Neonatal cholestasis

Gene: ADK

Comment on list classification: There are 18 reported cases in 13 unrelated families of homozygous or compound heterozygous variants in this gene associated with hypermethioninaemia and (in most cases) conjugated hyperbilirubinaemia; liver biopsy in 4 cases demonstrated cholestasis. Some cases responded to methionine restriction, justifying the 'treatable' tag.

Created: 27 Jul 2018, 5:07 a.m.

Comment on publications: In PMID:26642971, in 9/11 cases, first presentation was usually with severe or prolonged conjugated hyperbilirubinaemia and hypoglycaemia; all patients except patients 9 and 10 (family VII) had intermittent increases of liver enzymes and/or cholestasis. Although this led the authors to conclude that ‘hepatic involvement is not a constant finding’, note that family VII were homozygous for a variant that has been classified as a VUS in ClinVar.

Created: 27 Jul 2018, 4:52 a.m.

Comment on list classification: More than 3 unrelated cases/families reported with homozygous variants in this gene and Hypermethioninemia due to adenosine kinase deficiency. In PMID: 21963049 liver biopsies for 4 cases revealed cholestasis in 3 cases. For the Swedish sublings reported, both were investigated for failure to thrive in the neonatal period and the older brother was also investigated for prolonged conjugated hyperbilirubinemia. Reduced activity was displayed in vitro assays with the variants identified compared to wild type.

Created: 25 Jul 2018, 3:39 p.m.

Comment on publications: PMID: 27500280 - a case report of a 3-year old girl with a history of poor feeding, irritability, respiratory infections, cholestasis, congenital heart disease, neurodevelopmental delay, hypotonia, sparse hair, facial dysmorphisms, liver dysfunction, severe hypermethioninemia and mild homocystinemia. Added the 'treatable' tag as a methionine-restricted diet normalized the liver function test results and improved her hypotonia.

Created: 25 Jul 2018, 3:27 p.m.