Natural history of children and adults with maple syrup urine disease in the NBS-MSUD Connect registry.
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ABSTRACT:
SUBMITTER: Kenneson A
PROVIDER: S-EPMC6047058 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
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Natural history of children and adults with maple syrup urine disease in the NBS-MSUD Connect registry.
Kenneson Aileen A Osara Yetsa Y Pringle Theresa T Youngborg Lauren L Singh Rani H RH
Molecular genetics and metabolism reports 20180128
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Project description:Maple syrup urine disease (MSUD) represents an infrequent metabolic disease precipitated by an insufficiency of the enzymatic complex known as branched-chain alpha-keto acid dehydrogenase. MSUD can be classified as classic (severe), intermediate, or intermittent based on the severity of the condition. The disease is associated with mutations in several genes, including BCKDHA, BCKDHB, DBT, and DLD. This study aimed to investigate the genetic landscape of MSUD in Iranian patients and explore the clinical implications of identified gene variants. A comprehensive analysis was conducted using various molecular techniques and bioinformatics tools to predict protein stability, pathogenicity, amino acid conservation, and secondary/tertiary structure. The in silico analysis highlighted high-risk pathogenic variants and provided insights into their potential impact on protein structure and function. Furthermore, the predicted 3D structures of wild-type and mutant proteins elucidated structural differences. Protein-protein interaction analysis shed light on the network of interactions involving MSUD-related proteins. The Iranome database uncovered a potential pathogenic variant (c.554C>T) in the Persian population. This research contributes to a better understanding of MSUD genetics in the Iranian population and outlines potential avenues for further clinical investigations. The findings have implications for genetic testing, prognosis, and genetic counseling in affected families.
| S-EPMC11416852 | biostudies-literature
Project description:Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterised by deficient activity of the branched-chain alpha-ketoacid dehydrogenase complex, required to metabolise the amino acids leucine, isoleucine and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been elucidated. Here we performed a comprehensive epigenomic analysis including fibroblasts derived from a cohort of MSUD patients (9) and unaffected controls (5) using the Infinium HumanMethylation EPIC platform.
2024-12-31 | E-MTAB-13822 | biostudies-arrayexpress
Project description:Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder. This disorder is usually caused by mutations in any one of the genes; BCKDHA, BCKDHB and DBT, which represent E1?, E1? and E2 subunits of the branched-chain ?-keto acid dehydrogenase (BCKDH) complex, respectively. This study presents the molecular characterization of 31 MSUD patients. Twenty one mutations including 14 new mutations were identified. The BCKDHB gene was the most commonly affected (45.2%) compared to BCKDHA gene (16.1%) and DBT gene (38.7%). In silico webservers predicted all mutations were disease-causing. In addition, structural evaluation disclosed that all new missenses in BCKDHA, BCKDHB and DBT genes affected stability and formation of E1 and E2 subunits. Majority of the patients had neonatal onset MSUD (26 of 31). Meanwhile, the new mutation; c.1196C?>?G (p.S399C) in DBT gene was noted to be recurrent and found in 9 patients. Conclusion: Our findings have expanded the mutational spectrum of the MSUD and revealed the genetic heterogeneity among Malaysian MSUD patients. We also discovered the p.S399C from DBT gene was noted as a recurrent mutation in Malay community and it suggested the existence of common and unique mutation in Malay population.
| S-EPMC6140420 | biostudies-literature
Project description:A metabolic disorder is due to a gene mutation that causes an enzyme deficiency which leads to metabolism problems. Maple Syrup Urine Disease (MSUD) is one of the most common and severe hereditary metabolic disorders in Saudi Arabia. Patients and families were burdened by complex and regular dietary therapy menus because of the lack of information on food labels, it was also difficult to keep track of MSUD's typical diet. The prototype smart plate system proposed in this work may help patients with MSUD and their caregivers better manage the patients' MSUD diet. The use of knowledge-based, food identification techniques and a device could provide a support tool for self-nutrition management in pediatric patients. The requirements of the system are specified by using questionaries. The design of the prototype is divided into two parts: software (mobile application) and hardware (3D model of the plate). The knowledge-based mobile application contains knowledge, databases, inference, food recognition, food plan, monitor food plan, and user interfaces. The hardware prototype is represented in a 3D model. All the patients agreed that a smart plate system connected to a mobile application could help to track and record their daily diet. A self-management application can help MSUD patients manage their diet in a way that is more pleasant, effortless, accurate, and intelligent than was previously possible with paper records. This could support dietetic professional practitioners and their patients to achieve sustainable results.
