RARE DISEASE
Maple syrup urine disease
Maple syrup urine disease
Maple syrup urine disease
Synonyms: BCKD deficiency, BCKDH deficiency, Branched-chain 2-ketoacid dehydrogenase deficiency, Branched-chain ketoaciduria, MSUD
Synonyms: BCKD deficiency, BCKDH deficiency, Branched-chain 2-ketoacid dehydrogenase deficiency, Branched-chain ketoaciduria, MSUD
Synonyms: BCKD deficiency, BCKDH deficiency, Branched-chain 2-ketoacid dehydrogenase deficiency, Branched-chain ketoaciduria, MSUD
Drug discovery
5
drugs
With orphan designations
Overview
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder caused by deficient activity of the branched-chain α-ketoacid dehydrogenase complex, leading to toxic accumulation of leucine, isoleucine, and valine. Classic neonatal presentation includes encephalopathy, feeding difficulties, and a distinctive maple syrup odor in bodily fluids. Early diagnosis via newborn screening and prompt dietary intervention are critical to prevent irreversible neurological damage or death. Lifelong management involves a protein-restricted diet, metabolic monitoring, and emergency protocols for decompensation. Liver transplantation remains a curative option but carries surgical risks [1][2][5].
Burden
Clinical: Risk of neurodevelopmental delays, psychiatric comorbidities, and acute metabolic crises triggered by catabolic stressors (e.g., infections) [6][9][17].
Management: Strict dietary adherence, frequent hospitalizations, and specialized care impose significant psychosocial and economic strain [6][16].
Mortality: Untreated cases are fatal within weeks; treated individuals face lifelong disability risks [1][5][16].
Therapies
Dietary management: Protein restriction with synthetic formulas lacking branched-chain amino acids (BCAAs) [1][5][16].
Monitoring: Regular blood leucine, isoleucine, and valine quantification [1][16].
Transplantation: Liver transplant resolves metabolic defects but requires lifelong immunosuppression [3][9][14].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
456 drug discovery papers about Maple syrup urine disease, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
456 drug discovery papers about Maple syrup urine disease, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-22 | Treatment strategies, radiological recovery, and neurodevelopmental outcomes in paediatric Maple Syrup Urine Disease: a 20-year single-centre experience from Türkiye.
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive metabolic disorder characterised by defective branched-chain amino acid (BCAA) catabolism, leading to neurotoxicity, recurrent metabolic crises, and neurodevelopmental impairment. Evidence on long-term outcomes in paediatric cohorts, particularly with pharmacological adjuncts such as sodium phenylbutyrate (NaPBA) and radiological recovery, remains limited. We undertook a retrospective review of 13 paediatric patients with MSUD (69.2% classic phenotype, 30.8% intermittent) followed at a tertiary metabolic centre in Türkiye between 2003 and 2022. Demographic, biochemical, neurodevelopmental, neuroimaging, and genetic data were evaluated, with specific attention to dietary management, haemodialysis during acute decompensation, and NaPBA therapy. All patients exhibited neurodevelopmental delay, which was more pronounced in the classic phenotype. Milestone-level analysis demonstrated delays in walking (85%), sentence formation (92.3%), and toilet training (92.3%). One year after dietary intervention, mean plasma concentrations of leucine, isoleucine, and valine decreased by 60.9%, 55.9%, and 65.0%, respectively (p < 0.01). Haemodialysis during metabolic crises rapidly reduced leucine (- 73.8%) and ammonia (- 66%), though was more frequently required in patients with the classic phenotype. NaPBA treatment was associated with lower leucine levels during follow-up (p < 0.05). Baseline MRI abnormalities were identified in 87% of patients; 57% showed complete resolution post-treatment, with partial radiological improvement observed alongside clinical follow-up. A phenotype-specific approach combining early dietary intervention, timely haemodialysis in acute crises, and selective use of NaPBA may support metabolic stabilisation and radiological improvement in selected patients. Larger multicentre studies are warranted to validate these findings and refine management protocols.
2026-06-07 | Management of acute metabolic decompensation in maple syrup urine disease: guidance based on international clinical practice.
