Corneal opacities in spondyloepiphyseal dysplasia tarda.

Spondyloepiphyseal dysplasia tarda is an inherited skeletal dysplasia involving the spine and epiphyses of long bones with onset in childhood, giving rise to disproportionate short stature and degenerative spine and hip disease. Associated ocular disease is not commonly recognized. We report a patient with spondyloepiphyseal dysplasia tarda and a unique pattern of corneal opacities. Bilateral, irregularly shaped, nodular, deeply posterior opacities confined to the peripheral cornea were noted in this patient. A central stromal granularity was also seen. Minimal visual loss was associated with these findings. An X-linked inheritance pattern is presumed but could not be confirmed.

Thiamin-responsive maple syrup urine disease in a patient antigenically missing dihydrolipoamide acyltransferase.

Maple syrup urine disease results from inherited defects in human nuclear genes for branched chain alpha-ketoacid dehydrogenase, a mitochondrial multienzyme complex. Thiamin pyrophosphate is necessary for complex activity and a thiamin-responsive form of maple syrup urine disease is known. Here we demonstrate the use of [1-13C]leucine oxidation to [13C]O2 quantified in breath samples as a means of assessing whole body leucine oxidation. Analysis of cultured cells from this patient shows the antigenic lack of the E2 subunit, yet she gained branched chain alpha-ketoacid dehydrogenase activity in response to diet supplementation with pharmacologic doses of thiamin. These cultured cells were used to seek a molecular basis for the observed thiamin response. Despite normal thiamin transport in these cells, medium supplementation of up to 1000 thiamin/liter failed to increase complex activity or cause the antigenic appearance of the missing protein. This lack of response in cultured cells suggests that the observed whole body response to thiamin must be a tissue-specific effect in liver, muscle, or kidney. In addition, allele-specific detection of paternal and maternal mutations was used to genotype family members in this pedigree.

Practical methods to estimate whole body leucine oxidation in maple syrup urine disease.

We report the comparison of noninvasive methods to estimate whole body leucine oxidation in patients who have maple syrup urine disease. We used both an i.v. and an oral bolus of L-[1-13C]leucine and quantitated 13CO2 in expired air. Both methods differentiated patients with maple syrup urine disease from heterozygous and control subjects. Eight patients, whose disease differed in clinical severity, were selected for study and had a range of impaired values for whole body leucine oxidation. Six h after an i.v. bolus dose of L-[1-13C]-L-leucine, 13CO2 recoveries ranged from 0.8 to 19.7%. Three of the eight patients had significant increases in 13CO2 production after supraphysiologic thiamine therapy. After the oral dose of L-[1-13C]leucine, homozygous affected children produced less 13CO2 than normal, age-matched, childhood controls. In addition, the oxidation of orally administered L-[1-13C]leucine was reduced significantly in adult heterozygotes compared with adult controls. The proportion of whole body leucine oxidation by affected children was comparatively greater than that by their cultured cells, but cellular oxidation correlated significantly with whole body oxidation of leucine among affected patients. We conclude that these simplified analyses of whole body leucine oxidation define the degree of impaired branched-chain alpha-ketoacid dehydrogenase activity in patients with differing types of maple syrup urine disease and distinguish the subpopulation who might benefit from thiamine supplementation.