Maple Syrup Urine Research Articles

Орфанная патология в республике Северная Осетия – Алания: структура, популяционно-генетические особенности, проблемы и перспективы

Currently, there are more than 8000–10000 rare disease (RDs), among which 75–80% are hereditary. In the Russian Federation (RF), patients are provided medical care in accordance with two lists: 17 chronic progressive and life-threatening diseases (RLTDs) and 14 high-cost nosologies (HCNs). The study was aimed to assess the range, prevalence, and genetic epidemiological characteristics of the RDs from the lists of RLTDs and HCNs in the Republic of North Ossetia–Alania and RF in general. We determined the number of patients from the RLTD (a total of 18,744 people in the RF, among them 8713 children; 129 and 42 people, respectively, in the Republic of North Ossetia–Alania) and HCN (28727 people/13454 children in the RF; 554 and 64 in the Republic of North Ossetia–Alania) lists and calculated the prevalence per 100,000 population. The global prevalence of RDs was estimated using the Orphanet database. The average prevalence of RLTDs in the whole population of the RF was 11.51 cases and that among children was 25.08. Similar data were obtained for the Republic of North Ossetia–Alania (19.38 and 29.44, respectively). It was found that idiopathic thrombocytopenic purpura, disorder of the complement system, maple syrup urine disease, porphyria were more common in the Republic of North Ossetia–Alania than in the RF in general, while galactosemia was less common. The analysis of disorders from the RLTD list has shown lower prevalence of hemophilia and pituitary dwarfism in the Republic of North Ossetia–Alania compared to the RF and Orphanet, along with the higher prevalence of type VI mucopolysaccharidosis, hemolytic uremic syndrome, and systemic juvenile rheumatoid arthritis. In the Republic of North Ossetia–Alania, the features of the range of genetic variation in the genes РАН (phenylketonuria) and CFTR (cystic fibrosis) have been identified. Thus, assessment of the RD prevalence in the regions is important and essential for raising awareness of medical personnel, as well as for expansion and improvement of medical care provision to patients with RLTDs and HCNs.

Exploratory Untargeted Metabolomics of Dried Blood Spot Samples from Newborns with Maple Syrup Urine Disease.

Currently, tandem mass spectrometry-based newborn screening (NBS), which examines targeted biomarkers, is the first approach used for the early detection of maple syrup urine disease (MSUD) in newborns, followed by confirmatory genetic mutation tests. However, these diagnostic approaches have limitations, demanding the development of additional tools for the diagnosis/screening of MUSD. Recently, untargeted metabolomics has been used to explore metabolic profiling and discover the potential biomarkers/pathways of inherited metabolic diseases. Thus, we aimed to discover a distinctive metabolic profile and biomarkers/pathways for MSUD newborns using untargeted metabolomics. Herein, untargeted metabolomics was used to analyze dried blood spot (DBS) samples from 22 MSUD and 22 healthy control newborns. Our data identified 210 altered endogenous metabolites in MSUD newborns and new potential MSUD biomarkers, particularly L-alloisoleucine, methionine, and lysoPI. In addition, the most impacted pathways in MSUD newborns were the ascorbate and aldarate pathways and pentose and glucuronate interconversions, suggesting that oxidative and detoxification events may occur in early life. Our approach leads to the identification of new potential biomarkers/pathways that could be used for the early diagnosis/screening of MSUD newborns but require further validation studies. Our untargeted metabolomics findings have undoubtedly added new insights to our understanding of the pathogenicity of MSUD, which helps us select the appropriate early treatments for better health outcomes.

