Gene: PLP1
Protein: myelin proteolipid protein
Clinical characteristics:
- Spectrum of phenotypes, ranging from severe neurodegenerative disorder to spastic paraparesis without central nervous system involvement
- Nystagmus
- Hypotonia
- Diffuse leukoencephalopathy
- Cognitive impairment may or may not be present
- Spasticity
- Ataxia
- Choreoathetosis
- Dysarthria
- Pharyngeal weakness and stridor
- Head titubation
Inheritance pattern: X-linked; carrier females may have mild to moderate symptoms.
What these tests can tell us:
Duplication:
Testing is performed by quantitative multiplex PCR to determine copy number of PLP1. Fluorescent primers are used to amplify select exons of the PLP1 gene, along with several reference genes. The quantity of each PCR product is determined by measuring the intensity of the fluorescence. Copy number is calculated based on the normalized ratio of the PLP1 gene to each of the reference genes for the patient and controls.
Duplications of variable size and other dosage changes (deletions, triplications, quintuplications) are found in at least 50% of males with PLP1-related disorders. This test will detect duplications and other dosage changes that are in tandem as well as duplications that are inserted elsewhere in the genome. Duplication testing alone will not detect point mutations or smaller deletions or insertions.
Sequencing:
Testing is performed by sequencing the entire coding region and intron-exon junctions of PLP1. This assay will detect point mutations, small deletions, and small insertions. Sequencing alone will not detect a partial or whole gene deletion or duplication.
Point mutations are found in 15% or less of males with PLP1-related disorders. A negative result will exclude the presence of a mutation in the regions tested with greater than 99% sensitivity. However, a negative result does not exclude the possibility that mutations are present in other regions of the PLP1 gene or in other genes.
Sensitivity:
If duplication testing and sequencing are both negative, it does not rule out a PLP1-related disorder. Approximately 40% of males with clinical findings consistent with the PLP1-related disorders do not have an identifiable mutation in the PLP1 gene, suggesting that mutations may occur in regions of the gene that are not analyzed or in another gene.
A negative test does not rule out a genetic cause of a neurologic disorder. There are many other genes associated with different types of neurologic disorders and leukodystrophies. Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive disorder caused by mutations in the GJC2 gene. Testing for PMLD is available in our laboratory and can be performed if clinically indicated. Mutations of the FAM126A gene cause an autosomal recessive syndrome known as hypomyelination and congenital cataract (HCC) or hypomyelinating leukodystrophy-5 (HLD5). Testing for HCC is also available in our laboratory and can be performed if clinically indicated.
Sample requirements: Draw one or two 4-cc tubes of blood in EDTA/purple-top tube (minimum of 1-2 cc for infants).
Turn around time: 4-6 weeks