Branched‐chain L‐amino acid metabolism in classical maple syrup urine disease after orthotopic liver transplantation

Abstract

We characterized the effect of orthotopic liver transplantation on the catabolism of branched-chain L-amino acids in a female patient with classical form of maple syrup urine disease. Transplantation was performed at the age of 7.4 years due to a terminal liver failure triggered by a hepatitis A infection. Since then, the patient is on an unrestricted diet and plasma concentrations of branched-chain L-amino and 2-oxo acids are stable, yet at moderately increased levels (2- to 3-fold of control). L-Alloisoleucine concentrations, however, remained remarkably elevated (> 5-fold of control). In vivo catabolism was investigated by measuring the metabolic L-alloisoleucine clearance and whole-body leucine oxidation in the postabsorptive state. In an oral loading test with 580 micromol alloisoleucine per kg body wt, the L-alloisoleucine elimination rate constant (0.067 h(-1)) was in the normal range (0.069+/-0.012 h(-1), n = 4). In an oral L-[1-13C]leucine load (38 micromol/kg body wt), 19.5% of the tracer dose applied was recovered in exhaled 13CO2 versus 18.9+/-3.6% in healthy subjects (n = 10). Thus, the patient exhibited obviously normal whole-body catabolic rates although branched-chain L-amino acid oxidation was confined to the liver transplant. Most likely, the enhanced substrate supply from extrahepatic sources led to an elevation of the plasma concentrations and thus induced a compensatory enhancement of the metabolic flux through the branched-chain 2-oxo acid dehydrogenase complex in the intact liver tissue.

DrosophilamiR-277 controls branched-chain amino acid catabolism and affects lifespan

“…The most dramatic form of this effect can be observed in patients suffering from maple syrup urine disease (MSUD), a hereditary deficiency resulting in complete loss of the BCKDH activity. During episodes of metabolic crisis, MSUD patients were reported to have plasma concentrations of up to 5 mM leucine, 1 mM valine and 1 mM isoleucine but 4.6 mM KIC, 1.5 mM α-keto-β-methyl-valeric acid (KMV) and 0.35 mM α-keto-isovaleric acid (KIV) 75 , 76 . While all compounds are substantially elevated, the proportional increase is much higher for the BCKAs and the normally 8‒10-fold excess of BCAAs over BCKAs is reduced to essentially equal levels.…”

Animal models of maple syrup urine disease

“…Orthotopic liver transplantation (OLT) has also been investigated as a treatment for MSUD (Bodner-Leidecker et al 2000;Netter et al 1994;Strauss et al 2006;Wendel et al 1999). Patients receiving OLT no longer require a BCAA-restricted diet and BCKDH enzyme activity is restored to at least the level of very mild MSUD patients.…”

Ataxia in children: early recognition and clinical evaluation

“…Several phenotypes of MSUD are recognized: in the intermittent MSUD type during stress or an infectious episode, children may present vomiting and ataxia. When not treated, the disorder can lead to lethargy until coma [26, 27]. Pyruvate dehydrogenase complex deficiency is typically a severe disorder with different clinical aspects and biochemical presentations.…”