Microbiome analysis and fecal microbiota transfer in pediatric gastroenterology - a structured online survey in German-speaking countries.

PURPOSE: To assess the current attitude and the status quo towards the use of microbiome analysis and fecal microbiota transfer (FMT) in pediatric patients in German-speaking pediatric gastroenterology centers. METHODS: A structured online survey among all certified facilities of the German-speaking society of pediatric gastroenterology and nutrition (GPGE) was conducted from November 01, 2020, until March 30, 2021. RESULTS: A total of 71 centers were included in the analysis. Twenty-two centers (31.0%) use diagnostic microbiome analysis, but only a few perform analysis frequently (2; 2.8%) or regularly (1; 1.4%). Eleven centers (15.5%) have performed FMT as a therapeutic approach. Most of these centers use individual in-house donor screening programs (61.5%). One-third (33.8%) of centers rate the therapeutic impact of FMT as high or moderate. More than two-thirds (69.0%) of all participants are willing to participate in studies assessing the therapeutic effect of FMT. CONCLUSIONS: Guidelines for microbiome analyses and FMT in pediatric patients and clinical studies investigating their benefits are absolutely necessary to improve the patient-centered care in pediatric gastroenterology. The long-term and successful establishment of pediatric FMT centers with standardized procedures for patient selection, donor screening, application route, volume, and frequency of use is highly required to obtain a safe therapy.

The Role of Psychotherapy in the Care of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue (ME/CFS) is a post-infectious, chronic disease that can lead to severe impairment and, even, total disability. Although the disease has been known for a long time, and has been coded in the ICD since 1969 (G93.3), medical research has not yet been able to reach a consensus regarding its physiological basis and how best to treat it. Against the background of these shortcomings, psychosomatic disease models have been developed and psychotherapeutic treatments have been derived from them, but their empirical testing has led to sobering results. According to the current state of research, psychotherapy and psychosomatic rehabilitation have no curative effect in the treatment of ME/CFS. Nevertheless, we see numerous patients in practices and outpatient clinics who suffer severely as a result of their illness and whose mental well-being and coping strategies would benefit from psychotherapeutic help. In this article, we outline a psychotherapeutic approach that serves this need, taking into account two basic characteristics of ME/CFS: firstly, the fact that ME/CFS is a physical illness and that curative treatment must therefore be physical; and secondly, the fact that post exertional malaise (PEM) is a cardinal symptom of ME/CFS and thus warrants tailored psychotherapeutic attention.

Spasmodic Abdominal Pain and Other Gastrointestinal Symptoms in Pontocerebellar Hypoplasia Type 2.

INTRODUCTION: Pontocerebellar hypoplasia type 2 (PCH2) is a rare neurodevelopmental disease with a high disease burden. Besides neurological symptoms, somatic symptoms, such as gastroesophageal reflux (GERD) and failure to thrive, are major contributors to this burden. METHODS: We report three patients with genetically confirmed PCH2A and significant gastrointestinal (GI) symptoms. RESULTS: Apart from impaired swallowing and GERD, which are frequently reported in patients with PCH2, all three patients suffered from episodes of spasmodic abdominal pain and restlessness. In one severely affected patient, lack of intestinal alkaline phosphatase (IAP) is demonstrated. CONCLUSION: GI symptoms are common in PCH2. We draw attention to episodes of spasmodic abdominal pain seriously, aggravating the condition of the patients, especially their movement disorder, and discuss the role of IAP.

CCDC115 Deficiency Causes a Disorder of Golgi Homeostasis with Abnormal Protein Glycosylation.

