Mutations in Myosin 5B in Children With Early‐onset Cholestasis

Cockar, Iram; Foskett, Pierre; Strautnieks, Sandra; Clinch, Y; Fustok, Jana; Rahman, Obydur; Sutton, Harry; Mtegha, Marumbo; Fessatou, Smaragdi; Kontaki, Elena; Papaevangelou, Vassiliki; Deheragoda, Maesha; Thompson, Richard J.; Grammatikopoulos, Tassos

doi:10.1097/mpg.0000000000002740

Cited by 16 publications

(29 citation statements)

References 21 publications

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“…Similar to the 37%-54% of patients diagnosed with MVID presenting symptoms of CLD, 21% of patients diagnosed with low/normal-GGT CLD were reported to present loose stools or diarrheal episodes. (4,5,7) Overlap of symptoms thus occurs, but there are more MVID patients who present cholestasis than there are patients with CLD who present diarrhea. An outstanding question is why MYO5B mutations cause either CLD or MVID with or without symptoms of MVID or CLD, respectively.…”

Section: Correlations Between Myo5b Genotype and Cldmentioning

confidence: 99%

“…These patients tested negative for mutations in other PFIC‐associated genes. ( 4‐7 ) MYO5B mutations may account for approximately 20% of pediatric patients with idiopathic low‐GGT intrahepatic cholestasis. ( 8 ) Based on microscopic analyses of liver biopsies, a reduced expression or mislocalization of BSEP was reported ( 4,5 ) but not in all patients.…”

Section: Myosin 5b–associated Cholestatic Liver Diseasementioning

confidence: 99%

“…( 8 ) Based on microscopic analyses of liver biopsies, a reduced expression or mislocalization of BSEP was reported ( 4,5 ) but not in all patients. ( 7 )…”

Section: Myosin 5b–associated Cholestatic Liver Diseasementioning

confidence: 99%

“…Based on microscopic analyses of liver biopsies, a reduced expression or mislocalization of BSEP was reported (4,5) but not in all patients. (7) MYO5B mutations were earlier reported to cause MVID. (9) MVID is a severe congenital enteropathy, characterized by severe intractable secretory diarrhea from the moment of birth and the inability to absorb any nutrients.…”

mentioning

confidence: 96%

“…(23) In another patient without MVID diagnosed with CLD and MYO5B mutations no mislocalization of BSEP was observed. (7) Furthermore, 5 patients with MVID showed reduction of cholestasis and pruritus when soybean oil-based lipids in the TPN were replaced by fish oil-based lipids, indicating aRtICle INFoRMatIoN:…”

mentioning

confidence: 99%

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Unequal Effects of Myosin 5B Mutations in Liver and Intestine Determine the Clinical Presentation of Low‐Gamma‐Glutamyltransferase Cholestasis

IJzendoorn

Qiu

et al. 2020

Hepatology

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Myosin 5B-Associated Cholestatic Liver Disease Cholestatic liver disease (CLD) is characterized by an increase in the serum concentrations of compounds that are normally excreted with bile, such as bile acids and bilirubin. (1) CLD clinically manifest with cholestasis, jaundice, and pruritis. Diagnosis involves evaluation of the patient's clinical manifestations, exclusion of common causes of childhood cholestasis, and analyses of blood biochemistry and liver histology. (1) One blood marker that aids in the differential diagnosis of liver diseases is gamma-glutamyltransferase (GGT), a liver enzyme which is typically elevated in serum upon liver damage. The best known CLDs characterized by low/normal GGT are the benign recurrent and progressive forms of familial intrahepatic cholestasis (BRIC/PFIC), which are caused by mutations in the adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) gene encoding the ATP8B1 protein (BRIC/PFIC1) or in the adenosine triphosphate-binding cassette family B member 11 (ABCB11) gene encoding the canalicular bile salt export pump (BSEP) (BRIC/PFIC2). (2,3) In hepatocytes, ATP8B1 and BSEP are localized to the apical bile canalicular domain, where they contribute to biliary secretion. When mutated as in PFIC1/2 patients, the respective proteins are less expressed or mislocalized and/or display impaired activity, leading to defective biliary secretion and, consequently, cholestasis. (2,3) Since 2017 four independent reports have identified in total 30 different myosin 5B (MYO5B) mutations in 22 patients with non-microvillus inclusion disease (MVID) who were diagnosed with intermittent, recurrent, or progressive cholestasis presenting with jaundice, pruritus, hepatomegaly, and low/normal serum levels of GGT (Fig. 1; Supporting Table S1). These patients tested negative for mutations in other PFIC-associated genes. (4-7) MYO5B mutations may account for approximately 20% of pediatric patients with idiopathic low-GGT intrahepatic cholestasis. (8)