Disorders in Amino Acid Metabolism Associated with Seizures

Seizures are a common presenting manifestation in children with amino acid metabolism disorders such as maple syrup urine disease (MSUD), nonketotic hyperglycinemia, sulfite oxidase deficiency, serine deficiency, and GABA-related disorders. In monoamine biosynthesis disorders, seizures are rare, but paroxysmal dystonia is often misdiagnosed as seizures. Metabolic changes, including amino acid turnover, have been noted during epileptogenesis and chronic epilepsy. Autophagy, a catabolic pathway crucial for maintaining tissue and organism homeostasis, is influenced by amino acids and plays a role in brain physiology and pathology, including epileptic disorders. Amino acid synthesis defects can cause neurological symptoms such as early-onset seizures, mental disability, and skin disorders. Besides neurological symptoms, amino acid metabolism disorders can impact other organ systems, resulting in various clinical manifestations. Early recognition and proper management of these disorders are vital for preventing long-term complications and enhancing patient outcomes. Ongoing research into the complex relationship between amino acid metabolism and neurological function may offer new insights into the pathogenesis of seizures and other neurological disorders.

Identifying Metabolic Diseases That Precipitate Neonatal Seizures.

Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly controlled neonatal epilepsy. Diagnosing neonatal-onset metabolic conditions proves a difficult task for clinicians; however, routine state newborn screening panels now include many IEMs. Three in particular-pyridoxine-dependent epilepsy, maple syrup urine disease, and Zellweger spectrum disorders-are highly associated with neonatal epilepsy and neurocognitive injury yet are often misdiagnosed. As research surrounding biomarkers for these conditions is emerging and gene sequencing technologies are advancing, clinicians are beginning to better establish early identification strategies for these diseases. In this literature review, the authors aim to present clinicians with an innovative clinical guide highlighting IEMs associated with neonatal-onset seizures, with the goal of promoting quality care and safety.

Evaluation of newborn screening program for maple syrup urine disease for optimization of amino acid ratio cutoffs: Experience from a single clinical chemistry laboratory

Evaluation of newborn screening program for maple syrup urine disease for optimization of amino acid ratio cutoffs: Experience from a single clinical chemistry laboratory

Newborn screening in France: news and perspectives

Newborn screening is a major public health concern. In France, it was established in 1972 with systematic screening for phenylketonuria. Subsequently, other screenings, including congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, and sickle cell disease, were added. The introduction of tandem mass spectrometry in screening laboratories in 2020 enabled the inclusion of eight additional inherited metabolic diseases: aminoacidopathies (tyrosinemia type I, maple syrup urine disease, and homocystinuria), organic acidurias (isovaleric and glutaric type I acidurias), and disorders of fatty acid metabolism (MCADD, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), and primary carnitine deficiency). We briefly present these newly added diseases, of which public awareness is still incomplete.

Persistently elevated alloisoleucine in a patient without maple syrup urine disease

Persistently elevated alloisoleucine in a patient without maple syrup urine disease

The oral phenotype and dental management in patients with maple syrup urine disease; case report and scoping review

Background and objectivesThe literature about oral manifestations and dental management in maple syrup urine disease (MSUD) is sparse. The aim of this report is to present a new case of MSUD with special emphasis on oral findings and to review the relevant literature.MethodA case report of a 4-year-old boy with MSUD was described according to the CARE guidelines for describing case reports. Scoping review of relevant literature was performed, according to the PRISMA-ScR guidelines, by searching PubMed, Medline, Embase, and the grey literature for articles describing dental management and/or oral manifestations in MSUD.ResultsThe initial search identified 219 articles, but only 4 met the inclusion criteria. Rampant caries and plaque induced gingivitis were the main oro-dental findings in MSUD. Other oral findings included enamel hypoplasia, skeletal abnormalities, and abnormal oral behaviors. Disease-related factors appeared to play a major role in the development of the observed oral phenotype.ConclusionOral health in MSUD seems to be influenced by the reliance on semi-synthetic diet and associated neurocognitive complications. Tailored oral health promotional interventions should be included in the multidisciplinary management of patients with MSUD.

