Classical Maple Syrup Urine Disease Research Articles

Lipid nanoparticle mRNA therapy improves survival and reduces serum branched-chain amino acids in mouse models of maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare, inherited, metabolic disorder characterized by dysfunction of the multi-subunit, mitochondrial enzyme complex branched-chain alpha-keto acid dehydrogenase (BCKDH). BCKDH catalyzes the oxidative decarboxylation of branched-chain amino acids (BCAAs). BCAAs and their neurotoxic alpha-keto intermediates can accumulate in the blood and tissues in the absence of functional BCKDH. We evaluated a lipid nanoparticle (LNP)-based treatment approach to address all possible genetic mutations that can cause MSUD (BCKDHA, BCKDHB, and DBT). In the intermediate MSUD mouse model, which harbors a mutation in the dihydrolipoamide branched-chain transacylase E2 (DBT) subunit of BCKDH, repeated administration of LNP-encapsulated mRNA therapy significantly extended survival and reduced serum leucine levels. We also evaluated our LNP approach in several models of classic MSUD, namely DBT knockout (KO) mice and the new BCKDHA KO and BCKDHB KO mice. The latter two were generated by CRISPR/Cas9 gene editing and contain the highly prevalent classic MSUD-causing mutations seen in the Mennonite and Costa Rican populations. Intravenous LNP-encapsulated mRNA administration extended survival and increased body weight in the DBT KO and BCKDHA KO models of classic MSUD but was not effective in BCKDHB KO mice. Our data provide a promising proof-of-concept that a universal, mutation-independent approach to treating MSUD is possible and viable.

Treatment Outcomes for Maple Syrup Urine Disease Detected by Newborn Screening.

Maple syrup urine disease (MSUD), a life-threatening metabolic disorder, is included in newborn screening (NBS) programs worldwide. The study aims to evaluate the impact of NBS on the long-term outcome of MSUD patients. We performed a prospective, national, multicenter, observational study. In the studied NBS cohort (N = 33; 22 classic MSUD [cMSUD], 11 variant MSUD [vMSUD]; median age at last visit 10.4 years), 32 (97%) patients survived, 58% of them had normal cognitive functions (median IQ 87). Initial peak leucine increased linearly with age in cMSUD (median: 1712 µmol/L), but not in vMSUD. Global IQ correlated inversely with the initial peak leucine concentration (P = .04; β = -0.0081) and the frequency of decompensations (P = .02; β = -9.133). A cluster analysis identified 2 subgroups differing in their long-term metabolic control (median leucine concentration: 162 vs 278 µmol/L; P < .001). In cMSUD, lower leucine concentrations were associated with a higher IQ (95.5 vs 80; P = .008). Liver transplantation (median age 5.8 years) was not associated with better cognitive outcome. NBS is highly sensitive for cMSUD, but vMSUD might be missed (N = 2 missed by NBS). NBS and the early start of treatment improve survival and long-term outcome in individuals with cMSUD. Disease severity is an important modifier of outcome; however, the time to NBS report and the quality of long-term metabolic control had an independent impact on cognitive outcome, highlighting the importance of an early diagnosis and the quality of treatment.

A Case of Maple Syrup Urine Disease Diagnosed in Adulthood

Classic maple syrup urine disease (MSUD) is typically diagnosed in newborns, whereas nonclassic forms may manifest at any age. We describe a 58-year-old man presenting with recurrent encephalopathy, found with a nonclassic form of MSUD. This patient case highlights the importance of considering inborn errors of metabolism in the differential diagnosis of adult patients presenting with neurologic symptoms of unclear cause.

A novel mutation in the DBT gene causes in an Azerbaijanian child classic maple syrup urine disease

A novel mutation in the DBT gene causes in an Azerbaijanian child classic maple syrup urine disease

EEG Pattern in Neonatal Maple Syrup Urine Disease: Description and Clinical Significance

ABSTRACT Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder characterized by deficiency of branched-chain keto acid dehydrogenase complex, which is required to metabolize the three branched chain amino acids (BCAAs), leucine, isoleucine and valine. This metabolic dysfunction results in progressive encephalopathy manifesting with lethargy, vomiting, posturing and abnormal movements during the neonatal period in the classic form of the disease. If untreated, progressive brain damage causes coma, seizures and death usually within a few weeks. EEG is an essential investigation in a neonate with progressive encephalopathy and seizures. EEG abnormalities in neonatal encephalopathies due to inborn error of metabolism (IEM) are widely variable depending on the severity. Central comb-like rhythm is an EEG marker of neonatal MSUD in appropriate clinical context. This pattern should not be mistaken for epileptic abnormalities, sleep spindles or other similar nonspecific activities. We describe a patient with classic MSUD who presented with an EEG pattern of comb-like rhythm. Background abnormalities and epileptic discharges are common along comb-like rhythm in MSUD patients. EEG technologists and interpreters should be able to identify this pattern to support the early diagnosis and treatment of MSUD.

