Biomedical subjects
Publications and source records attributed to H Northrup.
A child with trisomy 21 had altered mental status and hyperammonemia at presentation and was found to have a congenital portosystemic shunt as a result of a congenital abnormality of the portal venous system. Anomalies of the portal venous system leading to portosystemic shunting, although they are infrequent, should be considered in the differential diagnosis of hyperammonemia.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder of unknown aetiology that affects numerous body systems including skin, brain and kidneys. Some TSC has been linked to chromosome 9, additional TSC genes on chromosomes 11 and 12 have been proposed, but the majority of TSC families remain unlinked. Using TSC families in which data had excluded linkage to chromosome 9, we failed to detect linkage with loci on chromosomes 11, 12 and others. One marker examined was D16S283, the closest locus on the proximal side of the polycystic kidney disease type 1 (PKD1) gene. Linkage between TSC and D16S283 demonstrated a lod score of 9.50 at theta = 0.02 with one family independently presenting a lod score of 4.44 at theta = 0.05. These data reveal an important TSC locus near the region of PKD1 on chromosome 16p13.
Much has been learned about tuberous sclerosis complex (TSC) since it was described at the end of the nineteenth century. TSC was recognized to be a genetic disease with autosomal dominant inheritance in the early twentieth century. The prevalence in the general population is at least 1 in 10,000 with two-thirds of cases occurring sporadically and one-third of cases being familial. The disease exhibits variable expression which may cause mildly affected individuals to be undiagnosed. Because the aberrant or missing proteins which result in TSC have eluded investigators, a positional cloning approach has been pursued to find the mutated genes. Genetic linkages have been reported to chromosomes 9, 11, and 12. There is definite evidence for a TSC-causing locus on chromosome 9 which is thought to account for between one-third and one-half of all familial cases. Investigators have narrowed the location on chromosome 9 to approximately two megabases of physical distance. There is some evidence for a locus on chromosome 11 which probably accounts only for a small percentage of familial cases. The locus proposed on chromosome 12 was reported by a single group and has not been confirmed by other research groups. Evidence for genetic heterogeneity is abundant. There is definitely a TSC-causing locus on chromosome 9q (TSC-1) and there is at least one additional locus, maybe more than one. As the molecular basis of TSC unfolds, new insight will be gained about the protean nature of the disorder and the genetic heterogeneity.
Linkage of tuberous sclerosis complex (TSC), an autosomal dominant disorder, to markers on chromosome 9 was reported first in 1987. This assignment was confirmed by an international collaborative study that suggested more than one locus may be responsible for the phenotype. We studied 14 multigenerational TSC families (13 previously unreported) with markers for nine loci in the linked region of chromosome 9q32-q34. Our results confirm the previous reports that the genetic locus in one-third to one-half of families maps to chromosome 9. Comparison of clinical findings in the chromosome 9-linked families with those in the chromosome 9-unlinked families reveals only a higher incidence of ungual fibromata in the chromosome 9-linked families.
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Prenatal diagnosis of citrullinaemia has been accomplished by three different methods to date: (1) enzyme assay of cultured fetal cells; (2) quantification of citrulline in amniotic fluid supernatant; and (3) incorporation of [14C]citrulline into protein by cultured fetal cells. Our laboratory has used these methods to perform prenatal diagnosis for 28 fetuses over a 10-year period. More recently, DNA polymorphisms were used for prenatal diagnosis by linkage analysis. Of the 28 fetuses studied, 23 were predicted to be unaffected, four were predicted to be affected, and results were conflicting in one case where [14C]citrulline incorporation erroneously indicated an affected fetus but linkage analysis correctly predicted an unaffected fetus. Because of low levels of enzyme activity in heterozygotes and in certain amniotic fluid cell types, biochemical diagnosis of citrullinaemia is complicated by the risk of false affected results, although [14C]citrulline incorporation is relatively reliable. When informative, linkage analysis is the preferable method for cases with a 25 per cent risk. The risk of false affected results makes prenatal diagnosis for cases with less than 25 per cent risk of questionable value.
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We have identified three restriction fragment length polymorphisms (RFLPs) from within the argininosuccinate synthetase (ASS) gene which maps to human chromosome 9q34-qter. Although RFLPs at pseudogene loci are detected by the cDNA, these are the first polymorphisms reported at the ASS locus. The three RFLPs are in linkage equilibrium with each other, and haplotypes for the ASS locus are highly informative. Two-locus recombination estimates between ASS and seven other 9q markers indicated that ASS is closest to the ABO blood group with a recombination fraction of 0.04 (0.005-0.11). A multilocus lod score analysis with these seven 9q markers indicated that ASS maps between ABL and MCT136 close to ABO, but it is uncertain if ASS is centromeric or telomeric to ABO.