| S-EPMC9859191 | biostudies-literature
Project description:Maple Syrup Urine Disease (MSUD) is a genetically heterogeneous metabolic disorder that is transmitted in an autosomal recessive manner. According to clinical data, MSUD prevalence in Lebanon is expected to be higher than the International prevalence because of consanguineous marriage. Novel mutations are still getting detected by using DNA sequencing for mutation analysis in MSUD patients. In the current study, we have extracted DNA from Lebanese MSUD patients in order to amplify the exonic and flanking intronic regions of the genes implicated in MSUD (BCKDHA, BCKDHB, and DBT) and sequenced the resultant amplified products to assess the molecular genetics of MSUD in the Lebanese population studied. All of the mutations identified occurred in the homozygous state, which reflects the high rate of consanguineous marriage in Lebanon. In the current study, we have identified one previously cited mutation and three novel mutations not previously described in the scientific literature. The identified mutations were distributed as follows: three patients (60%) had two nucleotide substitutions in the DBT gene (c.224G>A and c.1430T>G), one patient (20%) had a gross deletion in the BCKDHA gene (c.488_1167+3del), and one patient (20%) had a small deletion in the BCKDHB gene (c.92_102del). The majority of the mutations identified in the Lebanese MSUD patients occurred in the DBT gene. Consanguineous marriage is a major risk factor for the prevalence of MSUD in Lebanon.
| S-EPMC5121290 | biostudies-literature
Project description:Untreated maple syrup urine disease (MSUD) results in mental and physical disabilities and often leads to neonatal death. Newborn-screening programs, coupled with the use of protein-modified diets, have minimized the severity of this phenotype and allowed affected individuals to develop into productive adults. Although inheritance of MSUD adheres to rules for single-gene traits, mutations in the genes for E1alpha, E1beta, or E2 of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex can cause the disease. Randomly selected cell lines from 63 individuals with clinically diagnosed MSUD were tested by retroviral complementation of branched-chain alpha-ketoacid dehydrogenase activity to identify the gene locus for mutant alleles. The frequencies of the mutations were 33% for the E1alpha gene, 38% for the E1beta gene, and 19% for the E2 gene. Ten percent of the tested cell lines gave ambiguous results by showing no complementation or restoration of activity with two gene products. These results provide a means to establish a genotype/phenotype relationship in MSUD, with the ultimate goal of unraveling the complexity of this single-gene trait. This represents the largest study to date providing information on the genotype for MSUD.
| S-EPMC1234918 | biostudies-literature
Project description:Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate in urea cycle disorder patients has been associated with a selective reduction in branched-chain amino acids (BCAA) in spite of adequate dietary protein intake. Based on this clinical observation, we investigated the potential of phenylbutyrate treatment to lower BCAA and their corresponding ?-keto acids (BCKA) in patients with classic and variant late-onset forms of maple syrup urine disease (MSUD). We also performed in vitro and in vivo experiments to elucidate the mechanism for this effect. We found that BCAA and BCKA are both significantly reduced following phenylbutyrate therapy in control subjects and in patients with late-onset, intermediate MSUD. In vitro treatment with phenylbutyrate of control fibroblasts and lymphoblasts resulted in an increase in the residual enzyme activity, while treatment of MSUD cells resulted in the variable response which did not simply predict the biochemical response in the patients. In vivo phenylbutyrate increases the proportion of active hepatic enzyme and unphosphorylated form over the inactive phosphorylated form of the E1? subunit of the branched-chain ?-keto acid dehydrogenase complex (BCKDC). Using recombinant enzymes, we show that phenylbutyrate prevents phosphorylation of E1? by inhibition of the BCKDC kinase to activate BCKDC overall activity, providing a molecular explanation for the effect of phenylbutyrate in a subset of MSUD patients. Phenylbutyrate treatment may be a valuable treatment for reducing the plasma levels of neurotoxic BCAA and their corresponding BCKA in a subset of MSUD patients and studies of its long-term efficacy are indicated.