Classical Maple Syrup Urine Disease successfully treated with living donor liver transplantation

Classical Maple Syrup Urine Disease successfully treated with living donor liver transplantation

Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes

Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.

Liver transplantation from a live donor to a patient with maple syrup urine disease: Two case reports

Liver transplantation were reported in patients with classic maple syrup urine disease in the literature. Branched chain alpha keto acid dehydrogenase activity can be improved in patients after transplant, and a protein-restricted diet is usually not needed. The first patient was a boy aged 2,5 years who presented with frequent ketosis attacks and epileptic seizures, and the second patient was an 11-month-old boy who also presented with frequent ketosis episodes, both despite adherence to diet therapy. Both patients received liver transplantations from live donors. A low protein diet was no longer required and no decline in cognitive functions was observed in either patient in the follow-up. We wanted to present these cases to show that despite a normal diet, plasma levels of branched- chain amino acids remained normal without any decline in cognitive function after liver transplantation in patients with classic maple syrup urine disease patients.

When Newborn Screens Fail, Maple Syrup Urine Disease in a Toddler

Introduction: Maple Syrup Urine Disease (MSUD) is a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) which is one of the enzymes responsible for breaking down the amino acids leucine, isoleucine, and valine. This disease is included in all newborn screens in Mississippi and most other states. If the disease is allowed to follow its natural progression it will result in psychomotor delay, feeding problems, and the maple syrup odor of the urine that gives the disease its name. Classic MSUD usually presents with symptoms during the first few days of …

A Classic Case of Maple Syrup Urine Disease and a Novel Mutation in the BCKDHA Gene

Background: Maple syrup urine disease (MSUD) is an inherited branched-chain amino acid metabolic disorder caused by the deficiency in the branched-chain alpha-keto acid dehydrogenase (BCKD) complex. In MSUD, elevation of the branched-chain amino acids, such as alpha-keto acid and alpha-hydroxy acid, occurs due to the BCKDC gene deficiency, appearing in the blood, urine, and cerebrospinal fluid, which leads to neurological damage and mental retardation. MSUD phenotypically penetrates due to the mutations in the coding genes of four subunits of the BCKD complex, including the BCKDHA, BCKDHB, DBT, and DLD genes.Case report: We aimed to report the cases of three families whose children were affected by MSUD and presented with symptomatic features during the first week of birth, which were identified by mass spectrometry. DNA study was performed as a diagnosis panel containing four encoded BCKDC subunit genes.Conclusion: In the current study, DNA analysis and phenotypic manifestations indicated a novel mutation of c.143delT, p.L48Rfs*15 in the BCKDHA gene in a homozygous state, which is a causative mutation for the classic MSUD phenotype. Early diagnosis and neonatal screening are recommended for the accurate and effective treatment of this disease

P 149 - Roles of branched-chain amino acids regulation in oxidative stress revealed by fibroblasts from classic Maple Syrup Urine Disease patients

Branched-chain amino acids (BCAAs) are essential amino acids commonly used in clinical procedures to improve patients outcome.However, their roles and cellular mechanisms are not clear.One effect of BCAAs supplementation is reduction of oxidative stress. BCAAs levels are regulated by their catabolism and the rate limiting enzyme is branched chain a-ketoacid dehydrogenase (BCKDH).Blockage in BCKDH activity leads to classic Maple Syrup Urine Disease (MSUD).To study the roles of BCAAs, we used cells with a single gene defect in BCKDH as a cellular model.We studied fibroblasts from four unrelated patients with null mutations in BCKDH and from controls.Fibroblasts from patients showed 2-fold increase in mitochondrial superoxide levels and 1.5-fold increase in protein carbonylation levels respect to controls.No changes in SOD2 protein levels were detected, indicating an increase production of mitochondrial superoxide and not an increase detoxification.Eleven proteins related to oxidative stress were differentially regulated in MSUD (p-value 0.05).Including up-regulated peroxiredoxin-4(PRDX4) and protein disulphide-isomerase(P4HB), as well as down-regulated prostaglandin G/H synthase 1 (PTGS1), also known as cyclooxygenase-1.These results correlate specific proteins to known effects of BCAAs in oxidative stress and shed light in the pharmacological mechanisms of BCAAs supplementation.

