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GENATLAS PHENOTYPE

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)

Mechanism(s)

Gene mutation	Chromosome rearrangement	Effect	Comments
	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

Remark(s)

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.