title: Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.
abstract: OBJECTIVE
  Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by magnetic resonance imaging (MRI) changes in basal ganglia. Both missense and nonsense mutations have been found in such patients in a gene encoding the mitochondrial pantothenate kinase (PANK2).
  
  
  METHODS
  We completed a mutation screen in 72 patients with the diagnosis NBIA based on clinical findings and radiological imaging. The entire coding region of the PANK2 gene (20p12.3) was investigated for point mutations and deletions.
  
  
  RESULTS
  We uncovered both mutant alleles in 48 patients. Deletions accounted for 4% of mutated alleles. Patients with two loss-of-function alleles (n = 11) displayed symptoms always at an early stage of life. In the presence of missense mutations (n = 37), the age of onset correlated with residual activity of the pantothenate kinase. Progression of disease measured by loss of ambulation was variable in both groups. We did not observe a strict correlation between the eye-of-the-tiger sign and PANK2 mutations. In 24 patients, no PANK2 mutation was identified.
  
  
  CONCLUSIONS
  Deletion screening of PANK2 should be part of the diagnostic spectrum. Factors other than enzymatic residual activity are determining the course of disease. There are strong arguments in favor of locus heterogeneity.
authors.affiliation: Institute of Human Genetics, GSF-National Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Monika B
authors.initials: MB
authors.lastname: Hartig
authors.forename: Konstanze
authors.initials: K
authors.lastname: Hörtnagel
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kmiec
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Kevin
authors.initials: K
authors.lastname: Rostasy
authors.forename: Marina
authors.initials: M
authors.lastname: Svetel
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Kostic
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.forename: Evelyn
authors.initials: E
authors.lastname: Botz
authors.forename: Adolf
authors.initials: A
authors.lastname: Weindl
authors.forename: Ivana
authors.initials: I
authors.lastname: Novakovic
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism* / Q000473:pathology; D005075:Biological Evolution; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D018703:Founder Effect; D018740:Genetic Heterogeneity; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016415:Sequence Alignment; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D007501:Iron; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase