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last update : 20-01-2015
Symbol PMDX
Location Xq22.2
Name Pelizaeus-Merzbacher disease, type 1
Other name(s)
  • Arena syndrome
  • leukodystrophy, hypomyelinative 1
  • Corresponding gene PLP1
    Other symbol(s) PMD, HLD1
    Main clinical features
  • leukodystrophy that causes severe dysmyelination in the central nervous system in infancy and early childhood
  • characterized by an early onset by anormal eye movements, progressive mental retardation, bilateral pyramidal signs and evidence of whitematter deficit (PLP deficiency or overdosage)
  • life-limiting disorder
  • Genetic determination sex linked
    genomic disorder
    Related entries spastic paraplegia type 2 (SPG2, Mim 312920) is an allelic X-linked disorder
    Function/system disorder neurology
    mental retardation
    Type disease
    Gene product
    Name proteolipid protein (PLP)
    Gene mutationChromosome rearrangementEffectComments
      duplication   genomic duplication in ~50-70p100 of cases(in some cases at non contiguous sites), variable size from 10kb to <7Mb, most commonly 600-700kb
      deletion   extremely rare genomic deletions usually less than 600kb
    missense   abnormal protein/loss of function cause ER retention and oligodendrocyte death
  • mutations that map into the extracellular loop region leads to the failure of oligodendrocytes to form the correct intramolecular disulfide bridges and to abnormal protein cross-links and endoplasmic reticulum retention and activates the unfolded protein response
  • misalignment of PLP1 transmembrane domains determines protein misfolding in Pelizaeus-Merzbacher disease (PMID: 22016529))
  • mutant PLP1 accumulates in the endoplasmic reticulum (ER) and induces ER stress (PMID: 23344956))
  • Genotype/Phenotype correlations A link was demonstrated between mild disease in males and symptoms in carrier female relatives. Conversely mutations causing severe disease in males rarely cause clinical signs in carrier female.