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1.
Int J Mol Sci ; 25(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38891907

RESUMO

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.


Assuntos
Biomarcadores , Teste em Amostras de Sangue Seco , Doença da Urina de Xarope de Bordo , Metabolômica , Triagem Neonatal , Humanos , Doença da Urina de Xarope de Bordo/sangue , Doença da Urina de Xarope de Bordo/diagnóstico , Recém-Nascido , Teste em Amostras de Sangue Seco/métodos , Biomarcadores/sangue , Metabolômica/métodos , Masculino , Feminino , Triagem Neonatal/métodos , Metaboloma , Espectrometria de Massas em Tandem
2.
Neonatal Netw ; 43(3): 139-147, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38816225

RESUMO

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.


Assuntos
Convulsões , Humanos , Recém-Nascido , Convulsões/diagnóstico , Triagem Neonatal/métodos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/complicações , Diagnóstico Diferencial , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/complicações
3.
BMC Oral Health ; 24(1): 362, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515181

RESUMO

BACKGROUND AND OBJECTIVES: The 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. METHOD: A 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. RESULTS: The 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. CONCLUSION: Oral 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.


Assuntos
Doença da Urina de Xarope de Bordo , Masculino , Humanos , Pré-Escolar , Doença da Urina de Xarope de Bordo/complicações , Doença da Urina de Xarope de Bordo/genética , Fenótipo , Assistência Odontológica
4.
Nutrients ; 16(3)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38337708

RESUMO

Strict adherence to a diet is an essential pillar of long-term treatment for many inborn errors of metabolism (IEMs). Tools that educate patients about dietary management can positively condition adherence and prevent morbidity. We designed a free online dietary calculation program (Odimet®, version 2.1.) for IEMs patients in 2008, updated in 2022, that provides detailed information on the content of amino acids, protein, lipids, carbohydrates, vitamins and minerals in >3000 food products, including specific medical foods for IEM. We analyzed the statistics on visits to Odimet® to evaluate its usefulness for long-term dietary management during a 5-year period focusing on three periods: pre-pandemic (15 March 2018-14 March 2020); pandemic 1 (15 March 2020-14 March 2021); and pandemic 2 period (15 March 2021-15 March 2023), in 120 patients with the following distribution: 84 patients with phenylketonuria (PKU); 12 with maple syrup urine disease (MSUD); 11 with urea cycle disorders (UCDs); and 13 with classical galactosemia. The evolutionary levels of their specific metabolic markers were evaluated, showing that globally, both pediatric and adult patients maintain a good metabolic control, even during a pandemic (median levels of phenylalanine in pediatric PKU patients 213.4 µmol/L and 482.3 µmol/L in adults; of leucine in MSUD patients: 144.2 µmol/L; of glutamine in UCDs: 726.8 µmol/L; and of galactose 1-phosphate levels in galactosemia: 0.08 µmol/L). The proportion of patients using Odimet® ranges from 78-100%. An increase in the number of diets being calculated was observed during COVID-19 pandemic. Currently, 14,825 products have been introduced (3094 from the general database, and 11,731 added by users to their own profiles). In 2023 63 emergency dietary adjustments in the studied intoxication-type pathologies were calculated in Odimet®. Our results suggest that its regular use contributes to maintaining metabolic stability in IEMs patients, allowing them to adapt their menus to their lifestyle, and represents a powerful complementary tele-health tool which can be used to perform remote real-time dietary follow-up.


Assuntos
COVID-19 , Galactosemias , Doença da Urina de Xarope de Bordo , Erros Inatos do Metabolismo , Fenilcetonúrias , Distúrbios Congênitos do Ciclo da Ureia , Adulto , Humanos , Criança , Pandemias , Dieta
5.
Paediatr Anaesth ; 34(4): 366-370, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38314877

RESUMO

An 11-month-old female infant diagnosed with classic subtype IB maple syrup urine disease underwent living donor liver transplantation. Blood samples for plasma amino acid analysis were collected during the three phases of the operation. Despite the perioperative prophylactic administration of 12.5% hypertonic dextrose solution with insulin and a 20% intralipid emulsion, the blood levels of the branched-chain amino acids increased dramatically during surgery, consistent with an acute intraoperative metabolic decompensation. However, these blood levels normalized soon after liver transplantation with an excellent outcome. We suggest that the occurrence of an intraoperative metabolic crisis during liver transplantation is not necessarily a sign of graft failure.