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by a deficiency of branched-chain ketoacid dehydrogenase, the enzyme involved in the second step of branched-chain amino acid catabolism. Of the three branched-chain amino acids (leucine, valine, and isoleucine), accumulation of leucine is the predominant factor causing acute metabolic decompensation in patients with MSUD. In February 2025, eight expert physicians met to discuss the management of acute metabolic decompensation and propose recommendations after literature review (four guidelines and 20 other articles of interest). A practical clinical algorithm was established. Newborn screening was acknowledged to be a successful method of diagnosing MSUD at birth, facilitating early intervention to prospectively manage MSUD and reduce the frequency and severity of acute metabolic decompensation, although it was noted that infants with severe MSUD often present with acute metabolic decompensation before being diagnosed. The experts also identified several barriers to and gaps in the management of acute metabolic decompensation, and MSUD more generally, proposing potential actions to improve clinical outcomes. Acute metabolic decompensation requires prompt, effective treatment by a multidisciplinary team to ensure that circulating plasma leucine levels are rapidly reduced without causing complications (particularly cerebral edema). Where available, intravenous branched chain amino acid-free solutions (e.g., Maapliv, now approved in Europe) may represent an important treatment option. Adequate resources (treatments, laboratory services, dialysis units) are essential for effective management of acute metabolic decompensation. Liver transplantation is an accepted viable option for the long-term prevention of acute metabolic decompensation in eligible patients. Research is ongoing into new treatment options for MSUD, such as gene therapy. Optimal management of acute metabolic decompensation in patients with MSUD requires prompt, effective treatment to reduce leucine levels without causing complications. A ready-to-use branched chain amino acid-free intravenous solution has been recently approved in Europe and research into new treatment options is ongoing.
2026-05-21 | The role of essential fatty acid deficiencies in cognitive function among patients with organic acidemias
Objective: Organic acidemias (OAs) are metabolic disorders characterized by enzyme deficiencies that impair amino acid catabolism, leading to metabolic imbalances. Essential fatty acids (EFAs), particularly Omega-3 and Omega-6, are vital for cellular and neurological functions but are often affected by protein-restricted diets used in OA management. The aim of this study was to evaluate the plasma EFA levels in OA patients and explores their clinical relevance. Materials and Methods: A prospective, case-control design was adopted, including 26 OA patients (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, maple syrup urine disease) and 22 healthy age- and gender-matched controls. Plasma EFA levels were quantified via gas chromatography-mass spectrometry. Cognitive and psychiatric evaluations were performed using standardized tests, including DSM-V-TR criteria, Wechsler Intelligence Scale for Children, and other psychometric tools. Statistical analyses assessed the relationships between EFA levels and clinical findings. Results: Organic acidemias patients exhibited significantly lower levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA, and Omega-3 compared to controls, with higher Omega-6/Omega-3 ratios. Despite these findings, no significant correlations emerged between EFA levels and cognitive or psychiatric outcomes. Conclusion: EFA deficiencies are prevalent among OA patients on protein-restricted diets, underscoring the potential need for targeted nutritional interventions. However, the absence of a direct association with clinical findings suggests multifactorial influences on disease outcomes. Future research should explore the longitudinal effects of EFA supplementation and its role in mitigating neurodevelopmental impairments in OA.
2026-05-15 | Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice.
Branched-chain 2-ketoacid dehydrogenase (BCKDH) deficiency (maple syrup urine disease; MSUD) causes lethal encephalopathy by disrupting cerebral metabolism, a process imperfectly reflected by circulating biomarkers. Diet and liver transplantation stabilize peripheral metabolites but fail to restore brain neurochemistry, demarcating the central nervous system as the decisive therapeutic compartment. To define the pathogenesis of intoxication and its therapeutic response, we performed paired serum-brain metabolomics in Bckdha-/- mice treated with a systemic AAV9 dual-gene vector encoding human BCKDHA and BCKDHB (A-BiP-B). Untreated neonates exhibited a 9-fold elevation of brain 2-ketoisocaproate accompanied by cerebral depletion of glutamate and glutamine, as well as shifts in tricarboxylic acid cycle and ketone body metabolism. These disturbances originated from reversal of branched-chain aminotransferase 2 flux and destabilization of glutamate-2-ketoglutarate mass balance, producing divergent metabolic endophenotypes in blood versus brain. A single intravenous injection of A-BiP-B rescued mice from fatal encephalopathy, partially restored cerebral BCKDHA mRNA expression, and brought core brain neurochemical endpoints within wild-type range despite persistent elevation of serum 2-ketoacids. These findings expose limitations of current MSUD management and establish systemic dual-gene therapy as a means of restoring neurochemical homeostasis while enabling survival on unrestricted protein intake.
2026-05-14 | Trial-ready external controls for gene therapy: The MATCH cohort in maple syrup urine disease.
Maple syrup urine disease (MSUD) is a life-threatening metabolic disorder for which randomized trials are infeasible. We present the MSUD Age-matched Standard Treatment Cohort (MATCH), a prospective natural history study of 11 infants with classic MSUD followed from neonatal diagnosis to liver transplantation. Aligned with Food and Drug Administration (FDA) guidance and International Council for Harmonisation (ICH) E9(R1), MATCH applies prespecified eligibility criteria, fixed visit cadence, adjudicated outcomes, and explicit handling of intercurrent events. Three of six outcome measures-proportional intact protein equivalent (PIPE), crisis management days (CMDs), and blood alloisoleucine concentration-are prespecified as estimands. Monte Carlo simulations show that a single-arm trial comparing 11 treated participants to MATCH controls achieves ≥90% power (p ≤ 0.025) to detect 64% fewer CMDs (3.0% vs. 8.4%), a 57% increase in PIPE (19.3% vs. 12.3%), and a 36% reduction in alloisoleucine (117 vs. 183 μM). MATCH demonstrates how protocolized natural history data serve as regulatory-grade external controls for single-arm trials.
