Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation

• Published in: Annals of neurology 2006-02, Vol.59 (2), p.248-256
• Main Authors: Hartig, Monika B., Hörtnagel, Konstanze, Garavaglia, Barbara, Zorzi, Giovanna, Kmiec, Tomasz, Klopstock, Thomas, Rostasy, Kevin, Svetel, Marina, Kostic, Vladimir S., Schuelke, Markus, Botz, Evelyn, Weindl, Adolf, Novakovic, Ivana, Nardocci, Nardo, Prokisch, Holger, Meitinger, Thomas
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age of Onset; Alleles; Animals; Basal Ganglia - metabolism; Basal Ganglia - pathology; Biological and medical sciences; Biological Evolution; Child; Child, Preschool; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis; Family Health; Female; Founder Effect; Genetic Heterogeneity; Humans; Iron - metabolism; Magnetic Resonance Imaging - methods; Male; Medical sciences; Middle Aged; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Mutation; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - physiopathology; Neurology; Phenotype; Phosphotransferases (Alcohol Group Acceptor) - genetics; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; Sequence Alignment; Statistics as Topic; Time Factors
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.20771

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. Interpretation 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. Ann Neurol 2006;59:248–256