Assuntos
Transplante de Fígado , Doença da Urina de Xarope de Bordo , Lactente , Criança , Humanos , Feminino , Aminoácidos de Cadeia Ramificada/metabolismo , Doença da Urina de Xarope de Bordo/metabolismo , Doença da Urina de Xarope de Bordo/cirurgia , Doadores Vivos
7.
Mol Genet Metab ; 141(3): 108123, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38219674

RESUMO

OBJECTIVES: Inherited 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. DESIGN: Retrospective 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). METHODS: We collected growth parameters, pubertal status, BMAD, body composition, protein-intake, and IGF1 throughout growth. RESULTS: Overall 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: ß, 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. CONCLUSIONS: In 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.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Doença da Urina de Xarope de Bordo , Recém-Nascido , Humanos , Estudos Longitudinais , Estudos Retrospectivos , Isoleucina , Transtornos do Crescimento , Erros Inatos do Metabolismo dos Aminoácidos/genética , Aminoácidos , Estatura
8.
J Inherit Metab Dis ; 47(1): 41-49, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36880392

RESUMO

Maple syrup urine disease (MSUD) is rare autosomal recessive metabolic disorder caused by the dysfunction of the mitochondrial branched-chain 2-ketoacid dehydrogenase (BCKD) enzyme complex leading to massive accumulation of branched-chain amino acids and 2-keto acids. MSUD management, based on a life-long strict protein restriction with nontoxic amino acids oral supplementation represents an unmet need as it is associated with a poor quality of life, and does not fully protect from acute life-threatening decompensations or long-term neuropsychiatric complications. Orthotopic liver transplantation is a beneficial therapeutic option, which shows that restoration of only a fraction of whole-body BCKD enzyme activity is therapeutic. MSUD is thus an ideal target for gene therapy. We and others have tested AAV gene therapy in mice for two of the three genes involved in MSUD, BCKDHA and DBT. In this study, we developed a similar approach for the third MSUD gene, BCKDHB. We performed the first characterization of a Bckdhb-/- mouse model, which recapitulates the severe human phenotype of MSUD with early-neonatal symptoms leading to death during the first week of life with massive accumulation of MSUD biomarkers. Based on our previous experience in Bckdha-/- mice, we designed a transgene carrying the human BCKDHB gene under the control of a ubiquitous EF1α promoter, encapsidated in an AAV8 capsid. Injection in neonatal Bckdhb-/- mice at 1014 vg/kg achieved long-term rescue of the severe MSUD phenotype of Bckdhb-/- mice. These data further validate the efficacy of gene therapy for MSUD opening perspectives towards clinical translation.


Assuntos
Doença da Urina de Xarope de Bordo , Animais , Humanos , Camundongos , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/química , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Doença da Urina de Xarope de Bordo/genética , Doença da Urina de Xarope de Bordo/terapia , Doença da Urina de Xarope de Bordo/diagnóstico , Fenótipo , Qualidade de Vida
9.
Anaesth Intensive Care ; 52(1): 64-68, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37994838

RESUMO

A 19-year-old woman with known maple syrup urine disease presented to hospital with metabolic crisis in the setting of influenza type A infection and intractable vomiting, rapidly progressing to acute cerebral oedema manifesting as refractory seizures and decreased level of consciousness needing emergency intubation and mechanical ventilation, continuous veno-venous haemodiafiltration and thiopentone coma. A computed tomography scan and magnetic resonance imaging of the brain demonstrated classic signs of cerebral oedema secondary to a metabolic crisis from the metabolic disorder. Her management posed multiple challenges to all teams involved due to lack of familiarity and experience in managing this clinical scenario in the adult intensive care setting.


Assuntos
Edema Encefálico , Doença da Urina de Xarope de Bordo , Feminino , Humanos , Adulto Jovem , Encéfalo , Edema Encefálico/complicações , Edema Encefálico/patologia , Imageamento por Ressonância Magnética , Doença da Urina de Xarope de Bordo/complicações , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/metabolismo , Doenças Raras/complicações , Doenças Raras/patologia
10.
Neurochem Res ; 49(3): 758-770, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38104040

RESUMO

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 (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/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.


