General description

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by defective metabolism of branched-chain amino acids. MSUD is an inborn error of metabolism caused by deficiency in the branched-chain α-ketoacid dehydrogenase (BCKAD) complex. This enzymatic defect results in the accumulation of branched-chain amino acids (BCAAs) - leucine, isoleucine, and valine - in plasma, along with their corresponding α-ketoacids in urine, and the production of alloisoleucine, a pathognomonic disease marker. The disorder has significant genetic heterogeneity, with biallelic pathogenic variants in several genes encoding the components of the BCKAD complex.

MSUD manifests with different clinical severities and is classified into five types: classic, intermediate, intermittent, thiamine-responsive, and E3-deficient. There is no clear correlation between genotype and phenotype, but these forms differ in their onset age, symptom severity, response to thiamine, and biochemical markers.

Classic MSUD is the most severe form, appearing in newborns who initially seem healthy but rapidly develop symptoms. Without treatment, metabolic intoxication progresses through distinct stages, leading to severe neurological impairment, coma, and respiratory failure. Key signs include poor feeding, breathing difficulties, hypotonia, seizures, and a distinct maple syrup odor. Plasma leucine levels are significantly elevated in affected individuals.

Intermediate MSUD presents with partial enzyme activity, allowing for a less severe course. Affected individuals may develop feeding difficulties, poor growth, intellectual disability, and episodic metabolic crises.

Intermittent MSUD, by contrast, allows for normal growth and neurological development under a regular diet, with metabolic issues only arising during periods of catabolic stress.

Thiamine-responsive MSUD, linked to mutations in the DBT gene, shares similarities with the intermediate form but can be managed with dietary control and thiamine supplementation.

References

1. Li, Yang, et al. "Brain magnetic resonance imaging findings and radiologic review of maple syrup urine disease: Report of three cases." World Journal of Clinical Cases 9.8 (2021): 1844.