Disorders of Golgi homeostasis form an emerging group of genetic defects. The highly heterogeneous clinical spectrum is not explained by our current understanding of the underlying cell-biological processes in the Golgi. Therefore, uncovering genetic defects and annotating gene function are challenging. Exome sequencing in a family with three siblings affected by abnormal Golgi glycosylation revealed a homozygous missense mutation, c.92T>C (p.Leu31Ser), in coiled-coil domain containing 115 (CCDC115), the function of which is unknown. The same mutation was identified in three unrelated families, and in one family it was compound heterozygous in combination with a heterozygous deletion of CCDC115. An additional homozygous missense mutation, c.31G>T (p.Asp11Tyr), was found in a family with two affected siblings. All individuals displayed a storage-disease-like phenotype involving hepatosplenomegaly, which regressed with age, highly elevated bone-derived alkaline phosphatase, elevated aminotransferases, and elevated cholesterol, in combination with abnormal copper metabolism and neurological symptoms. Two individuals died of liver failure, and one individual was successfully treated by liver transplantation. Abnormal N- and mucin type O-glycosylation was found on serum proteins, and reduced metabolic labeling of sialic acids was found in fibroblasts, which was restored after complementation with wild-type CCDC115. PSI-BLAST homology detection revealed reciprocal homology with Vma22p, the yeast V-ATPase assembly factor located in the endoplasmic reticulum (ER). Human CCDC115 mainly localized to the ERGIC and to COPI vesicles, but not to the ER. These data, in combination with the phenotypic spectrum, which is distinct from that associated with defects in V-ATPase core subunits, suggest a more general role for CCDC115 in Golgi trafficking. Our study reveals CCDC115 deficiency as a disorder of Golgi homeostasis that can be readily identified via screening for abnormal glycosylation in plasma.

[Health damages after ingestion of button batteries in childhood]. / Gesundheitsschäden nach Ingestion von Knopfzellbatterien im Kindesalter.

BACKGROUND: Exposure of children under 5 years to button batteries may result in severe corrosive injury, especially when they get stuck in the oesophagus. The injury is caused by the discharge current of the batteries. An increasing number of button battery ingestions have been described worldwide. OBJECTIVES: The aim of this study was to describe incidence and complications after battery ingestion in children in Germany. MATERIALS AND METHODS: Paediatric gastroenterologists and paediatric surgeons were asked to report complicated battery ingestions in children between 2011 and 2016 retrospectively. The survey was done using a structured questionnaire. In addition, button battery ingestion calls to a German poison centre were analysed retrospectively. RESULTS: In 116 cases the button battery was located in the oesophagus. Severe complications developed in 47 patients and 5 of these children died. Serious complications occurred also in children with removal of the button batteries within less than 3 h after the intake. The Freiburg poison centre received 258 paediatric ingestions of button batteries. Out of these, seven button batteries were stuck in the oesophagus and five in the nose causing corrosion injury. CONCLUSIONS: Serious complications and even death after button battery ingestion are described in Germany. Button batteries impacted in the oesophagus should be removed emergently to minimize corrosive injury. Because no symptoms or only slight discomfort are developed initially, awareness of button batteries as a unique corrosive hazard among the public and clinicians is an important requirement for prompt diagnosis and treatment resulting in a satisfactory outcome.

An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking.

Microvillus inclusion disease (MVID) is a rare intestinal enteropathy with an onset within a few days to months after birth, resulting in persistent watery diarrhea. Mutations in the myosin Vb gene (MYO5B) have been identified in the majority of MVID patients. However, the exact pathophysiology of MVID still remains unclear. To address the specific role of MYO5B in the intestine, we generated an intestine-specific conditional Myo5b-deficient (Myo5bfl/fl;Vil-CreERT2) mouse model. We analyzed intestinal tissues and cultured organoids of Myo5bfl/fl;Vil-CreERT2 mice by electron microscopy, immunofluorescence, and immunohistochemistry. Our data showed that Myo5bfl/fl;Vil-CreERT2 mice developed severe diarrhea within 4 d after tamoxifen induction. Periodic Acid Schiff and alkaline phosphatase staining revealed subapical accumulation of intracellular vesicles in villus enterocytes. Analysis by electron microscopy confirmed an almost complete absence of apical microvilli, the appearance of microvillus inclusions, and enlarged intercellular spaces in induced Myo5bfl/fl;Vil-CreERT2 intestines. In addition, we determined that MYO5B is involved not only in apical but also basolateral trafficking of proteins. The analysis of the intestine during the early onset of the disease revealed that subapical accumulation of secretory granules precedes occurrence of microvillus inclusions, indicating involvement of MYO5B in early differentiation of epithelial cells. By comparing our data with a novel MVID patient, we conclude that our mouse model completely recapitulates the intestinal phenotype of human MVID. This includes severe diarrhea, loss of microvilli, occurrence of microvillus inclusions, and subapical secretory granules. Thus, loss of MYO5B disturbs both apical and basolateral trafficking of proteins and causes MVID in mice.

Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea.

Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na(+)/H(+) antiporter 3 (NHE3), which is the major intestinal brush-border Na(+)/H(+) exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.

Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency.

UNLABELLED: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G-class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. CONCLUSIONS: PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis.

