Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ‐glutamyltransferase cholestasis

Abstract

Hereditary cholestasis in childhood and infancy with normal serum gamma‐glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low‐GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow‐up. Liver biopsy specimens revealed giant‐cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP‐deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated‐cholestasis patients (11 of 38 vs. 0 of 13). Conclusion: MYO5B deficiency may underlie 20% of previously undiagnosed low‐GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655‐1669).

TJP2 hepatobiliary disorders: Novel variants and clinical diversity

“…Genome DNA manipulation and analysis in WES were as described (Qiu et al, ), as was panel sequencing (Wang et al, ). Briefly, WES was done on HiSeq 2500 sequencers with 2 × 150 paired‐end modules (Illumina, San Diego, CA).…”

“…The sequencing depth of 98% targeted regions is above 20×. Filtering procedure for both initially removes sequencing errors and variants with a frequency >1% in public and in‐house databases; secondly, identify suspected genes with pathogenic/predictedly pathogenic variants; finally, designate the primary disease‐causing candidate gene, taking into account autosomal recessive inheritance pattern and recurrence rate in families and/or individual samples (Qiu et al, ; Wang et al, ). Criteria for designating variants as pathogenic/predictedly pathogenic were (a) allele frequency <0.01 in both the 1000 Genomes Project (1000G, http://www.internationalgenome.org/data) and the Exome Aggregation Consortium Browser (ExAC, http://exac.broadinstitute.org); (b) pathogenicity predicted by at least one of the three programs MutationTaster (Schwarz, Cooper, Schuelke, & Seelow, ), Polymorphism Phenotyping v2 (Polyphen‐2; Adzhubei, Jordan, & Sunyaev, ), and Sorting Tolerant From Intolerant (SIFT; Kumar, Henikoff, & Ng, ).…”

Advances in Evaluation of Chronic Diarrhea in Infants

“…More recently a non-PN-related phenotype with normal GGT cholestasis was described in patients demonstrating MYO5B mutations with and without the MVID intestinal phenotype. 63,96,97 Patients with MVID require PN support for life and can benefit from liver/in-testine transplantation if they develop PN-associated complications.…”

An Intravenous Fish Oil–Based Lipid Emulsion Successfully Treats Intractable Pruritus and Cholestasis in a Patient with Microvillous Inclusion Disease

“…Similar to the efficacy of FOLE in treating PNALD, it seems likely that the resolution of symptoms for this case is multifactorial and we hypothesize that it was due to (1) resolution of cholestasis; (2) shift in epidermal inflammatory properties induced by O3FA present in FO; and (3) reduction in circulating pruritogenic BA. Properties of FOLE make it an option for treating intractable pruritus in patients with PNALD and MVID.…”