Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.
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.
Hartig
Monika B
MB
Institute of Human Genetics, GSF-National Research Center for Environment and Health, Neuherberg, Germany.
Hörtnagel
Konstanze
K
Garavaglia
Barbara
B
Zorzi
Giovanna
G
Kmiec
Tomasz
T
Klopstock
Thomas
T
Rostasy
Kevin
K
Svetel
Marina
M
Kostic
Vladimir S
VS
Schuelke
Markus
M
Botz
Evelyn
E
Weindl
Adolf
A
Novakovic
Ivana
I
Nardocci
Nardo
N
Prokisch
Holger
H
Meitinger
Thomas
T
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
D012333:RNA, Messenger; D007501:Iron; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase