title: The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN.
abstract: Mutations in the C19orf12 gene cause mitochondrial membrane protein associated neurodegeneration (MPAN), an autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). A limited number of patients with C19orf12 mutations, particularly those with adult onset of symptoms, have been reported.
  
  
  
  We sequenced the entire coding region of C19orf12 in 15 Turkish adult probands with idiopathic NBIA. We also performed haplotype analysis in families with a recurrent C19orf12 mutation. Clinical features were collected using a standardized form.
  
  
  
  Nine of our 15 probands (60%) carried the homozygous c.32C > T mutation in C19orf12 (predicted protein effect: p.Thr11Met). This homozygous mutation co-segregated with the disease in all affected relatives available for testing (16 homozygous subjects). Haplotypes across the C19orf12 locus were identical for a very small region, closest to the mutation, suggesting an old founder, or, two independent founders. The clinical phenotype was characterized by adult onset in most cases (mean 24.5 years, range 10-36), and broad spectrum, including prominent parkinsonism, pyramidal signs, psychiatric disturbances, cognitive decline, and motor axonal neuropathy, in various combinations. On T2- or susceptibility weighted-MRI images, all patients displayed bilateral hypointensities in globus pallidus and substantia nigra, without an eye-of-the-tiger sign; however, hyperintense streaking of the medial medullary lamina between the external and internal parts of globus pallidus was observed frequently.
  
  
  
  The C19orf12 p.Thr11Met mutation is frequent among adult Turkish patients with MPAN. These findings contribute to the characterization of this important NBIA form, and have direct implications for genetic testing of patients of Turkish origin.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Olgiati
authors.affiliation: Department of Neurology, Medical Faculty, Mersin University, Mersin, Turkey.
authors.forename: Okan
authors.initials: O
authors.lastname: Doğu
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tufekcioglu
authors.affiliation: Neurology Clinic, Ümraniye Research and Training Hospital, Istanbul, Turkey.
authors.forename: Yunus
authors.initials: Y
authors.lastname: Diler
authors.affiliation: Department of Neurology, Medical Faculty, Hacettepe University, Ankara, Turkey.
authors.forename: Esen
authors.initials: E
authors.lastname: Saka
authors.affiliation: Department of Neurology, Erciyes University Faculty of Medicine, Kayseri, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Gultekin
authors.affiliation: Department of Neurology, Medical Faculty, Mersin University, Mersin, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Kaleagasi
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Demy
authors.initials: D
authors.lastname: Kuipers
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Josja
authors.initials: J
authors.lastname: Graafland
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.affiliation: Neurology Clinic, Ümraniye Research and Training Hospital, Istanbul, Turkey.
authors.forename: Reyhan
authors.initials: R
authors.lastname: Sürmeli
authors.affiliation: Neurology Clinic, Ümraniye Research and Training Hospital, Istanbul, Turkey.
authors.forename: Gülin
authors.initials: G
authors.lastname: Sünter
authors.affiliation: Neurology Clinic, Ümraniye Research and Training Hospital, Istanbul, Turkey.
authors.forename: Tuğrul
authors.initials: T
authors.lastname: Doğan
authors.affiliation: Neurology Clinic, Ümraniye Research and Training Hospital, Istanbul, Turkey.
authors.forename: Ayşe Destina
authors.initials: AD
authors.lastname: Yalçın
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Başar
authors.initials: B
authors.lastname: Bilgiç
authors.affiliation: Department of Neurology, Medical Faculty, Hacettepe University, Ankara, Turkey.
authors.forename: Bülent
authors.initials: B
authors.lastname: Elibol
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Emre
authors.affiliation: Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Hasmet A
authors.initials: HA
authors.lastname: Hanagasi
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. Electronic address: v.bonifati@erasmusmc.nl.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008715:Methionine / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D013912:Threonine / Q000235:genetics; D014421:Turkey; D055815:Young Adult
chemical_list: C568481:C19orf12 protein, human; D024101:Mitochondrial Proteins; D013912:Threonine; D008715:Methionine
keywords: C19orf12; Iron accumulation; MPAN; Mutation; Neurodegeneration; Parkinsonism