Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

Center for Integrative Brain Research Seattle Children's Research Institute Seattle Washington USA

Clinical Genomics Program GeneDx Gaithersburg Maryland USA

Department of Medicine Washington University School of Medicine Saint Louis Missouri USA

Department of Paediatrics Sykehuset Ostfold HF Fredrikstad Norway

Department of Pediatrics and Inherited Metabolic Disorders Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatrics University of California Irvine School of Medicine Irvine California USA

Department of Pediatrics Washington University School of Medicine in St Louis Saint Louis Missouri USA

Division of Genetic Medicine Department of Pediatrics University of Washington Seattle Washington USA

Division of Genetics and Metabolism University of South Florida Tampa Florida USA

Division of Metabolic Disorders Children's Hospital of Orange County Orange County California USA

Human Genetics Program Sanford Children's Health Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla California USA

Office of the Clinical Director NICHD NIH Bethesda Maryland USA

Section on Molecular Dysmorphology NICHD NIH Bethesda Maryland USA

Undiagnosed Diseases Program Common Fund National Institutes of Health Bethesda Maryland USA

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Chang IJ, He M, Lam CT. Congenital disorders of glycosylation. Ann Transl Med. Dec 2018;6(24):477. doi:10.21037/atm.2018.10.45 PubMed DOI PMC

Jaeken J Congenital disorders of glycosylation. Ann N Y Acad Sci Dec 2010;1214:190–8. doi:10.1111/j.1749-6632.2010.05840.x PubMed DOI

Marques-da-Silva D, Dos Reis Ferreira V, Monticelli M, et al. Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature. J Inherit Metab Dis. Mar 2017;40(2):195–207. doi:10.1007/s10545-016-0012-4 PubMed DOI

Starosta RT, Boyer S, Tahata S, et al. Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up. Orphanet J Rare Dis. Jan 7 2021;16(1):20. doi:10.1186/s13023-020-01630-2 PubMed DOI PMC

Chikh K, Vey S, Simonot C, Vanier MT, Millat G. Niemann-Pick type C disease: importance of N-glycosylation sites for function and cellular location of the NPC2 protein. Moi Genet Metab. Nov 2004;83(3):220–30. doi:10.1016/j.ymgme.2004.06.013 PubMed DOI

Sidhu R, Kell P, Dietzen DJ, et al. Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1. Moi Genet Metab. Dec 2020;131 (4):405–417. doi:10.1016/j.ymgme.2020.11.005 PubMed DOI PMC

Sidhu R, Kell P, Dietzen DJ, et al. Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease. Moi Genet Metab. Apr 2020;129(4):292–302. doi:10.1016/j.ymgme.2020.01.007 PubMed DOI PMC

Giese AK, Mascher H, Grittner U, et al. A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease. Orphanet J Rare Dis.Jun 17 2015;10:78. doi:10.1186/s13023-015-0274-1 PubMed DOI PMC

Brown AJ, Jessup W. Oxysterols: Sources, cellular storage and metabolism, and new insights into their roles in cholesterol homeostasis. Mol Aspects Med. Jun 2009;30(3):111–22. doi:10.1016/j.mam.2009.02.005 PubMed DOI

Jiang X, Sidhu R, Porter FD, et al. A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma. J Lipid Res. Jul 2011;52(7):1435–45. doi:10.1194/jlr.D015735 PubMed DOI PMC

Porter FD, Scherrer DE, Lanier MH, et al. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. Nov 3 2010;2(56):56ra81. doi:10.1126/scitranslmed.3001417 PubMed DOI PMC

Takaki Y, Mizuochi T, Takei H, et al. Urinary and serum oxysterols in children: developmental pattern and potential biomarker for pediatric liver disease. Sci Rep. Apr 21 2020;10(1):6752. doi:10.1038/s41598-020-63758-2 PubMed DOI PMC

