title: New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.
abstract: OBJECTIVE
  To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype.
  
  
  METHODS
  Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject.
  
  
  RESULTS
  A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures.
  
  
  CONCLUSIONS
  MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase-associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, USA.
authors.forename: Penelope
authors.initials: P
authors.lastname: Hogarth
authors.forename: Allison
authors.initials: A
authors.lastname: Gregory
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
authors.forename: Lynn
authors.initials: L
authors.lastname: Sanford
authors.forename: Wendy
authors.initials: W
authors.lastname: Wagoner
authors.forename: Marvin R
authors.initials: MR
authors.lastname: Natowicz
authors.forename: Robert T
authors.initials: RT
authors.lastname: Egel
authors.forename: S H
authors.initials: SH
authors.lastname: Subramony
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Goldman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Foulds
authors.forename: Simon R
authors.initials: SR
authors.lastname: Hammans
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Callum
authors.initials: C
authors.lastname: Wilson
authors.forename: Andrea
authors.initials: A
authors.lastname: Diedrich
authors.forename: Sarah
authors.initials: S
authors.lastname: Green
authors.forename: Huong
authors.initials: H
authors.lastname: Tran
authors.forename: Lindsay
authors.initials: L
authors.lastname: Reese
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
mesh_terms: D000293:Adolescent; D000328:Adult; D001923:Brain Chemistry / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D004421:Dystonia / Q000209:etiology; D004569:Electroencephalography; D004576:Electromyography; D005242:Fecal Incontinence / Q000209:etiology; D005260:Female; D020233:Gait Disorders, Neurologic / Q000209:etiology; D006801:Humans; D007150:Immunohistochemistry; D019190:Iron Overload / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D020961:Lewy Body Disease / Q000473:pathology; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D009460:Neurologic Examination; D010641:Phenotype; D011859:Radiography; D014549:Urinary Incontinence / Q000209:etiology; D055815:Young Adult
chemical_list: C568481:C19orf12 protein, human; D024101:Mitochondrial Proteins; D004247:DNA