Assuntos
Doença da Urina de Xarope de Bordo , Ratos , Animais , Doença da Urina de Xarope de Bordo/tratamento farmacológico , Doença da Urina de Xarope de Bordo/metabolismo , Memantina/farmacologia , Memantina/uso terapêutico , Acetilcolinesterase , Modelos Animais de Doenças , Aminoácidos de Cadeia Ramificada , Antioxidantes/farmacologia , Inflamação
11.
Clin Lab ; 69(12)2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38084699

RESUMO

BACKGROUND: Maple syrup urine disease (MSUD) is a severe life-threatening metabolic disorder. Patients' poor outcomes could be prevented by early diagnosis and regular monitoring, which mainly depend on the analysis of branched amino acids (BCAAs) in plasma. The study aimed to test whether the analysis of BCAAs by ultra-performance liquid chromatography (UPLC) is an alternative to an analysis by ion-exchange chromatography (IEC) for the diagnosis and monitoring of MSUD. METHODS: The two methods analyzed fifty plasma samples obtained from treated and untreated patients with MSUD. Data were analyzed using Passing-Bablok and Bland-Altman methods. RESULTS: The slope of the regression lines was equal or close to one for the three BCAAs, indicating no significant proportional differences between the two methods. A slight positive or negative bias was found for leucine and alloisoleucine, respectively. However, for each amino acid, one or two measurement pairs were out of statistical interval of agreement. Despite small analytical differences, the two methods could be considered in clinical agreement since the differences have no impact on the diagnosis and management of patients. CONCLUSIONS: UPLC and IEC methods are in clinical agreement for plasma BCAAs analysis. The UPLC method could be used simultaneously or interchangeably with the IEC method for diagnosing and monitoring MSUD patients. However, for reasons of practicability, the alternative method should only be used when the usual method cannot be carried out.


Assuntos
Aminoácidos , Doença da Urina de Xarope de Bordo , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/terapia , Isoleucina , Diagnóstico Precoce
12.
Int J Mol Sci ; 24(21)2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37958982

RESUMO

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.


Assuntos
Doença da Urina de Xarope de Bordo , Doenças Metabólicas , Humanos , Doença da Urina de Xarope de Bordo/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Amiloide/genética , Mutação , Proteínas Amiloidogênicas/genética
13.
J Pediatr Endocrinol Metab ; 36(12): 1146-1153, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37795793

RESUMO

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Desnutrição , Doença da Urina de Xarope de Bordo , Síndrome Metabólica , Doenças não Transmissíveis , Terapia Nutricional , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Sobrepeso , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Fatores de Risco , Aminoácidos
14.
Pediatr Transplant ; 27(8): e14603, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37658594

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.


Assuntos
Doença Hepática Terminal , Transplante de Fígado , Doença da Urina de Xarope de Bordo , Acidemia Propiônica , Humanos , Criança , Transplante de Fígado/métodos , Doença da Urina de Xarope de Bordo/cirurgia , Estudos Retrospectivos , Doadores Vivos , Doença Hepática Terminal/cirurgia
15.
Transplant Proc ; 55(8): 1934-1937, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37648577

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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."


Assuntos
Varizes Esofágicas e Gástricas , Transplante de Fígado , Doença da Urina de Xarope de Bordo , Masculino , Adulto , Humanos , Criança , Adolescente , Idoso , Transplante de Fígado/métodos , Doadores Vivos , Hemorragia Gastrointestinal , Doença da Urina de Xarope de Bordo/cirurgia
16.
Clin Chim Acta ; 548: 117483, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37421976

