title: Compensating for central nervous system dysmyelination: females with a proteolipid protein gene duplication and sustained clinical improvement.
abstract: A submicroscopic duplication that contains the entire proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease, an X-linked central nervous system dysmyelinating disorder. Previous studies have demonstrated that carrier females for the duplication are usually asymptomatic. We describe 2 unrelated female patients who present with mild Pelizaeus-Merzbacher disease or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results have improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, has also shown clinical improvement. Interphase fluorescent in situ hybridization identified a proteolipid protein gene duplication in both patients. Interphase fluorescent in situ hybridization analyses of the family members indicated that the duplication in both patients occurred as de novo events. Neither skewing of X inactivation in the peripheral lymphocytes nor proteolipid protein gene coding alterations were identified in either patient. These findings indicate that, occasionally, females with a proteolipid protein gene duplication can manifest an early-onset neurological phenotype. We hypothesize that the remarkable clinical improvement is a result of myelin compensation by oligodendrocytes expressing one copy of proteolipid protein gene secondary to selection for a favorable X inactivation pattern. These findings indicate plasticity of oligodendrocytes in the formation of central nervous system myelin and suggest a potential role for stem cell transplantation therapies.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: F
authors.initials: F
authors.lastname: Scaglia
authors.forename: A
authors.initials: A
authors.lastname: Araki
authors.forename: L G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D001921:Brain / Q000473:pathology / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D004303:Dosage Compensation, Genetic; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D020440:Gene Duplication; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy
chemical_list: D018991:Myelin Proteolipid Protein