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Mol Genet Metab. 2018 Jul;124(3):228-235. doi: 10.1016/j.ymgme.2018.05.002. Epub 2018 May 9.

CCDC115-CDG: A new rare and misleading inherited cause of liver disease.

Author information

1
AP-HP, Necker University Hospital, Hepatology and Gastroenterology Unit, French National Reference Centre for Biliary Atresia and Genetic Cholestasis, France; Paris Descartes University, France.
2
AP-HP, French National Reference Centre for Wilson Disease, Neurology Department, Lariboisière Hospital, Paris, France.
3
AP-HP, Necker University Hospital, Department of Pathology, Paris, France.
4
AP-HP, Necker University Hospital, Hepatology and Gastroenterology Unit, French National Reference Centre for Biliary Atresia and Genetic Cholestasis, France.
5
AP-HP, Necker University Hospital, Department of Genetics, Paris, France.
6
Service de Pharmacologie et d'Immunoanalyse (SPI), Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, F-91191 Gif-sur-Yvette, France.
7
Service de Pharmacologie et d'Immunoanalyse (SPI), Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, F-91191 Gif-sur-Yvette, France; Institut Galien Paris-Sud, UMR CNRS 8612, Proteins and Nanotechnology in Analytical Science (PNAS), Université Paris-Sud, Châtenay-Malabry, France.
8
Biochemistry, CHU Purpan, Toulouse, France.
9
Department of Pathology, University Hospital Toulouse, Paul Sabatier University, Toulouse, France.
10
Department of Pediatric Gastroenterology, CHU, Rennes, France.
11
AP-HP, Bichat University Hospital, Biochemistry, Paris, France.
12
AP-HP, Bichat University Hospital, Biochemistry, Paris, France; Paris Descartes University, France.
13
Internal Medicine-Digestive Department CHU Purpan, UMR152 IRD Toulouse 3 University, France.
14
AP-HP, Necker University Hospital, French National Reference Centre for Inborn Errors of Metabolism, Paris, France.
15
AP-HP, Bichat University Hospital, Biochemistry, Paris, France; INSERM UMR-1193 "Mécanismes cellulaires et moléculaires de l'adaptation au stress et cancérogenèse", Université Paris-Sud, Châtenay-Malabry, France. Electronic address: arnaud.bruneel@aphp.fr.

Abstract

Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement. Biological results were similar to previously described patients, including hypercholesterolemia, elevated alkaline phosphatases and defects in copper metabolism. CDG screening and glycosylation study finally led to the molecular diagnosis of CCDC115-CDG. Besides pointing to the importance of CDG screening in patients with unexplained and severe liver disease, these reports expand the clinical and molecular phenotypes of CCDC115-CDG. The hepatic involvement is particularly addressed. Furthermore, hypothesis concerning the pathogenesis of the liver disease and of major biological abnormalities are proposed.

KEYWORDS:

CCDC115; CDG; Copper; Glycosylation; Liver fibrosis; Liver steatosis

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