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.

• MeSH
• Child MeSH
• Glycosylation MeSH
• Hydrolases MeSH
• Infant MeSH
• Humans MeSH
• Niemann-Pick Disease, Type C * MeSH
• Oxysterols * MeSH
• Vacuolar Proton-Translocating ATPases * MeSH
• Congenital Disorders of Glycosylation * MeSH
• Bile Acids and Salts MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Congenital disorders of glycosylation (CDG) represent a wide range of >140 inherited metabolic diseases, continually expanding not only with regards to the number of newly identified causative genes, but also the heterogeneity of the clinical and molecular presentations within each subtype. The deficiency of ATP6AP1, an accessory subunit of the vacuolar H+ -ATPase, is a recently characterised N- and O-glycosylation defect manifesting with immunodeficiency, hepatopathy and cognitive impairment. At the cellular level, the latest studies demonstrate a complex disturbance of metabolomics involving peroxisomal function and lipid homeostasis in the patients. Our study delineates a case of two severely affected siblings with a new hemizygous variant c.221T>C (p.L74P) in ATP6AP1 gene, who both died due to liver failure before reaching 1 year of age. We bring novel pathobiochemical observations including the finding of increased reactive oxygen species in the cultured fibroblasts from the older boy, a striking copper accumulation in his liver, as well as describe the impact of the mutation on the protein in different organs, showing a tissue-specific pattern of ATP6AP1 level and its posttranslational modification.

• MeSH
• Fatal Outcome MeSH
• Phenotype MeSH
• Infant MeSH
• Humans MeSH
• Copper metabolism   MeSH
• Metabolomics MeSH
• Mutation MeSH
• Liver Diseases diagnosis   genetics   metabolism   MeSH
• Oxidative Stress genetics   MeSH
• Protein Processing, Post-Translational MeSH
• Siblings MeSH
• Immunologic Deficiency Syndromes diagnosis   genetics   metabolism   MeSH
• Vacuolar Proton-Translocating ATPases deficiency   genetics   MeSH
• Congenital Disorders of Glycosylation diagnosis   genetics   metabolism   MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH