Anne Tschentscher1, Gabriele Dekomien1, Sophia Ross2, Kirsten Cremer3, Guido M Kukuk4, Jörg T Epplen5, Sabine Hoffjan6. 1. Department of Human Genetics, Ruhr-University, Bochum, Germany. 2. Pediatric Neurology, Children's Hospital Erlangen, Germany. 3. Department of Human Genetics, University of Bonn, Germany. 4. Department of Radiology, University of Bonn, Germany. 5. Department of Human Genetics, Ruhr-University, Bochum, Germany; Faculty of Health, University Witten/Herdecke, Witten, Germany. 6. Department of Human Genetics, Ruhr-University, Bochum, Germany. Electronic address: sabine.hoffjan@ruhr-uni-bochum.de.
Abstract
BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with movement disorders and brain iron deposits. In addition to NBIA subtypes caused by mutations in PANK2 and PLA2G6, mutations in the C19orf12 gene were recently described as the third frequent cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Additionally, the X-linked gene WDR45 was found causative for a special subtype named static encephalopathy in childhood with neurodegeneration in adulthood (also called BPAN); however, analysis of this gene in a broader spectrum of NBIA has not been reported yet. METHODS: In a heterogeneous cohort of 69 patients with suspected NBIA that did not carry mutations in PANK2 and PLA2G6, the coding region of C19orf12 was evaluated by Sanger sequencing. The WDR45 gene was analyzed via high resolution melting and subsequent sequence analysis. RESULTS: Previously described homozygous C19orf12 mutations were found in 3/69 NBIA patients (4.3%). Analysis of the WDR45 gene revealed a novel heterozygous missense mutation in one female NBIA patient showing psychomotor retardation with secondary decline. CONCLUSIONS: C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood.
BACKGROUND:Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with movement disorders and brain iron deposits. In addition to NBIA subtypes caused by mutations in PANK2 and PLA2G6, mutations in the C19orf12 gene were recently described as the third frequent cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Additionally, the X-linked gene WDR45 was found causative for a special subtype named static encephalopathy in childhood with neurodegeneration in adulthood (also called BPAN); however, analysis of this gene in a broader spectrum of NBIA has not been reported yet. METHODS: In a heterogeneous cohort of 69 patients with suspected NBIA that did not carry mutations in PANK2 and PLA2G6, the coding region of C19orf12 was evaluated by Sanger sequencing. The WDR45 gene was analyzed via high resolution melting and subsequent sequence analysis. RESULTS: Previously described homozygous C19orf12 mutations were found in 3/69 NBIApatients (4.3%). Analysis of the WDR45 gene revealed a novel heterozygous missense mutation in one female NBIApatient showing psychomotor retardation with secondary decline. CONCLUSIONS:C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood.