title: Neurodegeneration associated with genetic defects in phospholipase A(2).
abstract: OBJECTIVE
  Mutations in the gene encoding phospholipase A(2) group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA). INAD is a severe progressive psychomotor disorder in which axonal spheroids are found in brain, spinal cord, and peripheral nerves. High globus pallidus iron is an inconsistent feature of INAD; however, it is a diagnostic criterion of NBIA, which describes a clinically and genetically heterogeneous group of disorders that share this hallmark feature. We sought to delineate the clinical, radiographic, pathologic, and genetic features of disease resulting from defective phospholipase A(2).
  
  
  METHODS
  We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations.
  
  
  RESULTS
  Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA. All patients with two null mutations had a more severe phenotype. On MRI, nearly all mutation-positive patients had cerebellar atrophy, and half showed brain iron accumulation. We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations.
  
  
  CONCLUSIONS
  Defects in phospholipase A(2) lead to a range of phenotypes. PLA2G6 mutations are associated with nearly all cases of classic infantile neuroaxonal dystrophy but a minority of cases of idiopathic neurodegeneration with brain iron accumulation, and genotype correlates with phenotype. Cerebellar atrophy predicts which patients are likely to be mutation-positive. The neuropathologic changes that are caused by defective phospholipase A(2) suggest a shared pathogenesis with both Parkinson and Alzheimer diseases.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, L103a, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gregory
authors.forename: S K
authors.initials: SK
authors.lastname: Westaway
authors.forename: I E
authors.initials: IE
authors.lastname: Holm
authors.forename: P T
authors.initials: PT
authors.lastname: Kotzbauer
authors.forename: P
authors.initials: P
authors.lastname: Hogarth
authors.forename: S
authors.initials: S
authors.lastname: Sonek
authors.forename: J C
authors.initials: JC
authors.lastname: Coryell
authors.forename: T M
authors.initials: TM
authors.lastname: Nguyen
authors.forename: N
authors.initials: N
authors.lastname: Nardocci
authors.forename: G
authors.initials: G
authors.lastname: Zorzi
authors.forename: D
authors.initials: D
authors.lastname: Rodriguez
authors.forename: I
authors.initials: I
authors.lastname: Desguerre
authors.forename: E
authors.initials: E
authors.lastname: Bertini
authors.forename: A
authors.initials: A
authors.lastname: Simonati
authors.forename: B
authors.initials: B
authors.lastname: Levinson
authors.forename: C
authors.initials: C
authors.lastname: Dias
authors.forename: C
authors.initials: C
authors.lastname: Barbot
authors.forename: I
authors.initials: I
authors.lastname: Carrilho
authors.forename: M
authors.initials: M
authors.lastname: Santos
authors.forename: I
authors.initials: I
authors.lastname: Malik
authors.forename: J
authors.initials: J
authors.lastname: Gitschier
authors.forename: S J
authors.initials: SJ
authors.lastname: Hayflick
mesh_terms: D000293:Adolescent; D001921:Brain / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D054522:Group VI Phospholipases A2 / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D011877:Radionuclide Imaging
chemical_list: D007501:Iron; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human
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