PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation: PANK2 and C19orf12 mutations in NBIA Patients

School of Biology, University College of Science, University of Tehran, Tehran, Iran.
Movement Disorders (Impact Factor: 5.68). 02/2013; 28(2). DOI: 10.1002/mds.25271
Source: PubMed


Neurodegeneration with brain iron accumulation (NBIA) constitutes a group of neurodegenerative disorders with pronounced iron deposition in the basal ganglia. PANK2 mutations are the most common cause of these disorders. C19orf12 was recently reported as another causative gene. We present phenotypic data and results of screening of PANK2 and C19orf12 in 11 unrelated Iranian NBIA patients.Methods
Phenotypic data were obtained by neurologic examination, magnetic resonance imaging, and interviews. Mutation screening of PANK2 and C19orf12 was performed by sequencing.ResultsPANK2 and C19orf12 mutations were found in 7 and 4 patients, respectively. Phenotypic comparisons suggest that C19orf12 mutations as compared with PANK2 mutations result in a milder disease course.Conclusions
Mutations in both PANK2 and C19orf12 contributed significantly to NBIA in the Iranian patients. To the best of our knowledge, this is the first genetic analysis reported on a cohort of NBIA patients from the Middle East. © 2012 Movement Disorder Society

Download full-text


Available from: Afagh Alavi
  • [Show abstract] [Hide abstract]
    ABSTRACT: In parallel to recent developments of genetic techniques, understanding of the syndromes of neurodegeneration with brain iron accumulation has grown considerably. The acknowledged clinical spectrum continues to broaden, with age-dependent presentations being recognized. Postmortem brain examination of genetically confirmed cases has demonstrated Lewy bodies and/or tangles in some forms, bridging the gap to more common neurodegenerative disorders, including Parkinson disease. In this review, the major forms of neurodegeneration with brain iron accumulation (NBIA) are summarized, concentrating on clinical findings and molecular insights. In addition to pantothenate kinase-associated neurodegeneration (PKAN) and phospholipase A2-associated neurodegeneration (PLAN), fatty acid hydroxylase-associated neurodegeneration (FAHN) NBIA, mitochondrial protein-associated neurodegeneration, Kufor-Rakeb disease, aceruloplasminemia, neuroferritinopathy, and SENDA syndrome (static encephalopathy of childhood with neurodegeneration in adulthood) are discussed.
    No preview · Article · Jun 2012 · Seminars in pediatric neurology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) is a group of rare and devastating disorders characterized by iron deposition in the brain. Mutations in C19orf12 cause autosomal recessive inherited mitochondrial membrane protein-associated neurodegeneration (MPAN), which may account for up to 30% of NBIA cases. The C19orf12 gene product is an orphan mitochondrial membrane protein, and most mutations are predicted to cause loss of function. From 67 MPAN cases so far reported, we describe here the clinical, radiological, and genetic features. Key clinical features are pyramidal and extrapyramidal signs, cognitive decline, neuropsychiatric abnormalities, optic atrophy, and motor axonal neuropathy. Magnetic resonance imaging shows the eponymous brain iron accumulation in globus pallidus and substantia nigra and in some cases a hyperintense streaking of the medial medullary lamina. The latter sign may discriminate MPAN from other NBIA subtypes. In two postmortem MPAN cases, neuropathology showed axonal spheroids, Lewy bodies, and hyperphosphorylated tau-containing inclusions.
    No preview · Article · Nov 2013 · International Review of Neurobiology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases the underlying cause of iron mis-metabolism is known, while in others our understanding is at best incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggest that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron modulating proteins, dysfunction of a specific pathway or selective absence of iron modulating protein(s) in systemic organs has provided important insight into the maintenance of iron homeostasis within the brain. Here we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mis-metabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders.
    Full-text · Article · Jul 2013 · Antioxidants & Redox Signaling
Show more