The Relationship between Dietary Intake, Growth, and Body Composition in Inborn Errors of Intermediary Protein Metabolism

To examine relationships between dietary intake, growth and body composition patterns in patients with inborn errors of intermediary protein metabolism and to determine a safe protein:energy ratio (P:E ratio) associated with optimal growth outcomes. Retrospective longitudinal data of growth and dietary intake in patients (n = 75) with isovaleric acidemia (IVA; n = 7), methylmalonic acidemia/propionic acidemia (MMA/PA; n = 14), urea cycle defects (UCD; n = 44), classical maple syrup urine disease (MSUD; n = 10) were collected. Prospective longitudinal data of growth, dietary intake, and body composition from 21 patients: IVA (n = 5), MMA/PA (n = 6), UCD (n = 7), and MSUD (n = 3) were collected at clinic visits. Fifty-two of 75 (66%), 49 of 74 (68%), and 44 of 65 (68%) patients had a z-score of 0 (±1) for lifetime weight, height, and body mass index, respectively. Patients with MMA/PA had the lowest median height and weight z-scores, and MSUD patients had highest median body mass index z-score at all ages. In IVA, MMA/PA, and UCD, total natural protein intake met or exceeded the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO)/United Nations University (UNU) recommended safe levels. Median percentage fat mass was 17.6% in IVA, 20.7% in MMA/PA, 19.4% in UCD, and 17.8% in MSUD. There was a significant negative correlation between percentage fat mass and total protein intake in IVA, MMA/PA, and UCD (r = -0.737; P = .010). The correlation between the P:E ratio and growth variables in IVA, MMA/PA, and UCD suggest a safe P:E ratio (>1.5 to < 2.9) g protein:100 kcal/day. Growth outcomes in inborn errors of intermediary protein metabolism are not always ideal. Most patients with IVA, MMA/PA, and UCD consume sufficient natural protein to meet FAO/WHO/UNU recommendations. A P:E ratio range of (>1.5 to < 2.9)g protein/100 kcal/day correlates with optimal growth outcomes.

Neurocognitive profiles in MSUD school‐age patients

Maple syrup urine disease (MSUD), an inborn error of amino acids catabolism is characterized by accumulation of branched chain amino acids (BCAAs) leucine, isoleucine, valine and their corresponding alpha-ketoacids. Impact on the cognitive development has been reported historically, with developmental delays of varying degree. Currently, earlier diagnosis and improved management allow a better neurodevelopment, without requirement of special education. However, specific impairments can be observed, and so far, results of detailed neurocognitive assessments are not available. The aim of this study was to analyse neurocognitive profiles of French MSUD patients. This was a multicentre retrospective study on MSUD patients who underwent neurocognitive evaluation at primary school age. Twenty-one patients with classical neonatal onset MSUD were included. The patients' mean age at the time of evaluation was 8.7years. The mean intellectual quotient (IQ) score was in the normal range (95.1 ± 12.6). In a subset of eight patients, a consistent developmental pattern of higher verbal than performance IQ was observed (mean of the difference 25.7 ± 8.7, p < 0.0001). No correlation could be established between this pattern and long-term metabolic balance (BCAA blood levels), or severity of acute metabolic imbalances, or leucine blood levels at diagnosis and time to toxin removal procedure. These data show that some MSUD patients may exhibit an abnormal neurocognitive profile with higher verbal than performance abilities. This might suggest an executive dysfunction disorder that would need to be further investigated by specialized testing. This pattern is important to detect in MSUD, as appropriate neuropsychological treatment strategies should be proposed.