2026-06-22 | Treatment strategies, radiological recovery, and neurodevelopmental outcomes in paediatric Maple Syrup Urine Disease: a 20-year single-centre experience from Türkiye.
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive metabolic disorder characterised by defective branched-chain amino acid (BCAA) catabolism, leading to neurotoxicity, recurrent metabolic crises, and neurodevelopmental impairment. Evidence on long-term outcomes in paediatric cohorts, particularly with pharmacological adjuncts such as sodium phenylbutyrate (NaPBA) and radiological recovery, remains limited. We undertook a retrospective review of 13 paediatric patients with MSUD (69.2% classic phenotype, 30.8% intermittent) followed at a tertiary metabolic centre in Türkiye between 2003 and 2022. Demographic, biochemical, neurodevelopmental, neuroimaging, and genetic data were evaluated, with specific attention to dietary management, haemodialysis during acute decompensation, and NaPBA therapy. All patients exhibited neurodevelopmental delay, which was more pronounced in the classic phenotype. Milestone-level analysis demonstrated delays in walking (85%), sentence formation (92.3%), and toilet training (92.3%). One year after dietary intervention, mean plasma concentrations of leucine, isoleucine, and valine decreased by 60.9%, 55.9%, and 65.0%, respectively (p < 0.01). Haemodialysis during metabolic crises rapidly reduced leucine (- 73.8%) and ammonia (- 66%), though was more frequently required in patients with the classic phenotype. NaPBA treatment was associated with lower leucine levels during follow-up (p < 0.05). Baseline MRI abnormalities were identified in 87% of patients; 57% showed complete resolution post-treatment, with partial radiological improvement observed alongside clinical follow-up. A phenotype-specific approach combining early dietary intervention, timely haemodialysis in acute crises, and selective use of NaPBA may support metabolic stabilisation and radiological improvement in selected patients. Larger multicentre studies are warranted to validate these findings and refine management protocols.
2026-06-07 | Management of acute metabolic decompensation in maple syrup urine disease: guidance based on international clinical practice.
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by a deficiency of branched-chain ketoacid dehydrogenase, the enzyme involved in the second step of branched-chain amino acid catabolism. Of the three branched-chain amino acids (leucine, valine, and isoleucine), accumulation of leucine is the predominant factor causing acute metabolic decompensation in patients with MSUD. In February 2025, eight expert physicians met to discuss the management of acute metabolic decompensation and propose recommendations after literature review (four guidelines and 20 other articles of interest). A practical clinical algorithm was established. Newborn screening was acknowledged to be a successful method of diagnosing MSUD at birth, facilitating early intervention to prospectively manage MSUD and reduce the frequency and severity of acute metabolic decompensation, although it was noted that infants with severe MSUD often present with acute metabolic decompensation before being diagnosed. The experts also identified several barriers to and gaps in the management of acute metabolic decompensation, and MSUD more generally, proposing potential actions to improve clinical outcomes. Acute metabolic decompensation requires prompt, effective treatment by a multidisciplinary team to ensure that circulating plasma leucine levels are rapidly reduced without causing complications (particularly cerebral edema). Where available, intravenous branched chain amino acid-free solutions (e.g., Maapliv, now approved in Europe) may represent an important treatment option. Adequate resources (treatments, laboratory services, dialysis units) are essential for effective management of acute metabolic decompensation. Liver transplantation is an accepted viable option for the long-term prevention of acute metabolic decompensation in eligible patients. Research is ongoing into new treatment options for MSUD, such as gene therapy. Optimal management of acute metabolic decompensation in patients with MSUD requires prompt, effective treatment to reduce leucine levels without causing complications. A ready-to-use branched chain amino acid-free intravenous solution has been recently approved in Europe and research into new treatment options is ongoing.
