Prenatal diagnosis of pyruvate dehydrogenase E1α subunit deficiency

Pyruvate dehydrogenase (PDH) E1α subunit deficiency is an X-linked inborn error of metabolism affecting males and females with equal frequency. The diagnosis is usually based on determination of enzyme activity, although this may present difficulties in some females because of X-inactivation patterns favouring expression of the normal X chromosome. This is a particular problem for prenatal diagnosis using chorionic villus cells where normal enzyme assay results do not necessarily exclude the diagnosis and confirmatory X-inactivation analysis may be complicated by variable methylation of active and inactive X chromosomes. We describe prenatal diagnosis in two pregnancies in a family following diagnosis of a PDH E1α deficient male. The first prenatal diagnosis was performed by enzyme assay, but by the time of the subsequent pregnancy, the underlying mutation in the affected male had been identified and direct gene analysis was possible. This study highlights the limitations of diagnosis of PDH E1α deficiency based on measurement of the gene product and illustrates the need for mutation analysis in affected individuals.     

Prospective risk in reciprocal translocation heterozygotes at amniocentesis as determined by potential chromosome imbalance sizes. Data of the european collaborative prenatal diagnosis centres

The Data of the European Cooperative Prenatal Diagnosis Laboratories (Boué and Gallano, 1984) of 596 prenatal (amniocyte) diagnoses of familial rep was examined as to relationships between balanced/unbalanced result and ascertainment, carrier parent and chromosome imbalance size (percentage haploid autosome length). Each rearrangement was graphed once with actual (unbalanced result) or potential (normal or balanced result) imbalances plotted with trisomy as the ordinate and monosomy as the abscissa. The graphed data was divided into 15 regions, each of 2·0 per cent trisomy and 0·75 per cent monosomy and the rate of unbalanced pregnancies determined for each region. The highest rates of chromosomally unbalanced progeny (excluding regions with inadequate data) were found closest to the origin (i.e. associated with the smallest imbalances) and these were for ascertainment category 1 (previous rep unbalanced child) 22·3 per cent for maternal carriers and 39 per cent for paternal carriers. Overall in pooled data for this ascertainment category (without reference to the imbalance graphs) there were for paternal carriers 28·6 per cent unbalanced pregnancies and for maternal carriers 18·1 per cent. The graphed data, therefore, revealed the higher rates associated with some of the rep with small potential (combined duplication/ deficiency) imbalances. Lesser rates were observed for ascertainment category 2 (carrier parent with a history of recurrent miscarriage) with overall percentages of imbalanced progeny ranging from 2·7 (paternal carriers) to 4·7 (maternal carriers). Again, higher rates were revealed in graphed data for small potential imbalances. All unbalanced results for this group (ascertainment category 2) plotted in the region closest to the origin with rates of 16 per cent (maternal carriers) and 9·5 per cent (paternal carriers) in this region. Remarkably in both ascertainment groups 1 and 2 there was no significant difference in the size of the imbalanced segments for unbalanced progeny. In ascertainment group 1 this was (dup/def; mean ±S.D.): 1·09±0·77/0·47 ± 0·45 and in ascertainment group 2: 1·09 ±0·80/0·66±0·71. From the graphed data which arguably denote viability relationships, a trisomy was approximately 2·7 times as likely to survive until amniocentesis as a monosomy of equivalent size. It is proposed that given further data, risk estimates could be determined for rep heterozygotes using the present approach where empiric data (from the family history or an analysed series of similar rep) is not available.