Rett syndrome and genetic drift.

An X chromosome gene is assumed to be responsible for the cause of Rett syndrome (RS). However, new genealogical observations suggest involvement of autosomal recessive gene(s) as well, at least in familial cases. To account for these and other recent observations, the theoretical model presented in 1990 by the authors of this paper is applied to the calculation of gene frequencies. Observed frequencies of sporadic and familial cases of RS are used, taking into account genetic drift in inbreeded areas. Moreover, an attempt is made to use the proportion of RS variants in familial and sporadic cases for the explanation of so called 'formes frustes', and as evidence for the existence of female as well as male carriers. The estimated frequency of the recessive autosome mutation, or possibly a frequent polymorphism, is 22.5%.

[Molecular diagnosis of cystic fibrosis]. / Molekulare Diagnose der zystischen Fibrose.

Cystic fibrosis [CF] is the most common autosomal recessively inherited disease in the caucasian population. Based upon the population frequency of approximately 1 in 2000 in Switzerland, the heterozygote frequency can be calculated to be 1 in 22. The genetic basis for CF has been shown to be mutations in the gene coding for an epithelial membrane chloride channel, the Cystic Fibrosis Transmembrane conductance Regulator [CFTR]. To date over 500 mutations have been characterized in this gene. The frequency of specific mutations varies amongst different ethnic groups. In Switzerland 8 mutations have been shown to account for approximately 90% of all CF causing alleles. The cloning and molecular characterization of the CFTR gene has lead to a major breakthrough in the understanding of the biochemical basis of CF pathogenesis. Advances through analysis of cellular and animal model systems have made a genetic based therapy for CF a real possibility.

The value of family investigations in newly detected Charcot-Marie-Tooth disease in children.

Charcot-Marie-Tooth disease (CMT) was diagnosed by nerve conduction velocity and histology of the sural nerve in two boys aged 3 and 6 years with clinical signs of a severe neuromuscular disease. DNA analysis revealed the typical duplication on chromosome 17p11.2 (2.7 kb allele) for CMT 1A. Although none of their family members reported symptoms of neuromuscular disease, the nerve conduction velocity was reduced in three members (father and two aunts). They were homozygous for the 2.7 kb allele and were assumed to carry three copies of this allele. The very differing clinical picture from one generation to the next in patients with identical neurophysiological and genetic results is discussed.

Paternal origin of the de novo deleted chromosome 4 in Wolf-Hirschhorn syndrome.

The parental origin of the de novo deleted chromosome 4 was studied in five cases of Wolf-Hirschhorn syndrome using polymorphic probes mapping in the 4p16.3 region. In all the patients the deleted chromosome was found to be of paternal origin and these results, together with similar ones obtained by another group, make the preferential paternal origin of the de novo chromosome 4 deletion highly significant.

Another model for the inheritance of Rett syndrome.

The fact that probably less than 1% of Rett syndrome cases are familial speaks in favor of a spontaneous mutation as the most common cause of Rett syndrome. However, the few familial cases (about 10) described in the literature, the elevated consanguinity rate in parents of Rett patients (2.4% vs. 0.5%), and the existence of "formes frustes" in relatives of Rett girls, suggest that inheritance must exist. A model based on a hypothetical form of inheritance, namely allelic and non-allelic metabolic interference, fits almost all available data, as well as the exclusive occurrence in females without increased abortion rate.

[DNA diagnostics in hemophilia A and B]. / DNA-Diagnostik bei Hämophilie A und B.

Carrier detection and prenatal diagnosis of hemophilia A and B are possible with cloned factor-VIII:C- and factor-IX-gene-specific or linked probes which detect restriction fragment length polymorphisms (RFLPs). In this study, 12 hemophilia-A- and 5 hemophilia-B-families were studied to identify carriers and provide adequate genetic counselling to women who were heterozygous for one or more of the intragenic or linked DNA probes with respect to future pregnancies.

Integrity of the thyroglobulin locus in tricho-rhino-phalangeal syndrome II.

The thyroglobulin gene has been mapped to chromosome band 8q24 by several investigators. This is the band implicated in the causation of Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome II). We have examined a restriction fragment length polymorphism at the thyroglobulin locus in a patient with Langer-Giedion syndrome and 8q deletion in order to: (1) localize the Langer-Giedion deletion more precisely, (2) define the relative map positions of the thyroglobulin gene and the Langer-Giedion locus. The results indicate that the locus of the thyroglobulin gene is intact in the patient with an interstitial deletion of proximal band 8q24.1 which confirms its more distal localization reported earlier by Bergé-Lefranc et al. (1985). It also assigns the critical region for the causation of Langer-Giedion syndrome to the proximal part of band 8q24, viz. 8q24.11----q24.13.

The tricho-rhino-phalangeal syndrome(s): chromosome 8 long arm deletion: is there a shortest region of overlap between reported cases? TRP I and TRP II syndromes: are they separate entities?

Critical cytogenetic (re)evaluation of 2 of our own cases of tricho-rhino-phalangeal syndrome II (TRP II), or Langer-Giedion syndrome (LGS), and 10 cases from the literature, suggests that the shortest region of overlap of the 8q deletion is a part of band q24.1. This region is assumed to be causally related to this syndrome, and possibly also to TRP I syndrome which, therefore, may not be a causally separate entity.

Improved double immunoenzyme labeling using alkaline phosphatase and horseradish peroxidase.

Alkaline phosphatase and peroxidase complexes were applied to tissue sections simultaneously to label two antigens. An azo-coupling method was used to demonstrate the alkaline phosphatase activity. The final result gave clear contrast between the two antigens and allowed the use of haematoxylin as the nuclear counterstain.