Introduction

More than 50 years ago a family was studied to explain the repeated loss of their children with death shortly after birth. Careful characterization of their newborn child found sweet smelling urine that was likened to maple syrup (Menkes et al., 1954). Examination of blood and urine from these patients eventually identified an increased concentration of the branched chain amino acids (BCAA) and their α-ketoacids formed by transamination reactions. It was the elevated presence of these six compounds in body fluids that gave the sweet smell akin to maple syrup (Menkes, 1959). Continued work demonstrated that increased leucine, isoleucine, and valine and their branched chain ketoacids (BCKA) resulted from a defective ability of the patient to decarboxylate the BCKA. Investigations further showed that BCAA catabolism occurred in the mitochondria of all mammalian cells. Since the children within the family that were dying did not have this activity, but the parents had normal conditions, it was reasoned that an autosomal recessive inherited trait was causing the disease and each parent carried a single mutant gene. An affected individual must have acquired two mutant alleles for the same gene although it took 20 plus years to identify the genes and their mutations to cause the disease (Chuang and Shih, 2001).

Starting in the 1960s most of the studies to characterize the cause of the disease, now named maple syrup urine disease (MSUD), were focused on protein(s) since the DNA and gene structure was not yet to the level of analysis.