A Novel Mutation in the BCKDHB Gene Causes in an Iranian Child Classic Maple Syrup Urine Disease

Background: Maple syrup urine disease (MSUD) is a rare metabolic disorder caused by deficiency in branched chain alpha-keto acid dehydrogenase complex (BCKD). Methods: In this study, the coding regions and flanking splice sites of the BCKDHA, BCKDHB, DBT and DLD genes have been sequenced in an Iranian 3 years old girl. Results: A novel homozygous mutation (p.Glu330Lys) was detected in the BCKDHB gene. In silico analysis showed significant change in the 3-D protein Structure. Conclusions: This alteration probably affects the structure and function of the E1β subunit of BCKD complex.

Clinical, biochemical and genetic features of 13 children with maple syrup urine disease

Objective To explore the clinical, treatment, and genetic findings of maple syrup urine disease (MSUD). Methods Six boys and 7 girls out of 13 patients from unrelated Chinese families were enrolled.MSUD was detected in one patient by newborn screening.Twelve patients had the onset from the age of 2 days to 1 year and 6 months.They presented vomiting, feeding difficulties, lethargy, coma and psychomotor retardation.Blood amino acids were analyzed, and gene analysis was performed. Results The patients were hospitalized, age ranging from 16 days to 1 year and 8 months.Among them, 11 cases were of classical type and had very early onset.Only 1 patient with interme-diate type had relatively late onset.The girl detected by newborn screening was treated at the age of 9 days.She was healthy now with unknown MSUD type.Eleven classical MSUD children were diagnosed because of significantly elevated blood branched chain aminoacids (leucine, isoleucine, valine and alloisoleucine). Fourteen mutations were found from 10 patients who accepted gene analysis, including 7 mutations in BCKDHA gene (c.178G>T, c. 491T>C, c. 659C>T, c. 740A>G, c. 1214_1219dupCCAACC, c.1234G>A and IVS6+ 1delG0), 5 mutations in BCKDHB gene (c.482T>G, c. 508C>T, c. 767A>G, c. 768C>G and IVS4, -2A>C), 2 mutations in DBT gene (c.1A>G and c. 1150A>G). Two patients had normal development.One patient died from respiratory failure at the age of 4 years and 6 months. Conclusions MSUD is a rare life-threatening disorder which leads to metabolic crisis and brain damage with high mortality.Neonatal screening, early diagnosis and dietary treatment are crucial to improve the outcome. Key words: Maple syrup urine disease; Branched chain amino acid; BCKDHA gene; BCKDHB gene; DBT gene

Identification of a novel BCKDHA deletion causing maple syrup urine disease

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of the catabolism of branched-chain amino acids. The disorder can be caused by mutations within any of the BCKDHA, BCKDHB, DBT and DLD genes encoding the branched-chain alpha-ketoacid dehydrogenase complex. The aim of the study was to identify the molecular genetic cause of classic MSUD in a male neonate reported by newborn screening on the fourth day of life. The genetic analyses involved polymerase chain reaction (PCR) and sequencing of the BCKDHA, BCKDHB, and DBT genes. The results showed that the patient was homozygous for a novel 3021 bp deletion within the BCKDHA gene including exon 4 (NG_013004.1:g.13869_16889del) of this gene. The lack of exon 4 causes a reading frame shift and a premature termination codon in BCKDHA exon 5 (NP_000700.1:p.Gly126ValfsTer3). This strongly suggests that the novel BCKDHA deletion is pathogenic and is the cause of classic MSUD in this patient.

Skin Lesions Associated with Dietary Management of Maple Syrup Urine Disease: a Case Report

