A 12-year old boy presented with lower limb spasticity (first signs by the age of 4), mild facial dysmorphism (downslanting palpebral fissures) and learning difficulties. There was no particular familial history, besides a maternal niece with club foot. The patient underwent physiotherapy on a regular basis during infancy. Array CGH analysis was performed as a first-tier test, but it returned normal. Subsequently, a neurodevelopmental disorders gene panel (1160 genes) was sequenced in trio (parents and patient). We detected a novel, hemizygous, likely pathogenic PLP1 missense mutation (NM_000533.3(PLP1):c.263C>T, p.(Ala88Val)), inherited from the presumably asymptomatic mother, compatible with PLP1-related spastic paraplegia (X-linked recessive inheritance). Carrier females occasionally develop mild to moderate signs of the disease, especially in families with mildly affected males. Therefore, careful clinical follow-up is advised for the heterozygous mother (and if needed other maternal relatives). This missense mutation seems to reside within one of the mutational hotspots of the PLP1 gene. Of interest, a number of other neighbouring amino acid changes and another missense mutation affecting the same codon (p.(Ala88Asp)) have already been described as pathogenic. The highly conserved Ala88 residue is located in the transmembrane helix TM2. Mutations affecting this residue are predicted to affect the organisation of the four transmembrane helices of PLP1, thereby interfering with its biological function as the primary component of myelin. Patients carrying PLP1 mutations affecting the same and other nearby residues were reported to have clinical heterogenous phenotypes and different degrees of severity, making clear genotype-phenotype correlations for PLP1-related disorders still puzzling.
Original languageEnglish
Publication statusAccepted/In press - 2019
EventAnnual symposium of the NVGH: Jointly organized with BeSHG, VKGL, VKGN and the NACGG - Konighof, Velhoven, Netherlands
Duration: 19 Sep 201920 Sep 2019
http://www.nvhg-nav.nl/page.aspx?page=congresinfo

Conference

ConferenceAnnual symposium of the NVGH
Abbreviated titleSymposium 2019 NVHG
CountryNetherlands
CityVelhoven
Period19/09/1920/09/19
Internet address

ID: 46759210