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. 2013 Jan;11(1):59-79.
doi: 10.2174/157015913804999469.

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Susanne A Schneider  1 , Petr Dusek, John Hardy, Ana Westenberger, Joseph Jankovic, Kailash P Bhatia
Affiliations

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

Susanne A Schneider et al. Curr Neuropharmacol. 2013 Jan.

Abstract

Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic. Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.

Keywords: Ceramide; MPAN; NBIA; PKAN; PLA2G6.; dystonia; iron; parkinsonism.

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Figures

Fig. (1)
Fig. (1)
Examples of brain MR imaging in NBIA disorders; showing a case of pantothenate kinase associated neurodegeneration (PKAN) (left), Kufor Rakeb disease (due to ATP13A2 mutations) (center) and neuroferritinopathy (due to FTL mutations) (right). In PKAN there is a classic eye of the tiger sign. Iron accumulation affects the putamen and caudate in our Kufor Rakeb disease patient. In this gene-proven neuroferritinopathy patient there is iron deposition in the basal ganglia, with a slight hint of thalamic involvement. Reproduced from [3].
Fig. (2)
Fig. (2)
Pathways of cellular iron homeostasis and neurological disorders associated with iron accumulation associated with these, adjusted from Madsen and Gitlin [192] and reproduced from [3]. Iron uptake occurs via the divalent transporter DMT1 (ferrous iron, Fe 2+, shown in the lower right of the figure)or via endocytosis of the transferrin receptor (ferric iron, Fe 3+, shown in the upper right of figure). Steap3 is a ferrireductase critical for transferrin-mediated iron release into the cell. Ferritin is the predominant storage protein consisting of heavy chains and light chains. Mutations in the gene encoding ferritin light chains are associated with neuroferritinopathy (1). Iron homeostasis is regulated by hepcidin which binds to ferroportin, the only known cellular iron exporter. Ceruloplasmin is a ferroxidase mediating efficient cellular iron release. Mutations in the gene encoding ceruloplasmin cause aceruloplasminemia (2). Iron enters mitochondria via mitoferrin, Frataxin is a mitochondrial protein mediating Fe-S cluster formation and heme biosynthesis. Mutations in frataxin cause Friedreich ataxia (3).
Fig. (3)
Fig. (3)
The figure shows simplified metabolic pathways of ceramide which is derived from two main sources operating in different cellular compartments: hydrolysis of membrane-derived sphingomylin and de novo synthesis from palmitoyl CoA and serine. Neurological diseases along the pathways are demonstrated (incomplete list). (for reference see King 2008 [203] and http://www.sphingomap.org/) 1 - Pantothenate kinase associated neurodegeneration (PKAN), 2 - Farber disease (ceraminidase deficiency), 3- Krabbe disease (beta galactosidase deficiency), 4 - Fabry disease (alpha galactosidase A deficiency), 5 - Metachromatic leukodystrophy (cerebroside sulphatase deficiency), 6 - Gaucher disease (glucocerebroisidase deficicency), 7 - Tay Sachs disease (hexosaminidase A deficiency), 8 - GM2 gangliosidosis (beta-galactosidase deficiency), 9 - Sandhoff disease (hexosaminidase A + B deficiency), 10 - PLA2G6-associated neurodegeneration, 11 - Nieman Pick disease (sphingomyelinase deficiency). Reproduced from Schneider et al. [3].
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References

    1. Fleming RE, Ponka P. Iron overload in human disease. N. Engl. J. Med. 2012;366:348–59. - PubMed
    1. Dusek P, Jankovic J, Weidong L. Iron dysregulation in movement disorders. Neurobiol. Dis. 2012;46:1–18. - PubMed
    1. Schneider S A, Hardy J, Bhatia K P. Syndromes of neurodegeneration with brain iron accumulation (NBIA): An update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Mov. Disord. 2012;27:42–53. - PubMed
    1. Crichton R R, Dexter D T, Ward R J. Brain iron metabolism and its perturbation in neurological diseases. J. Neural. Transm. 2011;118:301–14. - PubMed
    1. Connor J R, Menzies S L, St Martin S M, Mufson E J. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J. Neurosci. Res. 1990;27:595–611. - PubMed