Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet

Molecular and Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 12/2008; 46(2):73-80. DOI: 10.1136/jmg.2008.061929
Source: PubMed


Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders characterised by high brain iron and the presence of axonal spheroids, usually limited to the central nervous system. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase associated neurodegeneration (PKAN). More recently, it was found that mutations in the PLA2G6 gene cause both infantile neuroaxonal dystrophy (INAD) and, more rarely, an atypical neuroaxonal dystrophy that overlaps clinically with other forms of NBIA. High brain iron is also present in a portion of these cases. Clinical assessment, neuroimaging, and molecular genetic testing all play a role in guiding the diagnostic evaluation and treatment of NBIA.

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Available from: Allison Gregory
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    • "c o m / l o c a t e / y n b d i the brain to adequately supply neurons, astrocytes, oligodendrocytes and microglia (Rouault, 2013; Kruer et al., 2012; Schneider et al., 2013; Levi and Finazzi, 2014). NBIA disorders are clinically characterized by a progressive movement disorder with complicating symptoms that can vary significantly in terms of range and severity, and frequently include neuropsychiatric disturbances, such as cognitive deficits, personality changes with impulsivity and violent outbursts, depression, emotional lability, and obsessive compulsive disorder (Gregory et al., 2009). This clinically heterogeneous picture is unified by focal brain iron accumulation, predominantly in the basal ganglia (Kruer et al., 2012; Schneider et al., 2013; Levi and Finazzi, 2014). "
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    ABSTRACT: 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.
    Full-text · Article · Dec 2015 · Neurobiology of Disease
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    • "Another typical pathologic finding in PKAN is the presence of axonal spheroids likely representing swollen and dystrophic axons. Defects in the axonal transport or membrane integrity possibly arising from insufficient neuronal energy metabolism are supposedly the cause of their formation (Gregory et al., 2009). Even though the precise role of PANK2 in CoA biosynthesis is not fully understood, the strong connection between this metabolic pathway, iron deposition and neurodegenerative processes is confirmed by the recent identification of mutations in COASY in two subjects with clinical and MRI features of NBIA (Dusi et al., 2014). "
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    ABSTRACT: 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. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Feb 2015 · The International Journal of Biochemistry & Cell Biology
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    • "'Neurodegeneration with Brain Iron Accumulation' (NBIA) encompasses a group of disorders characterised by progressive motor symptoms , neurological regression and radiologically discernible brain iron accumulation [1] [2] [3] [4]. The major childhood NBIA syndromes include pantothenate kinase associated neurodegeneration (PKAN; MIM#234200) [5], fatty acid hydroxylase associated neurodegeneration (FAHN; MIM#612319) [6], mitochondrial membrane protein associated neurodegeneration (MPAN; MIM#614298) [7], beta-propeller protein associated neurodegeneration (BPAN; MIM#300894) [8], and phospholipase A 2 associated neurodegeneration (PLAN; MIM#256600). "
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    ABSTRACT: Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of the classical PLAN features as well as ‘apparent claval hypertrophy’ is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.
    Full-text · Article · Jun 2014 · Molecular Genetics and Metabolism
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