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.
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.
Authors: Arcangela Iuso; Marit Wiersma; Hans-Joachim Schüller; Ben Pode-Shakked; Dina Marek-Yagel; Mathias Grigat; Thomas Schwarzmayr; Riccardo Berutti; Bader Alhaddad; Bart Kanon; Nicola A Grzeschik; Jürgen G Okun; Zeev Perles; Yishay Salem; Ortal Barel; Amir Vardi; Marina Rubinshtein; Tal Tirosh; Gal Dubnov-Raz; Ana C Messias; Caterina Terrile; Iris Barshack; Alex Volkov; Camilla Avivi; Eran Eyal; Elisa Mastantuono; Muhamad Kumbar; Shachar Abudi; Matthias Braunisch; Tim M Strom; Thomas Meitinger; Georg F Hoffmann; Holger Prokisch; Tobias B Haack; Bianca J J M Brundel; Dorothea Haas; Ody C M Sibon; Yair Anikster Journal: Am J Hum Genet Date: 2018-05-10 Impact factor: 11.025