Screening of patients with hereditary spastic paraparesis and Addison's disease for adrenoleukodystrophy/adrenomyeloneuropathy.

X-linked adrenoleukodystrophy/adrenomyeloneuropathy presents a wide variation of clinical manifestations and may mimic several diseases. A screening investigation by measuring plasma saturated very long-chain fatty acids was performed in two groups of patients. Among six patients with hereditary spastic paraparesis one woman was detected to be a heterozygous gene carrier. However, in a group of eleven adult men with idiopathic Addison's disease the plasma concentrations of very long-chain fatty acids were all within normal limits. We conclude that X-linked adrenoleukodystrophy and symptomatic heterozygous females should be considered in cases of progressive spastic paraparesis.

[Keratosis follicularis--new genetic aspects]. / Keratosis follicularis--neue genetische Aspekte.

A hypothesis according to which two types of keratosis follicularis (below) should be differentiated is discussed with reference to clinical findings recorded during mass screening in kindergartens and in a dermatological practice: (1) condition improves, to normal in early adulthood, a type in which the for which heritability not cannot be identified by mass screening; (2) a type with growing incidence, primarily among women up to 30 years of age, caused by an X-linked dominant gene.

[Androgen receptor gene polymorphism analysis: application to screening of heterozygote and to prenatal diagnosis of androgen insensitivity syndrome]. / Analyse des polymorphismes du gène du récepteur des androgènes: application au dépistage de l'hétérozygotie et au diagnostic anténatal des syndromes d'insensibilité aux androgènes.

Androgen insensitivity syndromes are X-linked disorders. Restriction fragment length polymorphism analysis of the androgen receptor gene showed that deletions were infrequent. Some mutations have been described. In these conditions, in high-risk family, carrier diagnosis is impossible unless identification of mutations is made. It is thus necessary to detect androgen receptor gene polymorphism in order to differentiate the two maternal X chromosomes. Two androgen receptor gene polymorphisms have been reported (Hind III and exon 1). In this study we analyzed these two gene polymorphisms to detect carriers in at-risk families. The combined results of the two analyses allowed us to detect carriers in 45% of the studied families. In two families the prenatal diagnosis of androgen insensitivity syndrome was performed.

Screening for the fragile X: how many cells should we analyse?

Since nationwide screening for the fragile X would involve the analysis of thousands of individuals within a short period of time, the number of cells, N, which should be analysed is of fundamental importance. When selecting N, the crucial parameter should be the degree of expression of the fragile site in the affected individuals in the population to be screened. However, this degree of expression is not known, and for routine diagnostic purposes, N = 100 has been accepted by many centers. By taking data from two large series of affected males/females with a known degree of expression (one series from New South Wales, one from Belgium), we have estimated the fraction of affected males/females which would have been missed if the two series were rescreened with the analysis of less than 100 cells. Assuming that the degree of expression within these two series is similar to the degree of expression in all affected individuals within the two populations, the results indicate that a reduction of N in a screening program, say from 100 to 50 cells, would reduce the detection rate between 1 and 5%. The reduction would be greater in females than in males, and greater in the Belgian than in the Australian population.

Screening developmentally disabled male populations for fragile X: the effect of sample size.

The fra(X) or Martin-Bell syndrome is the most common cause of inherited mental retardation (MR) in males. It is also associated with a variety of unusual behavioral and developmental disorders. Recent studies found great variability in the estimated strength of association between "autism" and the fra(X) syndrome, but not between MR and fra(X). We examined 31 studies which investigated the association of fra(X) syndrome with either MR or "autism" and found that the conclusion of those researchers could be significantly affected by sample size. Different behavioral and cytogenetic protocols will also influence the strength of association between fra(X) and autism.

Sexing of human sperm by discontinuous Percoll density gradient and its clinical application.

A discontinuous Percoll density gradient was employed for the selective isolation of human X-bearing sperm. The fraction rich in X-bearing sperm that sedimented through eight steps of a Percoll density gradient was inseminated into healthy volunteers. Six couples achieved pregnancy and each delivered a female baby without abnormality. For further separation, a Percoll density gradient consisting of 12 steps gave a 94% purification of X-bearing sperm (contamination with Y-bearing sperm: 6.4 +/- 1.8%) with a mean recovery of 23.3 +/- 6.4% (n = 6).

Motility, expression of surface antigen, and X and Y human sperm separation in in vitro fertilization medium.

The influence of surrounding medium on human sperm swimming behavior has been characterized. In modified Ham's F-10 serum-supplemented in vitro fertilization medium, the straight-track swimming pattern of sperm in semen changed rapidly into circular tracks, and a new surface antigen was detected soon after this change. The circular tracks alternated between clockwise and counterclockwise directional movements. Addition of 17 beta-estradiol in a concentration range found in follicular fluid increased the frequency of clockwise movement twofold, suggesting that a steep concentration gradient created by an aduterine flow during ovulation, is likely to direct sperm migration up the gradient in the ipsilateral oviduct. Separation of X and Y sperm raised the possibility that a female carrier of an X-linked disease might choose to have a daughter, instead of taking the chance of having an affected son.

Genetic counseling by the primary care physician.

This paper has presented, in a rather concise and limited form, an outline of basic genetic principles which are necessary for the primary physician to provide good genetic counseling and good patient care. The assistance of a genetic center with prenatal diagnostic facilities allows consultation to proceed in a logical and constructive manner. The primary physician is in an excellent position to determine the pedigree, especially if he has the opportunity to examine the proband's immediate family and close relatives. The diagnosis may be easily made by the primary physician or it may require the combined efforts of the genetics clinic and the primary physician. In either case, the decision to terminate future pregnancies or to limit future offspring is made by the proband and his family, not the physician. The decision-making process may be affected by the primary physician who provides a sufficient amount of relevant information to his patients and allows them to reach a rational decision. Whether the decision appears rational to the physician or not, he must help his patients deal with it.