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Section: Correlations Between Myo5b Genotype and Cldmentioning

confidence: 99%

Section: Myosin 5b–associated Cholestatic Liver Diseasementioning

confidence: 99%

“…( 8 ) Based on microscopic analyses of liver biopsies, a reduced expression or mislocalization of BSEP was reported ( 4,5 ) but not in all patients. ( 7 )…”

Section: Myosin 5b–associated Cholestatic Liver Diseasementioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 99%

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Unequal Effects of Myosin 5B Mutations in Liver and Intestine Determine the Clinical Presentation of Low‐Gamma‐Glutamyltransferase Cholestasis

IJzendoorn

Qiu

et al. 2020

Hepatology

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Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1

Grammatikopoulos¹,

Hadžić²,

Foskett³

et al. 2021

Hepatol Commun

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Mutations in the transaldolase 1 (TALDO1) gene have been described in a limited number of cases. Several organs can be affected and clinical manifestations are variable, but often include liver dysfunction and/or hepatosplenomegaly. We report 4 patients presenting with liver disease: 2 with early-onset hepatocellular carcinoma (HCC). Patients with cholestasis and mutations in TALDO1 were identified by next-generation sequencing. Clinical, laboratory, and histological data were collected. Four (1 male) patients were identified with variants predicted to be damaging in TALDO1. Three patients were homozygous (two protein truncating/one missense mutations), 1 one was compound heterozygous (two missense mutations). Median age at presentation was 4 months (range, 2-210 days) with jaundice ( 3), hepatosplenomegaly (3), and pancytopaenia (1). The diagnosis was corroborated by detection of minimal transaldolase enzyme activity in skin fibroblasts in two cases and raised urine polyols in the third. Three patients underwent liver transplantation (LT), 2 of whom had confirmed HCC on explanted liver. One patient suddenly died shortly after LT. The nontransplanted case has a chronic liver disease with multiple dysplastic liver nodules, but normal liver biochemistry and alphafetoprotein. Median follow-up was 4 years (range, 1-21). Conclusion: Transaldolase deficiency can include early-onset normal gamma-glutamyltransferase liver disease with multisystem involvement and variable progression. Patients with this disease are at risk of early-onset HCC and may require early LT. (Hepatology Communications 2022;6:473-479).T ransaldolase deficiency (OMIM 606003) is a rare inborn error of metabolism caused by defects in the TALDO1 gene, encoding one enzyme of the pentose phosphate pathway. (1) Within this pathway, transaldolase is important for the generation of erythrose 4-phosphate, which is necessary for synthesis of aromatic amino acids. Transaldolase deficiency has been described in more than 34 cases (25 families), and 11 different mutations in TALDO1 have been reported. (2)(3)(4) Clinical manifestations vary but can include liver dysfunction and/or hepatosplenomegaly, growth retardation, congenital heart disease, and endocrine dysfunction. (5)(6)(7)(8)(9) We report here 4 patients, genetically diagnosed with transaldolase deficiency, manifesting liver disease, and in two cases early-onset liver carcinogenesis.

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Familial Intrahepatic Cholestasis

Grammatikopoulos

2021

Textbook of Pediatric Gastroenterology, Hepatology and Nutrition

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Mutations in Myosin 5B in Children With Early‐onset Cholestasis

Cited by 16 publications

References 21 publications

Unequal Effects of Myosin 5B Mutations in Liver and Intestine Determine the Clinical Presentation of Low‐Gamma‐Glutamyltransferase Cholestasis

Unequal Effects of Myosin 5B Mutations in Liver and Intestine Determine the Clinical Presentation of Low‐Gamma‐Glutamyltransferase Cholestasis

Liver Disease and Risk of Hepatocellular Carcinoma in Children With Mutations in TALDO1

Familial Intrahepatic Cholestasis

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