Prevalence and outcome of inborn errors of metabolism among high-risk neonates: an Egyptian single-center study

Background Inborn errors of metabolism (IEM) are genetic disorders caused by incompetence in enzymatic reactions of intermediary metabolism due to an insufficient amount or unstable form of the involved enzyme. Aim To assess the prevalence and outcome of IEM among high-risk neonates for early diagnosis and detection of treatable causes to minimize morbidity and mortality rate in neonates. Methods This cross-sectional study was carried out on 684 neonates at the Neonatal Intensive Care Unit in the Pediatrics Department at Zagazig University Children’s Hospital from February 2020 to February 2023. Extended metabolic screen (EMS) was done for full-term neonates and preterm of more than 32 weeks of gestation. Further investigations such as plasma ammonia, plasma lactate, urine organic acid analysis, blood gas, serum anion gap, and the blood glucose level were also measured. Results The prevalence of IEM was 4.4%. The most common presentations among the cases of IEM were not doing well, respiratory distress, encephalopathy, and convulsion. As regards provisional diagnosis, 11 cases were diagnosed as maple syrup urine disease, 5 cases with glycine encephalopathy, 5 cases with medium-chain acyl CoA dehydrogenase deficiency,4 cases with methylmalonic acidemia, 2 cases with isovaleric acidemia, 2 cases with citrullinemia type 1, and one case with propionic academia; 12 (40%) of IEM cases died. Conclusion IEM disorders are not rare diseases in high-risk neonates with attention to consanguinity, which is a common tradition in our country. The delay in diagnosis of IEM leads to high morbidity and mortality.

Liver-directed gene therapy for inherited metabolic diseases.

Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver-directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver-targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler-Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow-up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver-targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.

Pubertal origin of growth retardation in inborn errors of protein metabolism: A longitudinal cohort study

ObjectivesInherited amino-acid metabolism disorders (IAAMDs) require lifelong protein-restricted diet. We aimed to investigate: 1/ whether IAAMDs was associated with growth, pubertal, bone mineral apparent density (BMAD) or body composition impairments; 2/ associations linking height, amino-acid mixture (AAM), plasma amino-acids and IGF1 concentrations. DesignRetrospective longitudinal study of 213 patients with neonatal-onset urea cycle disorders (UCD,n = 77), organic aciduria (OA,n = 89), maple syrup urine disease (MSUD,n = 34), or tyrosinaemia type 1 (n = 13). MethodsWe collected growth parameters, pubertal status, BMAD, body composition, protein-intake, and IGF1 throughout growth. ResultsOverall final height (n = 69) was below target height (TH): −0.9(1.4) vs. -0.1(0.9) SD, p < 0.001. Final height was ≤ TH-2SD in 12 (21%) patients. Height ≤ − 2SD was more frequent during puberty than during early-infancy and pre-puberty: 23.5% vs. 6.9%, p = 0.002; and vs. 10.7%, p < 0.001. Pubertal delay was frequent (26.7%). Height (SD) was positively associated with isoleucine concentration: β, 0.008; 95%CI, 0.003 to 0.012; p = 0.001. In the pubertal subgroup, height (SD) was lower in patients with vs. without AAM supplementation: −1.22 (1.40) vs. -0.63 (1.46) (p = 0.02). In OA, height and median (IQR) isoleucine and valine concentrations(μmol/L) during puberty were lower in patients with vs. without AAM supplementation: −1.75 (1.30) vs. −0.33 (1.55) SD, p < 0.001; and 40 (23) vs. 60 (25) (p = 0.02) and 138 (92) vs. 191 (63) (p = 0.01), respectively. No correlation was found with IGF1. Lean-mass index was lower than fat-mass index: −2.03 (1.15) vs. -0.44 (0.89), p < 0.001. ConclusionsIn IAAMDs, growth retardation worsened during puberty which was delayed in all disease subgroups. Height seems linked to the disease, AAM composition and lower isoleucine concentration, independently of the GH-IGF1 pathway. We recommend close monitoring of diet during puberty.

