Congenital disorder of glycosylation caused by mutation of ATP6AP1 gene (c.1036G>A) in a Chinese infant: A case report

Abstract

BACKGROUND The ATP6AP1 gene coding for the accessory protein Ac45 of the vacuolar-type adenosine triphosphatases (V-ATPase) is located on chromosome Xq28. Defects in certain subunits or accessory subunits of the V-ATPase can lead to congenital disorders of glycosylation (CDG). CDG is a group of metabolic disorders in which defective protein and lipid glycosylation processes affect multiple tissues and organs. Therefore, the clinical presentation of patients with ATP6AP1 -CDG varies widely. In this report, we present a case of ATP6AP1 -CDG in a Chinese infant, with clinical features and genotype. CASE SUMMARY An 8-mo-old boy was admitted to our hospital because unexplained hepatosplenomegaly and elevated transaminases that had been noted while he was being treated for a cough at a local hospital. A post-admission examination at our hospital revealed abnormalities in the infant’s liver, brain, and immune system. Trio-based whole exome gene analysis identified a hemizygous pathogenic mutation c.1036G>A (p.E346K) in exon 9 of the ATP6AP1 gene. This variant of the ATP6AP1 gene has not been reported in East Asian countries until now. CONCLUSION Based on the infant’s clinical manifestations and the results of genetic detection, he was clearly diagnosed with ATP6AP1 -CDG. The clinical manifestations of children with CDG vary widely. Genetic testing analysis helps in the clinical diagnosis of children with CDG.

Expanding the phenotype of ATP6AP1 deficiency

“…Among 20 individuals (Jansen et al 2016;Dimitrov et al 2018;Witters et al 2018;Gumm et al 2020;Ondruskova et al 2020;Tvina et al 2020;Yang et al 2021) summarized in Table 2 (18 reported in the literature and two from the current study), 17 showed hepatomegaly/liver failure/cirrhosis, 16 showed recurrent infection, 13 showed splenomegaly, 8 showed neurological symptoms, 6 showed cutis laxa, 5 were reported to have cardiac abnormalities or bilateral inguinal hernias, and 3 had a congenital diaphragmatic hernia. None of the individuals reported in the literature with ATP6AP1-CDG have been reported with ventriculomegaly, umbilical hernia, pectus carinatum, micropenis, or hypospadias, which we found in the probands in this study.…”

Fractionated plasma N‐glycan profiling of novel cohort of ATP6AP1‐CDG subjects identifies phenotypic association

“…9 Many patients have laboratory abnormalities, including low serum copper and/or ceruloplasmin and hypercholesterolemia. 1,[8][9][10][11][12][13] Neurological manifestations of ATP6AP1-CDG vary among patients and include epilepsy, sensorineural hearing loss (SNHL), intellectual disability, and developmental delay. 1,9,13 Here we report 11 new patients with ATP6AP1-CDG from eight different families and four novel ATP6AP1 variants and provide clinical manifestation updates and glycomic results on a previously reported patient.…”

“…ATP6AP1‐CDG was first identified in 2016 in eleven patients from six families 1 . Subsequently, eight more ATP6AP1‐CDG cases from another six families have been reported in the literature 8–13. Affected patients frequently exhibit coagulopathy, elevated liver enzymes, cholestatic jaundice, low immunoglobulins, recurrent infections, and reduced response to vaccines.…”

“…1,[8][9][10][11][12][13] Neurological manifestations of ATP6AP1-CDG vary among patients and include epilepsy, sensorineural hearing loss (SNHL), intellectual disability, and developmental delay. 1,9,13 Here we report 11 new patients with ATP6AP1-CDG from eight different families and four novel ATP6AP1 variants and provide clinical manifestation updates and glycomic results on a previously reported patient. 8 Given the striking hepatic dysfunction and immunodeficiency phenotype of ATP6AP1-CDG and the successful use of liver transplant as a treatment, we profiled N-glycans from fractionated subsets of plasma proteins including purified immunoglobulins, transferrin, and the remaining plasma glycoprotein fractions.…”

“…Pancreatic insufficiency has been reported with low trypsin and pancreatic elastase, and reduced fat‐soluble vitamins 9 . Many patients have laboratory abnormalities, including low serum copper and/or ceruloplasmin and hypercholesterolemia 1,8–13 . Neurological manifestations of ATP6AP1‐CDG vary among patients and include epilepsy, sensorineural hearing loss (SNHL), intellectual disability, and developmental delay 1,9,13 …”