Pediatric gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) and European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Guideline Executive summary.

This Executive summary of the Guideline on pediatric gastrointestinal endoscopy from the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) refers to infants, children, and adolescents aged 0 - 18 years. The areas covered include: indications for diagnostic and therapeutic esophagogastroduodenoscopy and ileocolonoscopy; endoscopy for foreign body ingestion; endoscopic management of corrosive ingestion and stricture/stenosis; upper and lower gastrointestinal bleeding; endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography. Percutaneous endoscopic gastrostomy and endoscopy specific to inflammatory bowel disease (IBD) have been dealt with in other Guidelines and are therefore not mentioned in this Guideline. Training and ongoing skill maintenance will be addressed in an imminent sister publication.

Inflammatory bowel disease caused by primary immunodeficiencies-Clinical presentations, review of literature, and proposal of a rational diagnostic algorithm.

Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis have a multifactorial pathogenesis with complex interactions between polygenetic predispositions and environmental factors. However, IBD can also be caused by monogenic diseases, such as primary immunodeficiencies (PID). Recently, an increasing number of these altogether rare diseases have been described to present often primarily, or solely, as IBD. Early recognition of these conditions enables adaption of therapies and thus directly benefits the course of IBDs. Here, we discuss the different clinical presentations in IBD and characteristic features of patient's history, clinical findings, and diagnostic results indicative for a causative PID. Possible predictors are early onset of disease, necessity of parenteral nutrition, failure to respond to standard immunosuppressive therapy, parental consanguinity, increased susceptibility for infections, certain histopathologic findings, and blood tests that are atypical for classic IBD. We illustrate this with exemplary case studies of IBD due to NEMO deficiency, chronic granulomatous disease, common variable immunodeficiency, CTLA-4 and LRBA deficiency. Taking these factors into account, we propose a diagnostic pathway to enable early diagnosis of IBD due to PID.

Paediatric Gastrointestinal Endoscopy: European Society for Paediatric Gastroenterology Hepatology and Nutrition and European Society of Gastrointestinal Endoscopy Guidelines.

This guideline refers to infants, children, and adolescents ages 0 to 18 years. The areas covered include indications for diagnostic and therapeutic esophagogastroduodenoscopy and ileocolonoscopy; endoscopy for foreign body ingestion; corrosive ingestion and stricture/stenosis endoscopic management; upper and lower gastrointestinal bleeding; endoscopic retrograde cholangiopancreatography; and endoscopic ultrasonography. Percutaneous endoscopic gastrostomy and endoscopy specific to inflammatory bowel disease has been dealt with in other guidelines and are therefore not mentioned in this guideline. Training and ongoing skill maintenance are to be dealt with in an imminent sister publication to this.

Mitochondrial dysfunction in liver failure requiring transplantation.

Liver failure is a heterogeneous condition which may be fatal and the primary cause is frequently unknown. We investigated mitochondrial oxidative phosphorylation in patients undergoing liver transplantation. We studied 45 patients who had liver transplantation due to a variety of clinical presentations. Blue native polyacrylamide gel electrophoresis with immunodetection of respiratory chain complexes I-V, biochemical activity of respiratory chain complexes II and IV and quantification of mitochondrial DNA (mtDNA) copy number were investigated in liver tissue collected from the explanted liver during transplantation. Abnormal mitochondrial function was frequently present in this cohort: ten of 40 patients (25 %) had a defect of one or more respiratory chain enzyme complexes on blue native gels, 20 patients (44 %) had low activity of complex II and/or IV and ten (22 %) had a reduced mtDNA copy number. Combined respiratory chain deficiency and reduced numbers of mitochondria were detected in all three patients with acute liver failure. Low complex IV activity in biliary atresia and complex II defects in cirrhosis were common findings. All six patients diagnosed with liver tumours showed variable alterations in mitochondrial function, probably due to the heterogeneity of the presenting tumour. In conclusion, mitochondrial dysfunction is common in severe liver failure in non-mitochondrial conditions. Therefore, in contrast to the common practice detection of respiratory chain abnormalities in liver should not restrict the inclusion of patients for liver transplantation. Furthermore, improving mitochondrial function may be targeted as part of a complex therapy approach in different forms of liver diseases.

Etiology, outcome and prognostic factors of childhood acute liver failure in a German Single Center.