Living with a child with MSUD: Psychosocial issues of Filipino parents with a child with maple syrup urine disease

PurposeMaple syrup urine disease (MSUD) is a common inborn error of metabolism diagnosed in the Philippines. A family may experience stress, anxiety, sorrow, or feelings of helplessness when a child is diagnosed to have a genetic disorder, which can lead to chronic care and disability. This study aims to explore the psychosocial issues experienced by Filipino parents with children having MSUD. MethodsThis is a descriptive and qualitative study. One-to-one interviews using a semi-structured set of questions were done between the months of November 2015 to March 2016. A total of 12 parents were interviewed. Thematic analysis was used. ResultsThe diagnosis of MSUD in a child is, indeed, a stressful event for the family. Parents experienced fear, confusion, and hurt, among other emotions. Having a child with MSUD had a negative impact on their families, especially in terms of financial burden, dietary restriction, and marital conflicts leading to separation. However, some parents reported positive effects, such as increased confidence in one’s abilities to care for the affected child and closer relationships among family members. ConclusionA diagnosis of MSUD on the child places considerable caregiver burden on the parents. Findings have important implications for genetic counselors.

Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease.

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort.

Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history of patients with OAs remains unresolved, specifically with regard to the impact of cardiac complications. We therefore performed a retrospective study to address this issue at our Referral Center for Pediatric Inherited Errors of Metabolism. Sixty patients with OAs (propionic (PA), methylmalonic (MMA) and isovaleric acidemias and maple syrup urine disease) diagnosed from 2000 to 2022 were systematically assessed at baseline and at follow-up. Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). The presence of DCM was associated with the worst prognosis. The rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA with cardiomyopathy; 35% in MMA with cardiomyopathy; and 23% in MMA without cardiomyopathy. Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. Cardiac involvement was documented in about one third of children diagnosed with classical OAs, confined to PA and MMA, and was often associated with poor outcome in over 50%. Etiological diagnosis of OAs is essential in guiding management and risk stratification.

Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology.

Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease.

Identification of genes in a genomic DNA sequence

Today, newer pyrosequencing methods have drastically cut the cost of sequencing and may eventually allow every person the possibility of personalized genome information. Being able to read how our genes are expressed offers the promise of advanced medical treatments, but it will certainly require considerable work to generate, understand, organize, and apply this massive amount of data to human disease. This study describes the results of the CFTR, MEFV, GALT, PAH, BCKDHB and DBT genes analysis of Azerbaijanian patients. The molecular diagnostics methods using specific primers to identify CFTR, MEFV, GALT, PAH, BCKDHB and DBT genes many mutations. A total 15 different mutations (R261Q, V245V, P281L, R241C, L385L, V399V, E280K, R261X, A434D, R176X, Ex6-96A&amp;gt; G, R241C, R243Q, R252Q, Y356X) and 2 different polymorphisms (Q232Q,V245V) were detected of the PAH gene. 4 different mutations (P325L, H132Q, Q334K, N314D ) were detected of the GALT gene, 6 different mutations (Phe508del, Phe508del/5T, R117H/R334W, R553X and 965 (T-C)) were found in the CFTR gene, polymorphisms (D102D, G138G, A165A, R202Q, R314R, G474G, G476G, D510D) were detected of the MEFV gene, 2 different mutations were found of the BCKDHB gene and one mutation detected of the DBT gene in patients from Azerbaijani population. To prophylaxis the phenylketonuria, galactosemia, maple syrup urine disease, cystic fibrosis disease and Fammilian Mediterranian Fever it is recommended to screen genetically newborns, to consult medical-genetically risky families, and to carry out prenatal diagnostics during pregnancies for those families.

Evaluation of the risk factors for noncommunicable diseases in patients with inborn errors of amino acid metabolism receiving nutrition therapy.

