Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56

Area of Science:

• Genetics
• Dermatology
• Neurology

Background:

• Pseudoxanthoma elasticum (PXE) is a genetic disorder affecting skin, eyes, and arteries, primarily caused by ABCC6 gene variants.
• A significant portion of PXE patients remain genetically undiagnosed despite extensive ABCC6 screening.

Purpose of the Study:

• To identify novel genes responsible for PXE in patients with unsolved ABCC6-negative cases.
• To investigate the role of CYP2U1 in PXE pathogenesis, particularly in cases with neurological involvement.

Main Methods:

• Family-based exome sequencing was conducted on an ABCC6-negative PXE patient with neurological features and relatives.
• CYP2U1 was sequenced in 46 additional ABCC6-negative PXE probands and six spastic paraplegia 56 (SPG56) patients.
• Functional analyses and plasma pyrophosphate levels were assessed.

Main Results:

• Biallelic pathogenic variants in CYP2U1 were identified in 6.4% of ABCC6-negative PXE patients, presenting with skin, eye, and neurological symptoms.
• CYP2U1 variants were confirmed to impair protein function, while plasma pyrophosphate levels remained normal.
• Two SPG56 patients exhibited phenotypic overlap with PXE.

Conclusions:

• Pathogenic variants in CYP2U1 are a cause of PXE in genetically unsolved patients, especially those with neurological findings like spastic paraplegia.
• This finding expands the phenotypic spectrum of SPG56 and underscores its overlap with PXE.
• Further research into the pathophysiology of ABCC6 and CYP2U1 is warranted to understand their roles in ectopic mineralization.