Pediatric acute liver failure (PALF) is a progressive, potentially fatal clinical syndrome occurring in previously healthy children. Our study aimed to determine the current leading causes of PALF in a single center in Germany, identifying possible prognostic markers. Thirty-seven pediatric patients with PALF were included. Medical records were reviewed for demographic, laboratory and clinical data. Laboratory results on admission and at peak value, PELD and MELD score on admission, and intensive care support were assessed. Fifteen patients recovered spontaneously, 14 died without transplantation, and 8 received a liver transplant. Patients who survived were significantly older than patients who died. Specific causes of PALF could be identified as infectious diseases (16%), metabolic diseases (14%), toxic liver injury (11%), immunologic diseases (8%), or vascular diseases (8%). Causes of PALF remained indeterminate in 43%. High ammonia, low albumin, and low ALT levels on admission were associated with worse outcome. Absence of need of ventilation, hemodialysis, and circulatory support predicted spontaneous recovery. In conclusion, infections are the most common known cause of PALF. However, in a large proportion of patients the cause for PALF remains cryptic. Ammonia and albumin levels may be of prognostic value to predict outcomes.

Pulse oximetry is insufficient for timely diagnosis of hepatopulmonary syndrome in children with liver cirrhosis.

OBJECTIVE: To prospectively investigate the prevalence of hepatopulmonary syndrome (HPS), the importance of pulse oximetry in diagnosing HPS, and the longitudinal course after liver transplantation in children with cirrhosis referred for liver transplantation. STUDY DESIGN: Fifty-six patients aged 1-17 years (mean age, 4.6 ± 5.0 years) with liver cirrhosis were screened for HPS by hyperemic capillary blood gas (CBG) analysis and contrast-enhanced transthoracic echocardiography. Eleven patients were excluded owing to conditions that can produce cardiopulmonary dysfunction, including 5 with cystic fibrosis, 1 with pulmonary arterial hypertension, and 5 with an intracardial shunt. HPS was classified in accordance with the European Respiratory Society Task Force criteria on pulmonary-hepatic disorders. Patient groups were compared for biochemical and clinical characteristics. RESULTS: Eighteen children (40%) with cirrhosis were intrapulmonary vasodilatation (IPVD)-positive and had a pulse oximetry oxygen saturation level >98%. Two of these patients (11%) exhibited moderate HPS with an elevated alveolar arterial oxygen gradient >15 mm Hg and PaO2 <70 mm Hg; they died before undergoing liver transplantation. The sensitivity and specificity of CBG analysis for detecting elevated alveolar arterial oxygen gradient in children with IPVD was 94% and 53%, respectively. HPS was associated with late hepatoportoenterostomy (P < .04). Liver transplantation led to resolution of HPS in all patients. CONCLUSION: IPVD is frequent in children with liver cirrhosis (40%). Pulse oximetry is insufficient for timely HPS diagnosis. Pathological CBG analysis data indicate IPVD in the majority of cases, but are imprecise in children aged <2 years. Contrast-enhanced transthoracic echocardiography and CBG analysis are recommended for evaluation of HPS in children with cirrhosis, regardless of liver synthesis capacity and clinical chemistry data.

Spectrum of pathogens in native liver, bile, and blood during pediatric liver transplantation.

During LTX, there may be a risk that pathogens of the native liver are released into the systemic circulation. No investigations on incidence/spectrum of pathogens in native livers have been published. We hypothesized that pathogens are found in the native liver of a large proportion of pediatric patients during LTX and investigated the microbiology of native livers. These data may help optimize antibiotic therapy. Twenty-two consecutive pediatric patients (median age 14 months, range, 5 months-15 yr) receiving LTX in our department from October 2010 to October 2011 were included in this prospective study. Tissue and bile were collected from the explanted liver and were cultivated on different media. All liver tissues were investigated using a broad-range PCR (SepsiTest(®)). In 16 patients, blood cultures were collected post-transplantation. Eleven patients (50%) had at least one pathogen detected; nine of these patients had an underlying diagnosis of biliary atresia. SepsiTest(®) was positive in seven patients. In four patients it was the only test detecting any pathogen. In detail, the positivity rate for liver tissue in all patients was 41% (n = 9); for bile 25% (n = 3); and for blood 25% (n = 4). Thirteen different pathogens (69% bacterial, 31% fungal) were isolated. A highly-sensitive broad-range PCR appears to be an effective method to detect pathogens in native livers of patients undergoing LTX. A high number and variety of microbes, including a high proportion of fungal pathogens, were detected.

