Acute liver failure due to DGUOK deficiency–is liver transplantation justified?

Jankowska, Irena; Czubkowski, Piotr; Rokicki, Dariusz; Lipiński, Patryk; Piekutowska‐Abramczuk, Dorota; Ciara, Elżbieta; Płoski, Rafał; Kaliciński, Piotr; Szymczak, Marek; Pawłowska, Joanna; Socha, Piotr

doi:10.1016/j.clinre.2020.02.018

Cited by 18 publications

(23 citation statements)

References 32 publications

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“…However, there have been some recent reports of successful LT in patients with DGUOK variants. A series of five patients 17 suggested that LT may not be contraindicated in those with minimal neurologic involvement. Only two of their patients were transplanted before the diagnosis could be confirmed; one died within 2 months, whereas the other remains alive after 3‐year follow‐up with mild hypotonia.…”

Section: Discussionmentioning

confidence: 99%

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience

Vara

Pinon

Fratter

et al. 2023

J of Inher Metab Disea

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Mitochondrial DNA depletion syndromes (MDDS) are a heterogeneous group and the hepato‐cerebral phenotype is highly variable. A single centre retrospective study of all patients with MDDS presenting between January 2002 and September 2019. In total, 24 (13 male) children were identified: 7 POLG, 7 DGUOK, and 10 MPV17. Median age at presentation was 3 months (0.06–189). Sixteen had acute liver failure (ALF) and eight chronic cholestasis and/or raised transaminases. Four POLG patients developed liver injury after starting sodium valproate; Six DGUOK patients had neonatal ALF (median age 12 days), liver involvement developed at a median age of 2.5 and 11 months with MPV17 and POLG patients, respectively. Eighteen patients showed neurological involvement. Liver histology from 10 patients showed variable degrees of necrosis, steatosis, cholestasis, and fibrosis. Mitochondrial respiratory chain enzymology was abnormal in 5. Seventeen patients died at a median age of 8 months (range, 1–312) after a median time of 5.6 months from presentation: 5/7 POLG at 53 months, 7/7 DGUOK at 8 months and 5/10 MPV17 at 8 months. Three patients with MPV17 mutations received liver transplant (LT) at a median age of 24 months (range 5–132): all alive at 19, 18 and 3 years post‐LT. Mutations in DGUOK and MPV17 genes are associated with a severe clinical phenotype characterised by early‐onset/neonatal ALF or rapidly progressive cholestasis and death before 12 months of age. A subset of MPV17 patients was amenable to LT. Consideration for LT in infantile ALF remains difficult and rapid genetic testing is advised.

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Section: Discussionmentioning

confidence: 99%

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience

Vara

Pinon

Fratter

et al. 2023

J of Inher Metab Disea

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“…The 14 patients with DGUOK deficiency and absent or mild neurologic involvement, including hypotonia, had far better outcomes with only one death occurring during the early posttransplant period and three deaths occurring within 2 years after transplant 7,15,20–23 . The remaining 10 patients were alive at follow‐up intervals from 2 years to 22 years posttransplant with mild neurologic involvement documented in some patients 2,4–7,14,16,21,24,25 . Of note, two of these patients developed HCC, one discovered at 12 months of age at the time of liver explant, 2 and one discovered at 5 months of age with liver transplant of living related donor occurring at 8 months of age 6 .…”

Section: Discussionmentioning

confidence: 99%

“…18 The 14 patients with DGUOK deficiency and absent or mild neurologic involvement, including hypotonia, had far better outcomes with only one death occurring during the early posttransplant period and three deaths occurring within 2 years after transplant. 7,15,[20][21][22][23] The remaining 10 patients were alive at follow-up intervals from 2 years to 22 years posttransplant with mild neurologic involvement documented in some patients. These studies highlight the significance of utilizing a multidisciplinary approach in making decisions regarding liver transplantation.…”

Section: It Is Challenging To Predict An Individual Patient's Clinica...mentioning

confidence: 99%

“…Historically, the presence of neurological symptoms, including nystagmus and hypotonia, was considered a contraindication to liver transplantation given possible progressive neurological deterioration and poor prognosis 4 . More recent literature suggests transplantation can improve outcomes even in the presence of neurological symptoms 5–7 . The decision regarding transplantation requires careful consideration and a multidisciplinary team approach.…”

