Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56

Abstract

Purpose. Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene (s) to solve the ABCC6-negative patients.Methods. First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients.Results. 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in Claire Pujol and Christelle M. Durand contributed equally to this work.

Implication of folate deficiency in CYP2U1 loss of function

“…1 A and Fig. S1 L), a feature also seen in SPG56 patients, especially macular atrophy in all adult patients for whom information was available (Table S1; Legrand et al, 2021). Even though further investigation on these late-onset ophthalmologic alterations should be considered, this aspect of the phenotype may be due to a neurodegenerative part of this disease.…”

“…So far, loss of function (LoF) mutations in CYP2U1 have been detected in 32 affected individuals ( Table S1 and Table S2 ) who developed early-onset spastic paraplegia with a wide spectrum of clinical signs, including upper limb involvement, dystonia, cognitive impairment, and heterogeneous neuroimaging features of brain calcification and hypomyelination. Mutations in this gene have recently been implicated in a neurocutaneous syndrome ( Legrand et al, 2021 ), and it has also been suggested that they could affect the retina ( Leonardi et al, 2016 ). To better understand the pathophysiology of the disease and dissect its underlying mechanisms, we combined lipidomics and proteomics using biological material from known and novel SPG56 patients and from a genetically modified mouse model mimicking the disease.…”

Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation

“…Liver cirrhosis with liver failure of any grade is associated with a deficit in plasma PPi, which is the result of a significant reduction in the gene expression levels of key regulators of PPi synthesis in the liver, i.e., ABCC6 and ENPP1 , concomitant to enhanced degradation via TNAP. We found that LT restores [PPi]pl 3 months post-surgery to within physiological range [ 17 , 37 ]. This is likely due to the normalization of the expression levels of ABCC6, ENPP1, NT5E , and ALPL in the newly and healthy transplanted livers.…”

“…Plasma ALP activity was assessed by absorbance at 450 nm of paranitrophenol at alkaline pH. Inorganic pyrophosphate concentrations were measured using a modified method based on the enzyme assay described by Jansen et al [ 15 ], as previously reported [ 17 , 37 ]. Briefly, PPi was converted into ATP using ATP sulfurylase (New England Biolabs, Ipswich, MA, USA, MO394L) in the presence of APS (adenosine-5′-phosphosulfate, Sigma-Aldrich, St. Louis, MO, USA, A5508).…”

Hereditary spastic paraplegia type 56: what a mouse can tell – a narrative review

“…Interestingly, CYP2U1 mutations have also recently been implicated in a neurocutaneous syndrome, [15] and it has also been suggested that they could affect the retina, leading to macular dystrophy. [13,[15][16][17] As often observed in HSPs, a huge intra-and inter-familial variability characterize the severity of symptoms presented by SPG56-HSP patients, even among those sharing the same causative mutation. A clear example of this phenomenon is provided by three families sharing a stop mutation (p.Arg390X) leading to the premature termination of CYP2U1 translation.…”