2026-05-21 | The role of essential fatty acid deficiencies in cognitive function among patients with organic acidemias
Objective: Organic acidemias (OAs) are metabolic disorders characterized by enzyme deficiencies that impair amino acid catabolism, leading to metabolic imbalances. Essential fatty acids (EFAs), particularly Omega-3 and Omega-6, are vital for cellular and neurological functions but are often affected by protein-restricted diets used in OA management. The aim of this study was to evaluate the plasma EFA levels in OA patients and explores their clinical relevance. Materials and Methods: A prospective, case-control design was adopted, including 26 OA patients (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, maple syrup urine disease) and 22 healthy age- and gender-matched controls. Plasma EFA levels were quantified via gas chromatography-mass spectrometry. Cognitive and psychiatric evaluations were performed using standardized tests, including DSM-V-TR criteria, Wechsler Intelligence Scale for Children, and other psychometric tools. Statistical analyses assessed the relationships between EFA levels and clinical findings. Results: Organic acidemias patients exhibited significantly lower levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA, and Omega-3 compared to controls, with higher Omega-6/Omega-3 ratios. Despite these findings, no significant correlations emerged between EFA levels and cognitive or psychiatric outcomes. Conclusion: EFA deficiencies are prevalent among OA patients on protein-restricted diets, underscoring the potential need for targeted nutritional interventions. However, the absence of a direct association with clinical findings suggests multifactorial influences on disease outcomes. Future research should explore the longitudinal effects of EFA supplementation and its role in mitigating neurodevelopmental impairments in OA.
2026-05-15 | Systemic dual-gene therapy reverses biochemical intoxication in the central metabolic compartment of Bckdha-/- mice.
Branched-chain 2-ketoacid dehydrogenase (BCKDH) deficiency (maple syrup urine disease; MSUD) causes lethal encephalopathy by disrupting cerebral metabolism, a process imperfectly reflected by circulating biomarkers. Diet and liver transplantation stabilize peripheral metabolites but fail to restore brain neurochemistry, demarcating the central nervous system as the decisive therapeutic compartment. To define the pathogenesis of intoxication and its therapeutic response, we performed paired serum-brain metabolomics in Bckdha-/- mice treated with a systemic AAV9 dual-gene vector encoding human BCKDHA and BCKDHB (A-BiP-B). Untreated neonates exhibited a 9-fold elevation of brain 2-ketoisocaproate accompanied by cerebral depletion of glutamate and glutamine, as well as shifts in tricarboxylic acid cycle and ketone body metabolism. These disturbances originated from reversal of branched-chain aminotransferase 2 flux and destabilization of glutamate-2-ketoglutarate mass balance, producing divergent metabolic endophenotypes in blood versus brain. A single intravenous injection of A-BiP-B rescued mice from fatal encephalopathy, partially restored cerebral BCKDHA mRNA expression, and brought core brain neurochemical endpoints within wild-type range despite persistent elevation of serum 2-ketoacids. These findings expose limitations of current MSUD management and establish systemic dual-gene therapy as a means of restoring neurochemical homeostasis while enabling survival on unrestricted protein intake.
2026-05-14 | Trial-ready external controls for gene therapy: The MATCH cohort in maple syrup urine disease.
Maple syrup urine disease (MSUD) is a life-threatening metabolic disorder for which randomized trials are infeasible. We present the MSUD Age-matched Standard Treatment Cohort (MATCH), a prospective natural history study of 11 infants with classic MSUD followed from neonatal diagnosis to liver transplantation. Aligned with Food and Drug Administration (FDA) guidance and International Council for Harmonisation (ICH) E9(R1), MATCH applies prespecified eligibility criteria, fixed visit cadence, adjudicated outcomes, and explicit handling of intercurrent events. Three of six outcome measures-proportional intact protein equivalent (PIPE), crisis management days (CMDs), and blood alloisoleucine concentration-are prespecified as estimands. Monte Carlo simulations show that a single-arm trial comparing 11 treated participants to MATCH controls achieves ≥90% power (p ≤ 0.025) to detect 64% fewer CMDs (3.0% vs. 8.4%), a 57% increase in PIPE (19.3% vs. 12.3%), and a 36% reduction in alloisoleucine (117 vs. 183 μM). MATCH demonstrates how protocolized natural history data serve as regulatory-grade external controls for single-arm trials.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
5 orphan drug designations for Maple syrup urine disease, including 1 approved therapy.
5 orphan drug designations for Maple syrup urine disease, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant AAV9 vector expressing functional, codon-optimized, human BCKDHA and BCKDHB genes which encode for catalytic E1alpha and E1beta subunits, respectively, of the BCKDH holoenzyme | gene therapies | FDA | 2025-05-15 | — | Plowshare Therapies LLC |
a modified version of a leucine decarboxylase enzyme from Planctomycetaceae bacterium | proteins | FDA | 2022-12-20 | — | Codexis, Inc. |
Sodium phenylbutyrate | small molecules | EMA | 2022-07-18 | — | Renantos Pharmavertriebsgesellschaft mbH |
Glycine, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-histidine, L-lysine monohydrate, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, taurine [Maapliv] | other | EMA | 2018-10-26 | 2025-07-29 | Recordati Rare Diseases |
sodium phenylbutyrate | small molecules | FDA | 2014-08-19 | — | Acer Therapeutics, Inc. |
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