Section: Introductionmentioning

confidence: 99%

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Considerations for liver transplantation in deoxyguanosine kinase deficiency: A case series and review of the literature

Duong,

Pacheco,

Hsu

et al. 2023

Pediatric Transplantation

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BackgroundDeoxyguanosine kinase (DGUOK) deficiency is a rare mitochondrial disorder characterized by early onset liver failure and varying degrees of neurologic dysfunction. Patients typically present during infancy with progressive hepatic dysfunction leading to liver failure, which can precede neurologic deterioration. Outcomes posttransplantation are historically worse than average and the role of liver transplantation remains controversial. These factors, in combination with the increasing number of patients being diagnosed via molecular genetic testing, may impede waitlist access.MethodsWe report our single‐center experience with three patients with DGUOK deficiency, all of whom were considered for transplant. We review the current literature regarding management and discuss the role of liver transplantation in DGUOK deficiency‐associated liver failure.ResultsTwo patients presented with hypoglycemia, conjugated hyperbilirubinemia, and lactic acidosis within the first week of life, were diagnosed with DGUOK deficiency prior to 2 months of age and had severe neurologic involvement. The third patient presented in later infancy was diagnosed with DGUOK deficiency at 18 months of age and had minimal neurologic involvement. All three patients were considered for transplant, though only two patients were listed. All three died from complications of end‐stage liver failure prior to liver transplantation between the ages of 5–20 months.ConclusionSelection for liver transplantation in DGUOK deficiency is complex, requiring a multidisciplinary team approach. Recent data suggest that liver transplantation can be successful in select patients with absent or mild neurologic manifestations. National databases reporting long‐term outcomes posttransplantation are needed.

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“…Currently, no satisfactory therapy is available for this MDDS. Liver transplantation remains an option but does not seem to improve survival in patients with liver failure and should be considered only in the absence of neurological features (5,10). Several DGUOK mutations have been identi ed in patients with hepatocerebral or isolated hepatic form of the disease.…”

Section: Introductionmentioning

confidence: 99%

Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

et al. 2023

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Background Deoxyguanosine kinase (DGUOK) deficiency is one of the genetic causes of mitochondrial DNA depletion syndrome (MDDS) in humans, leading to the hepatocerebral or the isolated hepatic form of MDDS. Mouse models are helpful tools for the improvement of understanding of the pathophysiology of diseases and offer the opportunity to examine new therapeutic options. Methods Herein, we describe the generation and metabolic characterization of a mouse line carrying a homozygous DguokF180S/F180S mutation derived from an N-ethyl-N-nitrosourea-mutagenesis screen. Energy expenditure (EE), oxygen consumption (VO2) and carbon dioxide production (VCO2) were assessed in metabolic cages. LC-MS/MS was used to quantify plasma adrenal steroids. Plasma insulin and leptin levels were quantified with commercially available assay kits. Results Mutant animals displayed significantly lower body weights and reduced inguinal fat pad mass, in comparison to unaffected littermates. Biochemically, they were characterized by significantly lower blood glucose levels, accompanied by significantly lower insulin, total cholesterol, high density lipoprotein and triglyceride levels. They also displayed an almost 2-fold increase in transaminases. Moreover, absolute EE was comparable in mutant and control mice, but EE in mutants was uncoupled from their body weights. Histological examination of inguinal white adipose tissue (WAT) revealed adipocytes with multilocular fat droplets reminiscent of WAT browning. In addition, mRNA and protein expression of Ucp1 was increased. Mutant mice also presented differing mitochondrial DNA content in various tissues and altered metabolic activity in mitochondria, but no further phenotypical or behavioral abnormalities. Preliminary data imply normal survival of DguokF180S/F180S mutant animals. Conclusion Taken together, DGUOK mutation F180S leads to a lean phenotype, with lower glucose, insulin, and lipid levels rendering this mouse model not only useful for the study of MDDS forms but also for deciphering mechanisms resulting in a lean phenotype.

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Acute liver failure due to DGUOK deficiency–is liver transplantation justified?

Cited by 18 publications

References 32 publications

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience

Considerations for liver transplantation in deoxyguanosine kinase deficiency: A case series and review of the literature

Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

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