 19.Hartig MB, Hortnagel K, Garavaglia B, et al. Genotype and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation Ann Neurol 2006;59: 248-256.Kotzbauer PT, Truax AC, Trojanowsli JQ, et al. Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation cause by abnormal processing of mutant pantothenase Kinase2. J Neurosci 2005;25:689-698.Poli M, Deosas M, Lusciete S, et al. Pantothenate Kinase2 silencing causes cell growth reduction and iron  deregulation Neurobiol Dis 2010;39: 204-210.Wakabayashi K, Fukushima T, Koide R, et al. Juvenile-nset generalized neuroaxonal dystrophy with  diffuse neurofibrillary and Lewy body pathology. ActaNeuropathonal 2000;99: 331-336.Galvin JE, Giasson B, Hurting HI, et al. Neurodegeneration with brain iron accumulation, type1 is characterized by alpha, beta and gamma-synuclein neuropathology, Am T Pathol 2000;157: 361-368.Li A, Paudel R, Johnson R, et al. Pantothenate Kinaseassocated neurodegeneration is not a  synucleinopathyneuropathol Appl Neurobiol(in press).Gregory A, Polster BJ, Hayflick SJ: Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46:73-80.Gregory A, Westaway SK, Holm IE, et al. Neurodegeneration associated with genetic defects in phospholipase A2. Neurology 2008;71:1402-1409.Harting MB, Lsao A, Haa KT, et al. Absence of an orphan mitochondrial protein, c19orf12 with brain iron accumulation, Am J Hum Genet 2011;89: 543-550.Najim al-Din AS, Wriekat A, Mubaidin A, et al. Pallidopyramidal degeneration, supraneuclearupgaze paresis and dementia: Kufor- Rakeb syndrome. Acta Neurol Scand 2011;89: 347-352.Tobias B Hoak, Penelope Hogarth, Micheal C Kruer et al. Am J Hum Genet 2012 Dec 7; 91 (6): 1144-49.Chummery PF, Crompton DE, Bircholl D, et al. Clinical features and matural history of Neuroferritinopathy caused by the FTL1 gene mutation. Brain 2007;130:110-119.Mc Neil A, Bircholl D, Hayflich SJ, et al. T2 and FSE MRI distinguishes L subtypes of NBIA, Neurology 2008;70: 1614- 1619. McNeil A , Pandolfo M, Kuhn J,et al.The Neurological presentation of ceruloplasmin gene  mutations. Eur Neurol 2008;60:200-205.Dusi S, Valletta L, Hoach TB, et al. Exone sequencing reveals mutations in Co A synthtas as a cause of neurodegeneration with brain iron accumulation: Am J Hum Genetic Jan2, 2014. Aras M Alazim, Amir Alsaif, Abdulaziz Al-Semari, et al. mutation in C2 orf 37, cause hypogonadism, diabetes Melitus, Mental retardation and extrapyramidal syndrome: Am J Hum Genetic. 2008 Dec 12; 83(6): 684-691