Intermittent maple syrup urine disease

Intermittent maple syrup urine disease (intermittent MSUD) is a milder variant of maple syrup urine disease, a rare inherited metabolic disorder caused by deficiency of the branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme complex. This enzyme is responsible for breaking down the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Unlike the classic severe form of MSUD, individuals with intermittent MSUD typically have normal growth and development during early life and may have near-normal BCAA levels under baseline conditions. However, during episodes of physiological stress—such as infections, surgery, fasting, or high protein intake—BCAA levels can rise dramatically, leading to metabolic crises characterized by the distinctive maple syrup odor in urine and earwax, ataxia, lethargy, vomiting, and potentially life-threatening encephalopathy. The condition primarily affects the nervous system, as elevated leucine levels are neurotoxic and can cause cerebral edema, seizures, and coma during acute decompensation episodes. Between crises, patients may appear clinically well, which can delay diagnosis. The disease is caused by pathogenic variants in the BCKDHA, BCKDHB, or DBT genes, which encode subunits of the BCKD enzyme complex. Residual enzyme activity in intermittent MSUD is typically higher (approximately 5–20% of normal) compared to the classic form, explaining the milder baseline presentation. Management focuses on prevention and rapid treatment of metabolic crises. Patients are advised to follow a protein-controlled diet, particularly limiting branched-chain amino acid intake, and to have an emergency protocol in place for periods of illness or stress. During acute episodes, treatment includes intravenous glucose and lipids to promote anabolism, along with close monitoring and correction of BCAA levels. Thiamine supplementation may be trialed, as some patients with intermittent MSUD are thiamine-responsive. Lifelong metabolic monitoring is essential, and genetic counseling is recommended for affected families. Liver transplantation has been used in severe MSUD variants but is generally not required for the intermittent form.

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