RESUMO

BACKGROUND: Maple syrup urine disease (MSUD) is a rare disease for which newborn screening (NBS) is feasible but not universally applied in China. We shared our experiences with MSUD NBS. METHODS: Tandem mass spectrometry-based NBS for MSUD was implemented in January 2003, and diagnostic methods included urine organic acid analysis via gas chromatography-mass spectrometry and genetic analysis. RESULTS: Six MSUD patients were identified from 1.3 million newborns, yielding an incidence of 1:219,472, in Shanghai, China. The areas under the curve (AUCs) of total leucine (Xle), Xle/phenylalanine ratio, and Xle/alanine ratio were all 1.000. Some amino acid and acylcarnitine concentrations were markedly low in MSUD patients. 47 MSUD patients identified here and in other centers were investigated, which included 14 patients identified by NBS and 33 patients diagnosed clinically. Forty-four patients were subclassified into classic (n = 29), intermediate (n = 11) and intermittent (n = 4) subtypes. Due to earlier diagnosis and treatment, screened classic patients showed a higher survival rate (62.5%, 5/8) than clinically diagnosed classic patients (5.2%, 1/19). Overall, 56.8% (25/44) of MSUD patients and 77.8% (21/27) of classic patients carried variants in the BCKDHB gene. Among 61 identified genetic variants, 16 novel variants were identified. CONCLUSION: MSUD NBS in Shanghai, China, enabled earlier detection and increased survivorship in the screened population.


Assuntos
Doença da Urina de Xarope de Bordo , Humanos , Recém-Nascido , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/genética , Triagem Neonatal/métodos , China , Leucina , Diagnóstico Precoce
17.
J Inherit Metab Dis ; 46(6): 1089-1103, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37494004

RESUMO

Maple syrup urine disease (MSUD) is an inborn error of branched-chain amino acid metabolism affecting several thousand individuals worldwide. MSUD patients have elevated levels of plasma leucine and its metabolic product α-ketoisocaproate (KIC), which can lead to severe neurotoxicity, coma, and death. Patients must maintain a strict diet of protein restriction and medical formula, and periods of noncompliance or illness can lead to acute metabolic decompensation or cumulative neurological impairment. Given the lack of therapeutic options for MSUD patients, we sought to develop an oral enzyme therapy that can degrade leucine within the gastrointestinal tract prior to its systemic absorption and thus enable patients to maintain acceptable plasma leucine levels while broadening their access to natural protein. We identified a highly active leucine decarboxylase enzyme from Planctomycetaceae bacterium and used directed evolution to engineer the enzyme for stability to gastric and intestinal conditions. Following high-throughput screening of over 12 000 enzyme variants over 9 iterative rounds of evolution, we identified a lead variant, LDCv10, which retains activity following simulated gastric or intestinal conditions in vitro. In intermediate MSUD mice or healthy nonhuman primates given a whey protein meal, oral treatment with LDCv10 suppressed the spike in plasma leucine and KIC and reduced the leucine area under the curve in a dose-dependent manner. Reduction in plasma leucine correlated with decreased brain leucine levels following oral LDCv10 treatment. Collectively, these data support further development of LDCv10 as a potential new therapy for MSUD patients.


Assuntos
Doença da Urina de Xarope de Bordo , Humanos , Camundongos , Animais , Leucina , Aminoácidos de Cadeia Ramificada , Proteínas , Terapia Enzimática , Primatas/metabolismo
18.
J Inherit Metab Dis ; 46(5): 906-915, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37395264

RESUMO

Organic acidurias (OAs), urea-cycle disorders (UCDs), and maple syrup urine disease (MSUD) belong to the category of intoxication-type inborn errors of metabolism (IT-IEM). Liver transplantation (LTx) is increasingly utilized in IT-IEM. However, its impact has been mainly focused on clinical outcome measures and rarely on health-related quality of life (HRQoL). Aim of the study was to investigate the impact of LTx on HrQoL in IT-IEMs. This single center prospective study involved 32 patients (15 OA, 11 UCD, 6 MSUD; median age at LTx 3.0 years, range 0.8-26.0). HRQoL was assessed pre/post transplantation by PedsQL-General Module 4.0 and by MetabQoL 1.0, a specifically designed tool for IT-IEM. PedsQL highlighted significant post-LTx improvements in total and physical functioning in both patients' and parents' scores. According to age at transplantation (≤3 vs. >3 years), younger patients showed higher post-LTx scores on Physical (p = 0.03), Social (p < 0.001), and Total (p =0.007) functioning. MetabQoL confirmed significant post-LTx changes in Total and Physical functioning in both patients and parents scores (p ≤ 0.009). Differently from PedsQL, MetabQoL Mental (patients p = 0.013, parents p = 0.03) and Social scores (patients p = 0.02, parents p = 0.012) were significantly higher post-LTx. Significant improvements (p = 0.001-0.04) were also detected both in self- and proxy-reports for almost all MetabQoL subscales. This study shows the importance of assessing the impact of transplantation on HrQoL, a meaningful outcome reflecting patients' wellbeing. LTx is associated with significant improvements of HrQol in both self- and parent-reports. The comparison between PedsQL-GM and MetabQoL highlighted that MetabQoL demonstrated higher sensitivity in the assessment of disease-specific domains than the generic PedsQL tool.


