title: Central nervous system abnormalities in patients with PMP22 gene mutations: a prospective study.
abstract: BACKGROUND
  Mutations of the peripheral myelin protein-22 (PMP22) gene are the most common cause of inherited disease of the peripheral nervous system (PNS), with its deletion resulting in hereditary neuropathy with liability to pressure palsies (HNPP), and its duplication inducing Charcot-Marie-Tooth 1A (CMT1A) disease. Although mainly expressed in the PNS, PMP22 mRNA and protein are also present in the central nervous system (CNS).
  
  
  OBJECTIVE
  To investigate whether patients with PMP22 mutations present with CNS abnormalities.
  
  
  METHODS
  Fifteen patients with HNPP and 15 patients with CMT1A disease were prospectively included and their brain MRI and neuropsychological assessment were compared with those of healthy subjects. We evaluated, in particular, the volumes of grey and white matter (GM and WM) and looked for metabolic changes using spectroscopy, and abnormal architecture using fractional anisotropy (FA) measurement. A post mortem examination of the CNS of a patient with PMP22 gene duplication was also performed.
  
  
  RESULTS
  We found a decrease in the volume of WM in 70% of patients, a reduced creatine level in WM in 28% and a cognitive impairment in 70%. FA was significantly altered in several areas of WM, including the columns of the fornix. The results for WM volume, creatine level in WM and cognitive testing showed that 47% of patients (patients with HNPP and those with CMT1A) presented with at least two abnormal results. Pathological examination of the brain of a patient with PMP22 gene duplication showed diffuse hypomyelination sparing the U fibres.
  
  
  CONCLUSIONS
  This study demonstrates that altered PMP22 gene expression induces significant CNS alterations in patients with HNPP and CMT1A, including cerebral WM abnormalities and cognitive impairment.
authors.affiliation: Department de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1 avenue Molière, Strasbourg 67000, France. jean-baptiste.chanson@chru-strasbourg.fr
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Chanson
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.forename: Frédéric
authors.initials: F
authors.lastname: Blanc
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacour
authors.forename: Laurent
authors.initials: L
authors.lastname: Ballonzoli
authors.forename: Stéphane
authors.initials: S
authors.lastname: Kremer
authors.forename: Izzie-Jacques
authors.initials: IJ
authors.lastname: Namer
authors.forename: Béatrice
authors.initials: B
authors.lastname: Lannes
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.forename: Patrick
authors.initials: P
authors.lastname: Vermersch
authors.forename: Jérôme
authors.initials: J
authors.lastname: de Seze
mesh_terms: D000368:Aged; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000097:blood; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics; D002490:Central Nervous System / Q000002:abnormalities* / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics / Q000523:psychology; D015331:Cohort Studies; D003401:Creatine / Q000097:blood; D038524:Diffusion Magnetic Resonance Imaging; D004185:Disability Evaluation; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D009185:Myelin Proteins / Q000235:genetics*; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D011446:Prospective Studies; D013116:Spinal Cord / Q000473:pathology; D020080:Tandem Repeat Sequences / Q000235:genetics; D055815:Young Adult
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human; D001224:Aspartic Acid; C000179:N-acetylaspartate; D003401:Creatine