Josh Botros

 Background: Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder caused by a deficiency of the branched-chain α-keto acid dehydrogenase (BCKD) complex, resulting in the accumulation of branched-chain amino acids (BCAAs).¹ Current primary treatment through dietary restriction or liver transplantation improves survival but does not fully normalize amino acid homeostasis or prevent long-term neurological dysfunction.¹ Despite dietary restriction of BCAAs, many patients continue to develop neurological complications such as cognitive impairment, intellectual disability, anxiety disorders, mood disorders, and attention deficit disorder.¹

Objective: To evaluate the effectiveness of recent therapeutic approaches, including gene therapy, L-carnitine supplementation, and oral enzyme therapy, in addressing the underlying metabolic and neurological pathology of MSUD.

Search Methods: A literature search was conducted using PubMed from 2018 to 2026 using the keywords “maple syrup urine disease,” “branched-chain amino acids,” “BCKDHA,” “BCKDHB,” “gene therapy,” “L-carnitine,” “neuropathology,” and “leucine decarboxylase.”

Results: Studies indicate that gene therapy may provide more effective metabolic control and neurological protection than current therapies. Wang et al. demonstrated that a recombinant AAV9 vector carrying BCKDHA and BCKDHB genes restored functional BCKD enzyme activity and normalized BCAA metabolism in mouse and calf models of MSUD.² Gene expression was restored in the liver, skeletal muscle, heart, and brain, and treated animals maintained metabolic stability during high-protein intake.² Another study comparing ubiquitous and liver-specific gene therapy further demonstrates that liver-only therapy is insufficient, and that restoration of BCKD activity in the brain and muscle is critical for preventing neurological complications.³ Additional treatments targeting neurologic injury and leucine accumulation have also shown promise. L-carnitine supplementation has shown neuroprotective, antioxidant, and anti-inflammatory effects by increasing brain-derived neurotrophic factor and platelet-derived growth factor-BB levels, as well as increasing BCKD enzyme activity in MSUD patients.⁴ Oral enzyme therapy using leucine decarboxylase also reduced plasma and brain leucine levels by degrading leucine in the gastrointestinal tract before absorption.⁵

Conclusion: These studies suggest that multi-tissue gene therapy combined with adjunctive treatments such as L-carnitine supplementation or oral leucine degradation may provide more effective prevention of long-term neurological damage in MSUD patients. These therapies may provide effective alternatives or adjuncts to dietary management and improve quality of life for patients with MSUD. Future studies should evaluate long-term clinical outcomes in human patients and explore combined treatment approaches.

Works Cited:

1. Strauss KA, Carson VJ, Soltys K, et al. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Molecular Genetics and Metabolism. 2020;129(3):193-206. doi:https://doi.org/10.1016/j.ymgme.2020.01.006
2. Wang J, Poskitt LE, Gallagher J, et al. BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease. Science Translational Medicine. 2025;17(787). doi:https://doi.org/10.1126/scitranslmed.ads0539
3. Pontoizeau C, Simon-Sola M, Gaborit C, et al. Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice. Nature Communications. 2022;13(1):3278. doi:https://doi.org/10.1038/s41467-022-30880-w
4. Girardi J, Faverzani JL, Lopes FF, et al. Neuroprotective, antioxidant and anti-inflammatory effect of carnitine in patients with Maple syrup urine disease: branched-chain amino acids and branched-chain keto acids levels. Metabolic brain disease. 2025;40(8):314. doi:https://doi.org/10.1007/s11011-025-01747-y
5. Skvorak KJ, Liu JF, Kruse N, et al. Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine levels in intermediate MSUD mice and healthy nonhuman primates. Journal of Inherited Metabolic Disease. Published online August 9, 2023. doi:https://doi.org/10.1002/jimd.12662