Assuntos
Transplante de Fígado , Doença da Urina de Xarope de Bordo , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Qualidade de Vida , Estudos Prospectivos , Doença da Urina de Xarope de Bordo/cirurgia , Pais
19.
Int J Dev Neurosci ; 83(6): 489-504, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37340513

RESUMO

Maple syrup urine disease (MSUD) is caused by a deficiency in the activity of the branched-chain α-ketoacid dehydrogenase (BCKD) complex, promoting the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their respective α-keto acids. MSUD is an autosomal recessive hereditary metabolic disorder characterized by ketoacidosis, ataxia, coma, and mental and psychomotor retardation. The mechanisms involved in the brain damage caused by MSUD are not fully understood. Early diagnosis and treatment, as well as proper control of metabolic decompensation crises, are crucial for patients' survival and for a better prognosis. The recommended treatment consists of a high-calorie diet with restricted protein intake and specific formulas containing essential amino acids, except those accumulated in MSUD. This treatment will be maintained throughout life, being adjusted according to the patients' nutritional needs and BCAA concentration. Because dietary treatment may not be sufficient to prevent neurological damage in MSUD patients, other therapeutic strategies have been studied, including liver transplantation. With transplantation, it is possible to obtain an increase of about 10% of the normal BCKD in the body, an amount sufficient to maintain amino acid homeostasis and reduce metabolic decompensation crises. However, the experience related to this practice is very limited when considering the shortage of liver for transplantation and the risks related to the surgical procedure and immunosuppression. Thus, the purpose of this review is to survey the benefits, risks, and challenges of liver transplantation in the treatment of MSUD.


Assuntos
Transplante de Fígado , Doença da Urina de Xarope de Bordo , Humanos , Doença da Urina de Xarope de Bordo/metabolismo , Aminoácidos de Cadeia Ramificada , Leucina , Dieta
20.
Ann Transplant ; 28: e939893, 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37248682

RESUMO

BACKGROUND Maple syrup urine disease (MSUD) is a rare genetic deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex that breaks down amino acids, resulting in multi-organ failure. This report is of 5 pediatric cases of domino liver transplantation (DLT) from live donors with MSUD from a single transplant center in Beijing. CASE REPORT All MSUD donors were confirmed to have disease-causing mutations in BCKDHA (branched-chain keto acid dehydrogenase E1, alpha polypeptide) or BCKDHB (branched-chain keto acid dehydrogenase E1, ß polypeptide) genes by peripheral blood whole-exon sequencing. Serum leucine and valine concentrations were significantly higher than normal values. Recipients ranged in age from 0.75 to 9 years old. Three patients underwent auxiliary liver transplantation, and the other children all underwent liver or partial liver transplantation. This case report was followed up for 25 to 79 months. The prognosis, growth, and development of patients were followed up. By the end of the last follow-up, all children had survived. All patients had normal serum leucine and valine concentrations after surgery. In case 1, portal vein stenosis post-operatively. In case 2, stenosis of hepatic artery and bile duct occurred. In case 5, hepatic artery and portal vein stenosis occurred, resulting in graft loss.   CONCLUSIONS The findings from our center support the findings from other pediatric liver transplant centers that liver transplantation using MSUD donors can have successful outcomes without the development of MSUD in the recipient.


Assuntos
Doadores Vivos , Doença da Urina de Xarope de Bordo , Criança , Humanos , Lactente , Pré-Escolar , Doença da Urina de Xarope de Bordo/cirurgia , Doença da Urina de Xarope de Bordo/genética , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Leucina/metabolismo , Constrição Patológica , Valina
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