The pathogenetic basis of the Rett syndrome (RS) is unknown: an X-linked dominant, male-lethal gene defect is thought likely. We present a girl with RS who has defects both of the urea cycle and of carbohydrate metabolism resulting in fasting hypoglycaemia, post-prandial hyperlactataemia and excess urinary orotic acid excretion after alanine load. Her sister has a similar clinical picture, but less marked metabolic anomalies. The mother of these sisters has abnormal urinary orotic acid excretion; she transmitted opposite ornithine carbomoyltransferase (OCT) alleles to the two girls. Another girl with RS has similar metabolic responses to fasting and to carbohydrate load. We conclude that RS may be an aetiologically homogeneous condition, but that it includes a variable pattern of metabolic anomalies, and that the gene defect is distinct from the OCT locus.

Adolescent↗

PubMed1990

Intracranial calcification and seizures: a case of central neurofibromatosis.

Periventricular calcification was found in an eight-year-old boy with seizures. The diagnosis of tuberous sclerosis was considered, but (like his mother) he has central neurofibromatosis. This condition must be considered in the differential diagnosis of children with intracranial calcification and seizures.

Brain↗

PubMed1990

Nonvalue of antigen detection immunoassays for diagnosis of candidemia.

We evaluated the Cand-Tec (Ramco Laboratories Inc., Houston, Tex.) and LA-Candida antigen detection system (Immuno-Mycologics Inc., Norman, Okla.) tests as possible rapid alternatives to blood cultures for the identification of patients with candidemia. Tests were performed on sera from (i) 33 patients with candidemia, (ii) 82 patients with fever and risk factors for invasive candidiasis, and (iii) 13 healthy controls. A total of 21 patients had no evidence of invasive candidiasis, as determined by clinical course, blood culture, and/or autopsy; results for 61 patients were indeterminate regarding the presence of invasive candidiasis, or else the patients had invasive candidiasis with organ involvement. By using a threshold positive Cand-Tec titer of greater than or equal to 1:4, the sensitivity in candidemic patients was 49%; the specificity was 43% (patients with true-negative results had neither candidemia nor other evidence of invasive candidiasis). Coexistent disseminated candidiasis in some candidemic patients may have accounted for some positive Cand-Tec tests and possible overestimation of the sensitivity of the test for candidemia. Cand-Tec test results were negative for healthy controls. All test results obtained by the LA-Candida antigen detection system assay were negative. Our findings indicate that neither of these assays reliably identifies patients with candidemia.

Adolescent↗

PubMed1990

X linked neonatal centronuclear/myotubular myopathy: evidence for linkage to Xq28 DNA marker loci.

We have studied the inheritance of several polymorphic Xq27/28 DNA marker loci in two three generation families with the X linked neonatal lethal form of centronuclear/myotubular myopathy (XL MTM). We found complete linkage of XLMTM to all four informative Xq28 markers analysed, with GCP/RCP (Z = 3.876, theta = 0.00), with DXS15 (Z = 3.737, theta = 0.00), with DXS52 (Z = 2.709, theta = 0.00), and with F8C (Z = 1.020, theta = 0.00). In the absence of any observable recombination, we are unable to sublocalise the XLMTM locus further within the Xq28 region. This evidence for an Xq28 localisation may allow us to carry out useful genetic counselling within such families.

Cell Nucleus↗

PubMed1990

Possible genetic heterogeneity in X linked hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia has been mapped to Xq11-q13 by linkage studies and by a translocation in a manifesting female. We report a family with hypohidrotic ectodermal dysplasia in which the disease did not segregate with this region of the X chromosome as expected. Ten DNA probes which are localised between Xp11 and Xq22 were used in the investigation. The difficulties in diagnosing the carrier state in this condition and the possibility of non-allelic heterogeneity are discussed.

Chromosome Mapping↗

PubMed1990

Mitochondrial genome: defects, disease, and evolution.

Defects of mitochondrial function are often caused by defects of the mitochondrial genome. The hypothesis that defective organelles may spread through syncytial tissues as a result of a process of subcellular Darwinian selection is proposed. Tissues are likely to be involved in mitochondrial disease if they are syncytial, are derived from a few embryonic cells only, have little redundancy of function, and are subject to repeated metabolic stress. These effects, together with the random distribution of genetically heterogeneous mitochondria within the fertilised zygote, may account for the varied clinical pictures of mitochondrial disease. Evolution will have favoured the shift of mitochondrial DNA sequences to the nucleus, once the differentiation of tissues had created body compartments in which defective mitochondria could flourish to the detriment of the organism. This model of mitochondrial disease allows the generation of several predictions, testable using currently available laboratory techniques. Avenues of potential therapeutic value are indicated, including the avoidance of hypoglycaemia and the use of selective mitochondrial toxins.

Biological Evolution↗

PubMed1990

Genetic imprinting in clinical genetics.

Genetic, and indeed genomic, imprinting does occur in humans. This is manifest at the level of the genome, the individual chromosome, subchromosomal region or fragile site, or the single locus. The best evidence at the single gene level comes from a consideration of familial tumour syndromes. Chromosomal imprinting effects are revealed when uniparental disomy occurs, as in the Prader-Willi syndrome and doubtless other sporadic, congenital anomaly syndromes. Genomic imprinting is manifest in the developmental defects of hydatidiform mole, teratoma and triploidy. Fragile (X) mental retardation shows an unusual pattern of inheritance, and imprinting can account for these effects. Future work in clinical genetics may identify congenital anomalies and growth disorders caused by imprinting: the identification of imprinting effects for specific chromosomal regions in mice will allow the examination of the homologous chromosomal region in humans.

Animals↗

PubMed1989