Karen Brøndum Nielsen

X-Linked mental retardation with fragile X. a pedigree showing transmission by apparently unaffected males and partial expression in female carriers

SummaryA large family is reported in which mental retardation associated with the fragile site at Xq28 was found. Three normal males seemed to have transmitted the trait through their daughters to affected grandchildren.A total of 19 family members were investigated cytogenetically. Mentally retarded males showed macroorchidism and the fragile X. Three mentally retarded females were found, with the fragile X in a high percentage of cells; in contrast, the obligate carriers showed no or only few cells with the fragile X.

Carrier detection and X-inactivation studies in the fragile X syndrome

SummaryCytogenetic investigations by three different lymphocyte culture methods in 63 obligate and potential carriers of the fragile X [fra(X)] are reported. A difference was observed between normal and retarded carriers in the manifestation of the fra(X). An inverse relationship between percentage positive cells and age was demonstrated in normal carriers, whereas retarded carriers generally showed higher percentages at all ages. X-inactivation studies in retarded carriers compared with normal carriers showed a tendency towards a skewed inactivation pattern with an excess of early replicating fra(X) in both groups when carriers expressing high percentages of fra(X) positive cells were compared. In normal carriers with low percentage expression the tendency was apparently reversed. The relationship between the replication pattern of the fragile X and the mental status of the individual is more complicated than suggested by previous studies.

Macroorchidism and fragile X in mentally retarded males

SummaryOne hundred and seventy eight males resident in an institution for the mentally retarded were screened clinically for the presence of macroorchidism, using the standard orchidometer. In this way 52 males with a testicular volume of 25 ml and over were found. Of these, 11 had pronounced macroorchidism (above 25 ml). All 52 males were examined cytogenetically for the fragile X. Two patients with pronounced macroorchidism showed this abnormality. Although the other nine patients with pronounced macroorchidism were reexamined with FUdR-addition to blood cultures, no further cases positive for the fragile X were found. Also, the thyroid function as well as the prolactin level in serum were investigated in all 52 males. No significant abnormalities were found. The high incidence of macroorchidism in mentally retarded males is underlined; however, it is suggested that the definition of macroorchidism should take into account several parameters.

Molecular identification of a small supernumerary marker chromosome by in situ hybridization: diagnosis of an isochromosome 18p with probe L1.84.

A dysmorphic child was found by cytogenetic analysis to have an extra small marker chromosome. The marker chromosome was shown to possess a chromosome 18 centromere by in situ hybridization, and probably represents an isochromosome 18p. Centromere specific probes should be of value in identifying extra small marker chromosomes, and thereby provide better understanding of the clinical significance of these.

Small metacentric nonsatellited extra chromosome

SummaryFive mentally retarded male patients with a supernumerary small metacentric nonsatellited chromosome were found to have many clinical features in common. The face showed characteristic small crowded features, the bodily habitus was asthenic, and the hands and feet had minor abnormalities. Renal anomalies were present in two patients. One patient had a myelomeningocele.Cytogenetic studies employing Q, R, and C banding in four patients showed the small extra chromosome to have staining properties compatible with an isochromosome of the short arm of chromosome 18.A comparison with previous case reports suggests a new syndrome. However, the identity of the extra chromosome has not yet been determined.

Apparent homozygosity for the fragile site at Xq28 in a normal female

SummaryA 29-year-old obligate carrier for X-linked mental retardation associated with the marker X, fra(X)(q28), showed the fragile site on both X chromosomes in two cells from independent cultures grown with methotrexate. Possible explanations include true homozygosity, artifact, and transposition of the fragile site.

Cytogenetic investigations in mentally retarded and normal males from 14 families with the fragile site at Xq28

SummaryLymphocyte cultures from 27 mentally retarded males aged 1 year to 77 years, and from 11 normal brothers from a total of 14 families with the fragile X segregating have been examined cytogenetically employing three different culture methods including methods for induction of fra(X) by FUdR (fluorodeoxyuridine) or MTX (methotrexate). All mentally retarded males showed unequivocal fra(X) expression. No statistically significant correlation between fra(X) expression and age could be demonstrated. No enhancement with FUdR was observed. Fibroblast cultures from 10 retarded males expressed fra(X) in a dose-response relationship to increasing concentrations of FUdR. None of the normal males showed fra(X). In vivo folic acid treatment of seven mentally retarded males resulted in marked reduction in fra(X) expression in lymphocyte cultures grown in medium 199. However, reinduction was achieved by FUdR or MTX, except in one case who temporarily received very high doses of folic acid.

Chromosomal studies in familial polyposis coli

A study of five patients with familial polyposis coli did not demonstrate any structural abnormalities of prometaphase chromosomes from methotrexate synchronized peripheral blood lymphocytes. No chromosomal heritable fragile sites were observed, nor was sister chromatid exchange increased.