Abstract Leucinosis (maple syrup urine disease - MSUD) is an inherited aminoacidopathy and organic aciduria caused by severe enzyme defect in the metabolic pathway of amino acids: leucine, isoleucine, and valine. The classical variant of the disease is characterized by accumulation of both amino and α-keto acids, particulary the most toxic rapid elevation of circulating leucine and its ketoacid, α-ketoisocaproate, which cause encephalopathy and life-threatening brain swelling. However, patients with the most severe form, classical maple syrup urine disease, may appear normal at birth, but develop acute metabolic decompensation within the first weeks of life with typical symptoms: poor feeding, vomiting, poor weight gain, somnolence and burnt sugar-smelling urine, reminiscent of maple syrup. Early diagnosis and dietary intervention improve the patient’s condition, prevent severe complications, and may allow normal intellectual development. We present a 4-month old infant with leucinosis dignosed 3 months earlier, due to elevated levels of amino acids: leucine, isoleucine and valine. The patient was full-term neonate with an uncomplecated delivery, without any family history of metabolic disorder or consanguinity. The infant was referred to a dermatologist, because of maculopapular exanthema on the scalp, trunk, upper and lower extremities, and exfoliative dermatitis of the perioral, particularly anogenital regions, associated with diarrhea. Skin involvement was associated with poor general condition of the infant exhibiting severe hypotension, anemic syndrome, dyspepsia and neurological symptoms. Exanthema developed a few days after the initiation of nutritional therapy for MSUD: isoleucine-, leucine-, and valine-free powdered medical food (MSUD-2) supplemented with iron. Zink levels were within normal ranges. Rapid skin improvement occurred after adequate branched-chain amino acids supplementation was commenced under regular laboratory control (normal zinc serum level with deficiencies of leucine and valine), skin hygiene with antiseptics, emollients and low potent topical corticosteroids. Treatment of acute metabolic decompensation and dietary restriction of branched-chain amino acids are the main aspects in the management of maple syrup urine disease. Common findings in patients with MSUD include: plasma amino acid imbalance, particularly of essential amino acids, failure to thrive attributed to restriction of particular precursor amino acids and natural proteins, micronutrient deficiencies or higher energy requirement due to chronic illness or inflammation. Due to low intake of branched-chain amino acids, some patients develop skin lesions known as acrodermatitis enteropathica-like syndrome. Here we report a case of an infant who developed acrodermatitis enteropathica-like skin eruptions due to branched-chain amino acid deficiency during treatment of maple syrup urine disease. According to available world literature, this is the first report of acrodermatitis enteropathica-like syndrome in an infant with maple syrup urine disease (leucinosis) in the Republic of Bulgaria.

Evolution of maple syrup urine disease in patients diagnosed by newborn screening versus late diagnosis.

Maple syrup urine disease (MSUD) is a rare metabolic disorder for which the newborn screening (NBS) is possible but it has not been yet implemented for most Spanish regions. In the present study, we assess the clinical features and outcome of 14 MSUD Spanish patients with similar treatment protocol diagnosed either by NBS or by clinical symptoms. Eight patients were detected by NBS, four classic and four moderate MSUD. The average age at detection was 4.6 days, the mean plasmatic concentration of leucine at diagnosis was 1807μM; the average number of days with leucine >1000μM was 0.7 (0-4) and the mean number of total hospitalizations was 1.6 (0-5). Mean follow-up time was 70 months. They had good evolution: all remain asymptomatic, but 2 patients have attention deficit and hyperactivity disorder. Six patients with late diagnosis of classic MSUD were followed during 41 months. All presented with acute encephalopathy during the first month of life, mean leucine levels of 2355μM, mean number of days with leucine >1000μM of 6.6 (1-13) and mean number of total hospitalizations of 5.3 (4-7). Only two patients have a psychomotor development index in the lower limit (80 and 83). For all patients a good genotype-phenotype correlation was found and four novel mutations were identified: p.A311H, p.T84S, p.T397L, pL398P. Our study support that NBS improves prognosis of MSUD patients. But early diagnosis and an aggressive treatment together with a close monitoring of leucine levels improveneurological evolution in MSUD patients, even for those not detected by NBS.

GENETIC AND METABOLIC URGENCIES IN THE NEONATAL INTENSIVE CARE UNIT: MAPLE SYRUP URINE DISEASE

Maple syrup urine disease (MSUD) is a hereditary disorder of branched chain amino/keto acid metabolism, caused by a decreased activity of the branched-chain alpha- ketoacid dehydrogenase complex (BCKAD), which leads to abnormal elevated plasma concentrations of branched-chain amino acids (BCAAs) clinically manifested as a heavy burden for Central Nervous system. The toxic accumulation of substrates promotes the development of a severe and rapidly progressive neonatal encephalopathy if treatment is not immediately given. This disorder has a specific medical management in acute phase in order to minimize mortality and morbidity. For all those reasons, it is important to include the MSUD as a possible diagnosis in a encephalopathic newborn. We present a colombian newborn with classical MSUD with fatal outcome as an example of metabolic emergency and a differential diagnosis in the encephalopathic newborn.

Diffusion-weighted magnetic resonance imaging in a case of severe classic maple syrup urine disease

Article Diffusion-weighted magnetic resonance imaging in a case of severe classic maple syrup urine disease was published on July 1, 2015 in the journal Journal of Pediatric Endocrinology and Metabolism (volume 28, issue 7-8).