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.

Download full-text


Available from: Allison Gregory,
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    The International Journal of Biochemistry & Cell Biology 02/2015; 63. DOI:10.1016/j.biocel.2015.01.018 · 4.05 Impact Factor
  • Source
    • "'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). "
    [Show abstract] [Hide abstract]
    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.
    Molecular Genetics and Metabolism 06/2014; 112(2). DOI:10.1016/j.ymgme.2014.03.008 · 2.63 Impact Factor
  • Source
    • "PKAN usually manifests in childhood with gait disturbances and rapidly progresses to a severe movement deficit with dystonia, dysarthria and dysphagia. The hallmark of this disease is the eyeof-the-tiger signal in the globus pallidus on T 2 -weighted MRI (Hayflick et al., 2003; Gregory et al., 2009) To date, the mechanistic connection linking PANK2 dysfunction, neurodegeneration and alteration of iron homeostasis has not been understood, thus preventing our comprehension of the pathogenesis of the disease and the design of efficient therapeutic strategies. It has been proposed that reduced PANK2 enzymatic activity determines the accumulation of cysteine, which may chelate iron thus promoting the formation of free radicals (Gregory et al., 2008); alternatively, defects in co-enzyme A and, as a consequence, in phospholipid metabolism may damage the membranes and lead to increased oxidative stress, which may alter iron homeostasis (Leonardi et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.
    Brain 12/2013; 137(1). DOI:10.1093/brain/awt325 · 9.20 Impact Factor
Show more