Pseudoxanthoma Elasticum overlaps Hereditary Spastic Paraplegia Type 56.
J Intern Med. 2021-03-31; 289(5): 709-725
DOI: 10.1111/joim.13193
Lire sur PubMed
1. J Intern Med. 2021 May;289(5):709-725. doi: 10.1111/joim.13193. Epub 2021 Mar 31.
Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.
Legrand A(1)(2), Pujol C(3), Durand CM(4), Mesnil A(5), Rubera I(6), Duranton
C(6), Zuily S(7), Sousa AB(8), Renaud M(9), Boucher JL(10), Pietrancosta N(10),
Adham S(2)(11), Orssaud C(12), Marelli C(13), Casali C(14), Ziccardi L(15),
Villain N(16), Ewenczyk C(17), Durr A(17), Mignot C(18), Stevanin G(19), Billon
C(1)(2), Hureaux M(1)(5), Jeunemaitre X(1)(2), Goizet C(4), Albuisson
J(1)(2)(20).
Author information:
(1)From the, Université de Paris, PARCC, INSERM, Paris, France.
(2)Centre de Référence des Maladies Vasculaires Rares, AP-HP, Hôpital européen
Georges Pompidou, Paris, France.
(3)Sorbonne Université; Inserm, U1127; CNRS, UMR 7225; Institut du Cerveau,
Paris, France.
(4)Inserm, U1211, Laboratoire Maladies Rares: Génétique et Métabolisme, Univ.
Bordeaux; Centre de Référence Neurogénétique, Service de Génétique Médicale, CHU
Bordeaux, Bordeaux, France.
(5)Département de Génétique AP-HP, Hôpital européen Georges Pompidou, Paris,
France.
(6)Université Côte d’Azur, CNRS-UMR 7370, Laboratoire de Physiomédecine
Moléculaire, LabEx ICST, Nice, France.
(7)Université de Lorraine, Inserm UMR_S 1116; CHRU de Nancy, Service de Médecine
vasculaire, Centre de Compétences Régional des Maladies Vasculaires Rares, Nancy,
France.
(8)Medical Genetics, Department of Pediatrics, Hospital de Santa Maria, Centro
Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, Lisboa,
Portugal.
(9)CHRU de Nancy, Service de Neurologie, Nancy, France.
(10)UMR 8601 CNRS, Université de Paris, Paris, France.
(11)Université de Paris, Paris, France.
(12)Unité fonctionnelle d’ophtalmologie, AP-HP, Hôpital Européen Georges
Pompidou, Paris, France.
(13)Inserm U1198 MMDN; Gui de Chauliac University Hospital, Department of
Neurology, Expert Centre for Neurogenetic Diseases and Adult Mitochondrial and
Metabolic Diseases, Montpellier, France.
(14)Department of SBMC, Sapienza University Rome, Rome, Italy.
(15)IRCCS- Fondazione Bietti, Neurophysiology of Vision and Neuroophthalmology
Unit, Rome, Italy.
(16)Sorbonne Université; Inserm, U1127; CNRS, UMR 7225; Institut du Cerveau;
Sorbonne Université, GRC n° 21, Alzheimer Precision Medicine; AP-HP, Hôpital de
la Pitié-Salpêtrière; Département de Neurologie, Institut de la Mémoire et de la
maladie d’Alzheimer, Paris, France.
(17)Sorbonne Université; Inserm, U1127; CNRS, UMR 7225; Institut du Cerveau;
AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France.
(18)Sorbonne Université; Inserm, U1127; CNRS, UMR 7225; Institut du Cerveau;
AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique; Centre de
Référence Déficiences Intellectuelles de Causes Rares, Paris, France.
(19)Sorbonne Université; Inserm, U1127; CNRS, UMR 7225; Institut du Cerveau; PSL
research University, Ecole Pratique des Hautes Etudes, Neurogenetics team, Paris,
France.
(20)Département de Biologie et Pathologie des Tumeurs, Centre Georges François
Leclerc, Dijon, France.
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 CYP2U1. PXE skin lesions with histological confirmation,
eye lesions including maculopathy or angioid streaks, and various neurological
symptoms were present. CYP2U1 missense variants were confirmed to impair protein
function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%)
presented some phenotypic overlap with PXE.
CONCLUSION: CYP2U1 pathogenic variants are found in unsolved PXE patients with
neurological findings, including spastic paraplegia, expanding the SPG56
phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and
CYP2U1 should be explored to explain their respective role and potential
interaction in ectopic mineralization.
© 2020 The Association for the Publication of the Journal of Internal Medicine.
DOI: 10.1111/joim.13193
PMID: 33107650 [Indexed for MEDLINE]