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.

• Klíčová slova
• ATP6AP1, congenital disorders of glycosylation, copper metabolism, glycosylation, metabolic disorder, oxidative stress,
• MeSH
• fatální výsledek MeSH
• fenotyp MeSH
• kojenec MeSH
• lidé MeSH
• měď metabolismus   MeSH
• metabolomika MeSH
• mutace MeSH
• nemoci jater diagnóza   genetika   metabolismus   MeSH
• oxidační stres genetika   MeSH
• posttranslační úpravy proteinů MeSH
• sourozenci MeSH
• syndromy imunologické nedostatečnosti diagnóza   genetika   metabolismus   MeSH
• vakuolární protonové ATPasy nedostatek   genetika   MeSH
• vrozené poruchy glykosylace diagnóza   genetika   metabolismus   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATP6AP1 protein, human MeSH Prohlížeč
• měď MeSH
• vakuolární protonové ATPasy MeSH

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.

• Klíčová slova
• ATP6AP1, N-palmitoyl-O-phosphocholineserine (PPCS), Niemann-pick type C (NPC), bile acids, congenital disorders of glycosylation (CDG), oxysterols,
• MeSH
• dítě MeSH
• glykosylace MeSH
• hydrolasy MeSH
• kojenec MeSH
• lidé MeSH
• Niemannova-Pickova nemoc typu C * MeSH
• oxysteroly * MeSH
• vakuolární protonové ATPasy * MeSH
• vrozené poruchy glykosylace * MeSH
• žlučové kyseliny a soli MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ATP6AP1 protein, human MeSH Prohlížeč
• hydrolasy MeSH
• oxysteroly * MeSH
• vakuolární protonové ATPasy * MeSH
• žlučové kyseliny a soli MeSH