Mother and daughter with a terminal Xp deletion: implication of chromosomal mosaicism and X-inactivation in the high clinical variability of the microphthalmia with linear skin defects (MLS) syndrome.

The microphthalmia with linear skin defects (MLS or MIDAS) syndrome is a rare X-linked dominant inherited disorder with male lethality, associated with segmental aneuploidy of the Xp22.2 region in most of the cases. However, we recently described heterozygous sequence alterations in a single gene, HCCS, in females with MLS. Beside the classical MLS phenotype, occasional features such as sclerocornea, agenesis of the corpus callosum, and congenital heart defects can occur. Although the majority of cases are sporadic, mother-to-daughter transmission has been observed and a high intra- and interfamilial phenotypic variability exists. We describe an asymptomatic mother and her daughter presenting with the typical features of MLS syndrome. By cytogenetic analysis both females were found to have a terminal Xp deletion with the breakpoint in Xp22.2, mapping near to or within the MSL3L1 gene which is located centromeric to HCCS. FISH analysis revealed that the mother is a mosaic with 45,X(11)/46,X,del(X)(p22.2)(89), while in all cells of the MLS-affected daughter a hybridization pattern consistent with a 46,X,del(X)(p22.2) karyotype was detected. By haplotype analysis we identified the paternal X chromosome of the mother to carry the terminal Xp deletion. X-inactivation studies showed a completely skewed pattern in mother and daughter with the deleted X chromosome to be preferentially inactivated in their peripheral blood cells. We suggest that both chromosomal mosaicism as well as functional X chromosome mosaicism could contribute to the lack of any typical MLS feature in individuals with a heterozygous MLS-associated mutation. The 45,X cell population, that most likely is also present in other tissues of the mother, might have protected her from developing MLS. Nonetheless, a non-random X-inactivation pattern in favor of activity of the wild-type X chromosome in the early blastocyte could also account for the apparent lack of any disease sign in this female.

A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy.

The following study describes the discovery of a new inherited metabolic disorder, dolichol kinase (DK1) deficiency. DK1 is responsible for the final step of the de novo biosynthesis of dolichol phosphate. Dolichol phosphate is involved in several glycosylation reactions, such as N-glycosylation, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and C- and O-mannosylation. We identified four patients who were homozygous for one of two mutations (c.295T-->A [99Cys-->Ser] or c.1322A-->C [441Tyr-->Ser]) in the corresponding hDK1 gene. The residual activity of mutant DK1 was 2%-4% when compared with control cells. The mutated alleles failed to complement the temperature-sensitive phenotype of DK1-deficient yeast cells, whereas the wild-type allele restored the normal growth phenotype. Affected patients present with a very severe clinical phenotype, with death in early infancy. Two of the patients died from dilative cardiomyopathy.

Cycling and penile oxygen pressure: the type of saddle matters.

OBJECTIVES: Temporary genital numbness is a common side effect of long-distance cycling; cases of impotence have even been reported. Recent reports have shown that perineal compression leads to a decrease in penile blood flow. Reduced oxygen tension leads to penile fibrosis, which works counterproductively to the achievement of an erection. The shape of the bicycle saddle could be a factor affecting penile perfusion. The aim of this study is to find out the influence of different saddle designs on penile perfusion. MATERIAL AND METHODS: In 20 healthy athletic young men (mean age 26.8 years, range 21-31 years) without history of erectile dysfunction, transcutaneous oxygen pressure (PtcO2), which correlates with arterial and tissue PO2, was measured at the glans of the penis using a transcutaneous measurement device. All men were measured in a standing position before cycling, then during cycling in a seated position on a stationary bicycle. Four different bike saddle designs were used: (A) narrow heavily padded seat; (B) narrow seat with medium padding and a V-shaped groove in the saddle nose ("body geometry"); (C) wide unpadded leather seat; (D) women's special wide seat with medium padding and no saddle nose. RESULTS: During cycling in all seats a decrease in penile oxygen pressure could be observed, reflecting perineal compression. But the differences were unexpected: seat (A) mean PtcO2 11.8 mmHg, decrease in initial oxygen pressure 82.4%; seat (B) mean PtcO2 20.8 mmHg, decrease in initial oxygen pressure 72.4%; seat (C) mean PtcO2 25.3 mmHg, decrease in initial oxygen pressure 63.6%; seat (D) mean PtcO2 62.3 mmHg, decrease in initial oxygen pressure 20.3%. CONCLUSIONS: Cycling in a seated position leads to a compression of perineal arteries with a consequent significant decrease in penile perfusion. But, there are unexpected differences between different saddle types. It was possible to demonstrate that the most important factor in safeguarding penile perfusion is not the amount of padding, but rather a saddle width which prevents sufficiently the compression of the perineal arteries.