Mitochondrial hepatopathy

OBJECTIVE: In non-alcoholic fatty liver disease (NAFLD), liver mitochondrial dysfunction plays an important role in the development of cardiac abnormalities independent of obesity per se. However, the mechanisms underlying the development of these abnormalities, and whether these are affected by sex remain unclear. In the present study, we sought to address this question using a mouse model of hepatic mitochondrial deficiency caused by loss of Lrpprc (H-Lrpprc-/- ) as these mice develop microvesicular steatosis and a NAFLD lipidomic-like profile without obesity...

Fatty acid oxidation defects (FAOD) and urea cycle defects (UCD) are among the most common metabolic liver diseases. Management of these disorders is dotted with challenges as the strategies differ based on the type and severity of the defect. In those with FAOD the cornerstone of management is avoiding hypoglycemia which in turn prevents the triggering of fatty acid oxidation. In this review, we discuss the role of carnitine supplementation, dietary interventions, newer therapies like triheptanoin, long-term treatment and approach to positive newborn screening...

Mitochondria, the powerhouse of a cell, are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond. Evolution supports a prokaryotic descent, and, unsurprisingly, the organelle is worthy of being labeled an organism in itself. Since highly metabolically active organs require a continuous feed of energy, any dysfunction in the structure and function of mitochondria can have variable impact, with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition...

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In the diagnostic work-up of a newborn infant with a metabolic crisis, lethal multiorgan failure on day six of life, and increased excretion of 3-methylglutaconic acid, we found using whole genome sequencing a homozygous SERAC1 mutation indicating MEGDHEL syndrome (3-methylglutaconic aciduria with deafness-dystonia, hepatopathy, encephalopathy, and Leigh-like syndrome). The SERAC1 protein is located at the contact site between mitochondria and the endoplasmic reticulum (ER) and is crucial for cholesterol trafficking...

BACKGROUND: The native liver of patients with maple syrup urine disease (MSUD) (1st recipients) can be used as a graft for non-MSUD patients with end-stage liver disease (2nd recipients). This study aimed to demonstrate the optimal operational procedures and the long-term outcomes of 2nd recipients. METHODS: Six 2nd recipients of living donor domino liver transplantation (LD-DLT) (age: 42.5 [22-169] months at DLT) received a native liver as a graft from an MSUD patient at our hospital between June 2014 and April 2020...

OBJECTIVE: To delineate the full phenotypic spectrum of BCS1L-related disease, provide better understanding of the genotype-phenotype correlations and identify reliable prognostic disease markers. METHODS: We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed...

OBJECTIVE: Neonatal-onset mitochondrial disease has not been fully characterised owing to its heterogeneity. We analysed neonatal-onset mitochondrial disease in Japan to clarify its clinical features, molecular diagnosis and prognosis. DESIGN: Retrospective observational study from January 2004 to March 2020. SETTING: Population based. PATIENTS: Patients (281) with neonatal-onset mitochondrial disease diagnosed by biochemical and genetic approaches...

MEGDEL syndrome gains its name for its following features: 3-methylglutaconic aciduria (MEG), deafness (D), encephalopathy (E), Leigh-like syndrome (L). This syndrome is caused by biallelic mutations in the serine active site-containing protein 1 ( SERAC1  ) gene. When these patients present with hepatopathy (H) in addition to the above manifestations the syndrome is labeled as MEGD(H)EL. The pathology of the disease shares features with different types of inborn errors of metabolism. We present the anesthetic management of a neonate who was diagnosed with MEGD(H)EL syndrome and underwent diagnostic magnetic resonance imaging of the brain at 14 days of postnatal age...

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Mitochondrial DNA (mtDNA) depletion syndrome comprises diseases resulting from a deficiency of proteins involved in mtDNA synthesis. MPV17 is a mitochondrial membrane protein whose mutation causes mitochondrial deoxynucleotide insufficiency. MPV17-related hepatocerebral mtDNA depletion syndrome is a rare autosomal recessive disease. This case report describes the clinical manifestations of MPV17-related hepatocerebral mtDNA depletion syndrome analyzed by performing whole-exome sequencing (WES). A 17-month-old girl presented with developmental delay, jaundice, and failure to thrive...

OBJECTIVE: To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology. STUDY DESIGN: We identified 148 under 10 years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed...

Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POLγA) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POLγA often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POLγA mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death...

A variant in the POLG gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with POLG -related disorders. We reported a 4-month-old infant who presented with developmental delay, fever, and diarrhea. Within two weeks after hospital admission, the patient developed hepatic failure and died. Liver necropsy demonstrated an extensive loss of hepatocytes and bile duct proliferations...

No abstract text is available yet for this article.

OBJECTIVES: Camptocormia and other orthopedic abnormalities have been only rarely reported as a phenotypic manifestation of a mitochondrial disorder (MID). Here we present an MID patient with multiple orthopedic abnormalities dominating the phenotype. CASE REPORT: The patient is a 55-year-old male in whom MID was diagnosed at age 34 upon clinical presentation, muscle biopsy, and biochemical investigations. Phenotypically, he manifested with multisystem disease including the brain (mental retardation, epilepsy, sleep disorder, cerebellar atrophy), eyes (cataract, myopia), ears (hypoacusis), heart (hypertrophic, cardiomyopathy, QT-prolongation, left anterior hemiblock, noncompaction), intestines (hepatopathy, cholecystolithiasis), muscle (myopathy), peripheral nerves (neuropathy), and the bone marrow (anemia)...

BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane. CASE PRESENTATION: We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia...

Mitochondrial fatty acid β-oxidation disorders (FAODs) are a group of about 20 diseases which are caused by specific mutations in genes that codify proteins or enzymes involved in the fatty acid transport and mitochondrial β-oxidation. As a consequence of these inherited metabolic defects, fatty acids can not be used as an appropriate energetic source during special conditions, such as prolonged fasting, exercise or other catabolic states. Therefore, patients usually present hepatopathy, cardiomyopathy, severe skeletal myopathy and neuropathy, besides biochemical features like hypoketotic hypoglycemia, metabolic acidosis, hypotony and hyperammonemia...

OBJECTIVE: In individuals with mitochondrial disease, respiratory viral infection can result in metabolic decompensation with mitochondrial hepatopathy. Here, we used a mouse model of liver-specific Complex IV deficiency to study hepatic allostasis during respiratory viral infection. METHODS: Mice with hepatic cytochrome c oxidase deficiency (LivCox10-/- ) were infected with aerosolized influenza, A/PR/8 (PR8), and euthanized on day five after infection following three days of symptoms...

Infantile cholestatic hepatopathy (ICH) is a clinical syndrome characterized by the accumulation of cytotoxic bile acids in infancy, leading to serious liver cirrhosis or liver failure. The aetiology of ICH is complicated and some of them is unknown. Regardless of the aetiology, the finial pathology of ICH is hepatocyte apoptosis caused by severe and persistent cholestasis. It is already known that activation of calcium-sensing receptor (CaSR) could lead to the apoptosis of cardiomyocytes. However, the mechanism by CaSR-mediated cholestasis-related hepatocyte apoptosis is not fully understood...