No 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...

We report two affected offspring with Osteogenesis Imperfecta, Type 2. The first child was born near term and expired shortly thereafter. Prenatal radiologic examination was consistent with O.I., Type 2. The second affected fetus was diagnosed at 19 weeks gestation by sonographic and radiographic imaging even though the amniotic fluid pyrophosphate was negative at 14% weeks gestation. The skull was poorly mineralized and compressed. Long bones were shortened, angulated, and markedly irregular. There was deficient ossification of the spine, extremities, and minimal patchy ossification of the calvarium. Pregnancy was terminated at 21 weeks following the radiographic diagnosis. Radiologic and pathologic examination of the abortus was consistent with the prenatal diagnosis. Although the diagnosis of this, as well as other bone dysplasias has been made in utero during late pregnancy, we conclude that radiographic and sonographic imaging may be the only method of diagnosis of O.I., Type 2 during midtrimester gestation.

No abstract