Liver cirrhosis in glycogen storage disease Ib.

Glycogen storage disease Ib is an inborn error of carbohydrate metabolism leading to impaired glycogenolysis and gluconeogenesis. Cardinal symptoms include fasting hypoglycemia, lactic acidosis and hepatomegaly as well as neutropenia. We report for the first time on the development of liver cirrhosis in a nine-year-old boy in the course of glycogen storage disease Ib and discuss possible underlying pathomechanisms.

Gilbert's syndrome--a frequent cause of unconjugated hyperbilirubinemia in children after orthotopic liver transplantation.

Gilbert's syndrome is one major cause for unconjugated hyperbilirubinemia in healthy individuals with the prevalence being approximately 3.2-8.6%. It is caused by a mutation in the promoter region of the UGT1A1-gene with a prolonged TAA-repeat coding for the enzyme bilirubin UDP-glucuronosyltransferase (A(TA)(7) TAA allele). After OLT, Gilbert's disease of the transplanted liver can cause unconjugated hyperbilirubinemia. Therefore, we looked for the presence of A(TA)(7) TAA alleles in pediatric liver transplant recipients with unconjugated hyperbilirubinemia. Laboratory results of 106 pediatric liver transplant recipients (aged 0-17 yr) were evaluated for elevated total bilirubin over 2.0 mg/dL (conjugated bilirubin <30%). In these patients, DNA of the liver graft was extracted from paraffin-embedded liver biopsy samples formerly taken for diagnostic reasons. The DNA was analyzed for A(TA)(7) TAA alleles in the promoter region of the UGT1A1-gene. In 4 of 106 pediatric liver transplant recipients we found unconjugated hyperbilirubinemia with total bilirubin above 2.0 mg/dL (conjugated bilirubin <30%). The analysis of the promoter region of the UGT1A1-gene of the liver grafts showed three homozygous A(TA)(7) TAA alleles (homozygous Gilbert's syndrome) and one heterozygous A(TA)(7) TAA allele (heterozygous Gilbert's syndrome). This study shows that pediatric liver transplant recipients with unconjugated hyperbilirubinemia are very likely to have received a liver graft from a donor with Gilbert's syndrome.

Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients--a single-center experience.

HEV infection appears to be an emerging disease in industrialized countries. The aim of this study was to evaluate the prevalence of HEV infection in pediatric solid organ transplant recipients. One hundred and twenty-four pediatric recipients of liver (n = 41) or kidney (n = 83) transplants aged between one and 18 yr were screened for anti-HEV IgG antibodies. Patients were tested for fecal HEV RNA excretion if they showed anti-HEV seropositivity. As a control group, 108 immunocompetent pediatric patients without liver disease aged between three and 18 yr were screened for anti-HEV IgG. HEV seroprevalence was 2.4% in renal Tx (2/83), 4.9% in liver Tx patients (2/41), and 3.2% overall (4/124). Three of these four patients were HEV RNA-negative. In one renal transplant patient, HEV genotype 3 RNA excretion persisted and liver enzymes were elevated, indicating chronic hepatitis. In the control group, eight patients (7.4%) were HEV IgG-positive without biochemical evidence of hepatitis. The prevalence of HEV infection in pediatric renal or liver transplant recipients is not higher compared with immunocompetent children. Chronic HEV infection with long-term carriage of the virus may develop in pediatric transplant recipients. Autochthonous HEV infection needs to be considered in uncertain cases of hepatitis in immunosuppressed as well as immunocompetent children.

Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations.

Combined respiratory chain deficiency accounts for about 30% of mitochondrial respiratory chain deficiencies and is frequently associated with mtDNA depletion, deletions or point mutations. However combined respiratory chain deficiency may also be caused by mutations in nuclear genes affecting mitochondrial translation. Here we describe a 2-year-old girl, who developed an acute, isolated, severe liver failure with mitochondrial pathology and decreased respiratory chain enzyme activities both in liver and skeletal muscle at 4 months of age. Her liver function improved significantly within a month, liver function tests returned to normal. Liver cirrhosis remained without any further complications so far. Pathogenic compound heterozygous mutations were identified in the TRMU gene. This condition is one of the few mitochondrial disorders with a life-threatening onset showing recovery later in life, therefore a prompt diagnosis and treatment of these patients has great importance in clinical practice. We suggest that TRMU deficiency should be considered in infants with acute liver disease.