Thiamine Response in Maple Syrup Urine Disease

Abstract

ABSTRACT. We measured the biochemical response for four patients with maple syrup disease to pharmacologic doses of thiamine, and correlated their response to their branched chain a-ketoacid dehydrogenase activity. We observed a linear correlation between the concentrations of each plasma branched-chain amino acid and its corresponding ketoacid analogue. In addition, the renal tubular reabsorption of branched-chain amino and ketoacids was nearly complete within these physiologic concentrations. Three children responded to thiamine therapy with a reduction in concentration of plasma and urinary branched-chain amino and ketoacids. Each responder had at least 5% activity for branched chain a-ketoacid dehydrogenase in their mononuclear blood cells and in whole cell fibroblasts from cultured skin when compared to the activity in normal control cells. We propose that each child with maple syrup urine disease be assessed for their response to thiamine by quantifying the concentration of branched-chain amino acids in plasma before and after vitamin supplementation. While taking 150 mg/day of thiamine, the brothers decreased their urinary excretion of BCKA and had increased activity of BCKAD as measured in peripheral blood lymphocytes. Based on these and additional in vivo and in vitro studies, Danner and coworkers (7, 8, 1 1-13) proposed that after its conversion to intracellular thiamine pyrophosphate, binding of this active cofactor to the multienzyme complex induced a conformational change which stabilized normal and mutant enzyme. This conformational change decreased the rate of biologic degradation of the complex and over time, increased overall enzyme activity (7,8,(11)(12)(13).Because of differences in reported doses and rapidity with which thiamine altered the patient's sensitivity to protein, it has remained unclear which patients would respond and which analysis could predict the response to thiamine therapy. The present study controlled for several variables, including the dietary intake of BCAA and the dose of thiamine. Plasma concentrations and renal transport of BCAA and BCKA were compared in four children affected with MSUD to determine whether pharmacologic doses of thiamine affect renal clearance of BCAA and BCKA. Each patient's biochemical response was correlated with residual activity of BCKAD in freshly isolated blood mononuclear cells and in their cultured skin fibroblasts. METHODS -- KIC, a-ketois~ca~roic acidClinical protocol. Four patients (Table I), whose parents gave KMV, a-keto-p-methylvaleric acid their informed consent, were studied. KIV, a-ketoisovaleric acid J.P., a 17-month-old black male, was diagnosed at 13 days of age. His developmental landmarks were moderately delayed.T.Mc., a 24/~2-yr-old white female, was diagnosed at 19 days of age. Despite normal development, she had recurrent bouts of More than 25 yr ago, Menkes et al. (I) described four siblings otitis, seizures, and ataxia.with progressive neurologic disorders and sugary-smelling urine.C.M., a 3'/12-yr-old white female, was t...

Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities

“…Individuals with maple syrup urine disease with residual enzyme activity of at least 5% were found to have a therapeutic response to thiamine over a 4 week treatment period. 35 Similarly, individuals with pyruvate dehydrogenase complex deficiency have been found to respond to thiamine treatment. 36 – 38 Moreover, 2 individuals with pathogenic variants located within the TPP binding domain of the pyruvate dehydrogenase E1α subunit ( PDHA1 ) were successfully treated with thiamine, which rescued the decreased affinity of the aberrant E1α subunit to TPP.…”

Gene Preference in Maple Syrup Urine Disease

“…1) and yet some decarboxylation of the ketoacid substrate occurs (Danner et al 1985;Ellerine et al 1993). Mutations in E2 have also been associated with the "thiamin-responsive" form of MSUD (Danner et al 1975;Fernhoff et al 1985;Ellerine et al 1993). One possible explanation for the thiamin response is that the E1 decarboxylase, which uses thiamin pyrophosphate as a cofactor in the reaction mechanism, can function independently of the E2 protein.…”

Genomic and biochemical analysis of repeatedly observed variants in DBT in individuals with maple syrup urine disease of Central American ancestry

“…Previous in vitro studies by others suggest that missense variants in DBT may be responsive to thiamine, showing enhanced enzyme activity and ameliorated phenotype with thiamine supplementation (Fernhoff et al, 1985). At least two missense variants in DBT are thiamine responsive (NM_001918.5( DBT )):c.827 T > G (p.Phe276Cys) [VCV000011943.13] (C. W. Fisher et al, 1991a; 1991b) and NM_001918.5( DBT ):c.1355A > G (p.His452Arg) [VCV000011952.1] (Chuang et al, 2004) (Figure 2).…”