| S-EPMC3024040 | biostudies-literature
Project description:Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain ?-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, ?-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients.
| S-EPMC5593394 | biostudies-literature
Project description:Maple Syrup Urine Disease (MSUD, OMIM# 248600) is an autosomal recessive inborn error of metabolism characterized by elevated branched chain amino acids (BCAA) leucine/isoleucine and valine in blood of affected children. The phenotypic and genotypic spectrum of MSUD is largely unreported in Egypt. We recruited ten patients (4 males/6 females, 2weeks-12years) from nine unrelated families with clinical and biochemical evidence of MSUD. We performed Sanger sequencing for the three most-commonly responsible genes: BCKDHA, BCKDHB and DBT and conducted exome sequencing for unresolved cases. Through Sanger sequencing, we detected eight homozygous pathogenic/likely pathogenic variants (four in BCKDHB, three in BCKDHA and one in DBT gene) in eight different families. The proband of family VI, who had no significant genetic findings by Sanger, had a peculiar phenotype and atypical radiological findings. His exome sequencing revealed a previously reported homozygous likely pathogenic variant in the RARS2 gene (NM_020320.5:c.1026G > A;p.(Met342Ile)) causing the mitochondrial-encephalopathy disorder pontocerebellar hypoplasia, type 6 (OMIM# 611523). Furthermore, the copy-number-variant analysis of the exome data revealed a biallelic duplication affecting exons 2-6 of the BCKDHB gene (GRCh38: Chr.6-g.80127496:80171441dup) evaluated as variant of uncertain significance but expected to cause a breakpoint and may disrupt gene function, which can explain the markedly elevated BCAA levels in the patient's blood. In conclusion, we expanded the genotypic and phenotypic spectrum of the disease and showed that aggressive intervention with specific treatment in the first few days of life resulted in normal development even in a developing country setting. Inclusion of MSUD in the national newborn screening program in Egypt is highly recommended.
| S-EPMC11570613 | biostudies-literature
Project description:BackgroundMaple syrup urine disease (MSUD) is an inherited disorder clinically characterized by ketoacidosis, seizures, coma, psychomotor delay, and intellectual disability. The treatment requires a life-long protein-restricted diet, rich in carbohydrates and fats, supplemented with a medical amino acid formula. Diet, oral health and general health influence each other in a vicious cycle. The aim of this study was to investigate the oral health status of children and young adults with MSUD in Turkey.MethodsA descriptive study was conducted on patients with MSUD who applied for routine follow-up to the pediatric metabolic diseases clinic at Hacettepe University, Children's Hospital in Ankara, Turkey in a 12-month period. Patients with any other concomitant genetic diseases and acute infection were excluded. A total of twenty-five patients were enrolled and underwent oral examination including DMFT/S, dmft/s (decayed/missing/filled teeth/surfaces for deciduous and primary teeth, respectively), plaque and gingival indices. Panoramic radiographs were obtained in 12 cooperative patients.ResultsMean age was 9.88 ± 5.68 s.d years. More than half of the parents had only primary school level education, and low income. Fourteen patients consumed medical formula during or right before sleep. Fourteen patients reported caries-associated pain. Gingival inflammation was present in all 15 patients who cooperated for evaluation. Seven out of twelve patients had at least one dental anomaly or alterations in mandibular morphology. Five patients had previously been treated for caries under general anesthesia. To our knowledge, this is the first study to document oral clinical and radiologic findings in patients with MSUD.ConclusionsImpaired oral health was observed in this rare disease population. Regular dental referral by physicians, preventive measures and dental treatments should be included in multidisciplinary management of maple syrup urine disease to promote oral health.
| S-EPMC7789418 | biostudies-literature