Polo G, Burlina A, Furlan F, et al. High level of oxysterols in neonatal cholestasis: a pitfall in analysis of biochemical markers for Niemann-Pick type C disease. Clin Chem Lab Med. Jul 1 2016;54(7):1221–9. doi:10.1515/cclm-2015-0669 PubMed DOI

Jiang X, Ory DS. Advancing Diagnosis and Treatment of Niemann-Pick C disease through Biomarker Discovery. Explor Neuroprotective Ther. Dec 30 2021;1(3):146–158. doi:10.37349/ent.2021.00012 PubMed DOI PMC

Retterer K, Juusola J, Cho MT, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. Jul 2016;18(7):696–704. doi:10.1038/gim.2015.148 PubMed DOI

Marelli C, Lamari F, Rainteau D, et al. Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain. Jan 1 2018;141(1):72–84. doi:10.1093/brain/awx297 PubMed DOI

Dimitrov B, Himmelreich N, Hipgrave Ederveen AL, et al. Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG. Mol Genet Metab. Mar 2018;123(3):364–374. doi:10.1016/j.ymgme.2018.01.008 PubMed DOI

Jansen EJ, Timal S, Ryan M, et al. ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nat Commun. May 27 2016;7:11600. doi:10.1038/ncomms11600 PubMed DOI PMC

Lipinski P, Rokicki D, Bogdanska A, Lesiak J, Lefeber DJ, Tylki-Szymanska A. ATP6AP1-CDG: Follow-up and female phenotype. JIMD Rep. May 2020;53(1):80–82. doi:10.1002/jmd2.12104 PubMed DOI PMC

Ondruskova N, Honzik T, Vondrackova A, et al. Severe phenotype of ATP6AP1-CDG in two siblings with a novel mutation leading to a differential tissue-specific ATP6AP1 protein pattern, cellular oxidative stress and hepatic copper accumulation. J Inherit Metab Dis. Jul 2020;43(4):694–700. doi:10.1002/jimd.12237 PubMed DOI PMC

Forgac M Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol. Nov 2007;8(11):917–29. doi:10.1038/nrm2272 PubMed DOI

Nishi T, Forgac M. The vacuolar (H+)-ATPases--nature's most versatile proton pumps. Nat Rev Mol Cell Biol. Feb 2002;3(2):94–103. doi:10.1038/nrm729 PubMed DOI

Zhong X, Malhotra R, Guidotti G. Regulation of yeast ectoapyrase ynd1p activity by activator subunit Vma13p of vacuolar H+-ATPase. J Biol Chem. Nov 10 2000;275(45):35592–9. doi:10.1074/jbc.M006932200 PubMed DOI

Cannata Serio M, Graham LA, Ashikov A, et al. Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease. Hepatology. Dec 2020;72(6):1968–1986. doi:10.1002/hep.31218 PubMed DOI PMC

Rujano MA, Cannata Serio M, Panasyuk G, et al. Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. J Exp Med. Dec 4 2017;214(12):3707–3729. doi:10.1084/jem.20170453 PubMed DOI PMC

Harrison KD, Miao RQ, Fernandez-Hernando C, Suarez Y, Davalos A, Sessa WC. Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates intracellular cholesterol trafficking. Cell Metab. Sep 2009;10(3):208–18. doi:10.1016/j.cmet.2009.07.003 PubMed DOI PMC

Kharel Y, Takahashi S, Yamashita S, Koyama T. In vivo interaction between the human dehydrodolichyl diphosphate synthase and the Niemann-Pick C2 protein revealed by a yeast two-hybrid system. Biochem Biophys Res Commun. May 21 2004;318(1):198–203. doi:10.1016/j.bbrc.2004.04.007 PubMed DOI

Raselli T, Hearn T, Wyss A, et al. Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis. J Lipid Res. Jul 2019;60(7):1270–1283. doi:10.1194/jlr.M093229 PubMed DOI PMC