There is growing concern about the low-protein and high-energy diet therapies used in the treatment of inherited amino acid metabolism disorders. We aimed to identify the risk factors for noncommunicable diseases that may arise from nutritional therapies and suggests approaches that may prevent the development of the noncommunicable diseases. The present study evaluates 112 patients, on long-term nutritional therapy for at least the last 2 years with a diagnosis of an inborn error of the amino acid metabolism, and their 28 healthy siblings. The participants are assessed for the development of overweight and metabolic syndrome based on an analysis of anthropometric parameters, body composition and the results of biochemical tests. Anthropometric measurements including BMI, weight Z-score, waist circumference and fat mass were not significantly different between patients and controls. Height Z-scores were similar in phenylketonuria patients compared to controls, but lower in urea cycle disorders, organic acidemia and maple syrup urine disease groups. No increased risk of development of overweight or metabolic syndrome was detected in the patient group, while there were findings suggesting malnutrition in patients diagnosed with urea cycle disorders. There was a correlation between patients' BMI and C3-carnitine levels in organic acidemia patients and leucine levels in maple syrup urine disease patients. All forms of malnutrition can be prevented in patient groups receiving limited nutrients under a dietary management protocol, based on the findings of anthropometric and biochemical evaluations and analyses of body composition.

Non-Enzymatic Formation of N-acetylated Amino Acid Conjugates in Urine

Unknown N-acylated amino acid (N-AAA) conjugates have been detected in maple syrup urine disease (MSUD) and other inborn errors of metabolism (IEMs). This study aimed to elucidate the mechanism behind the formation of urinary N-AAA conjugates. Liquid–liquid extraction was employed to determine the enantiomeric composition of N-AAA conjugates, followed by liberation of conjugated amino acids through acid hydrolysis. Gas chromatography–mass spectrometry (GC–MS) was used to separate amino acid enantiomers. In vitro experiments were conducted to test the non-enzymatic formation of N-AAA conjugates from 2-keto acids and ammonia, with molecular modelling used to assess possible reaction mechanisms. Adequate amounts of N-AAA conjugates were obtained via organic acid extraction without concurrent extraction of native amino acids, and hydrolysis was complete without significant racemisation. GC–MS analysis successfully distinguished amino acid enantiomers, with some limitations observed for L-isoleucine and D-alloisoleucine. Furthermore, investigation of racemic N-AAA conjugates from an MSUD case confirmed its non-enzymatic origin. These findings highlight the value of employing chiral strategy and molecular modelling to investigate the origin of unknown constituents in biological samples. Additionally, these conjugates warrant further investigation as potential factors contributing to MSUD and other IEMs.

Domino liver transplantation for maple syrup urine disease in children: A single-center case series.

Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long-term outcomes. It was a retrospective study. All children with MSUD were paired with either recipients with end-stage liver disease (ESLD) or non-MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living-related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split-liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type-1, one GSD type-3, and one Citrullinemia. Post-LT ICU and hospital stays were comparable (p > .05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow-up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft-related complications were seen in the post-transplant period. No occurrence of MSUD was noted in DLT recipients. DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.

Living Donor-Initiated Domino Split-Liver Transplantation in Pediatric Setup: A Case Report With Literature Review

In patients undergoing liver transplantation for metabolic diseases, removing the patient's liver for transplantation to another recipient is called "domino liver transplantation." The extracted liver can be divided and transplanted into 2 recipients, which is called domino split-liver transplantation in the literature. However, in our study, the domino liver was obtained from a pediatric patient. A patient with maple syrup urine disease (MSUD) underwent a living donor liver transplant, and the explanted liver was divided in situ into right and left lobes and transplanted to 2 separate patients. Demographic data, surgical techniques, postoperative period, and patient follow-ups were evaluated. The father's left lobe liver graft was transplanted into a 12-year-old boy with MSUD. The removed liver was divided in situ into right and left lobes. The left lobe was transplanted to a 14-year-old male patient, whereas the right lobe was transplanted to a 67-year-old male patient. The donor and the first recipient were discharged on postoperative days 5 and 22. The second pediatric patient who underwent domino split-left lobe transplantation was discharged on postoperative day 23. The adult patient who underwent domino split-right lobe transplantation died on postoperative day 12 owing to massive esophageal variceal bleeding. Patients who underwent liver transplantation due to MSUD are among the best donor choices for domino liver transplantation. If the extracted liver has a sufficient volume and anatomic features for a split, it can be used in "selected cases."