Deletion of 20p 11.23→pter with normal growth hormone-releasing hormone genes

Using a molecular analysis of the DNA from a patient with a deletion of chromosome 20 [46,XX,del(20)(p11.23)], we have excluded the growth hormone-releasing hormone (GHRH) gene from the region 20p11.23→pter. The patient had minor facial anomalies, Rieger eye anomaly, a congenital heart defect, severe failure to thrive, and a neurosecretory problem in growth hormone (GH) secretion. Since the GHRH gene was previously mapped to chromosome 20, we used molecular genetic methods to determine whether the growth abnormalities were due to the deletion of this gene. DNAs of the patient and 2 normal control subjects were analyzed by quantitative Southern blotting using a DNA probe for the GHRH gene and 2 reference DNA probes mapping to chromosome 21. The GHRH gene was found to be present in 2 copies in the patient. This indicates that the gene for GHRH maps to the region outside the patient's deletion, in 20p11.23→qter. Furthermore, our results suggest that genes other than GHRH on 20p are important for developmental steps leading to normal neurosecretory function of GH and may also be involved in generating Rieger eye anomaly. Finally, GH deficiency and Rieger eye anomaly should be sought in other patients with deletions of 20p.     

Klinefelter syndrome is a common cause for mental retardation of unknown etiology among prepubertal males

Klinefelter syndrome (KS) has not typically been associated with mental retardation (MR), however, in recent years a growing body of evidence suggested that KS boys often experience language deficits and academic difficulties. In this study, we screened DNA samples from 1205 patients originally referred for fragile X syndrome (FRAX) testing, because of MR of unknown etiology and detected 8 KS patients. A similar number of males in the same age group were found to have FRAX; 3 of them had a family history of FRAX. Based on these findings, KS might be the most common cause of MR of unknown etiology among prepubertal males. Because of the significant benefits of early recognition and treatment of KS, we emphasize the importance of cytogenetic testing of all prepubertal males with cognitive impairment even without dysmorphic features.     

Effects of knee joint angles and fatigue on the neuromuscular control of vastus medialis oblique and vastus lateralis muscle in humans

The effects of different knee joint angles and fatigue on the neuromuscular control of the vastus medialis oblique (VMO) and vastus lateralis (VL) muscles were investigated in 17 (11 men, 6 women) young subjects. The electromyogram (EMG) activities and the force generation capacities were monitored before and after a fatigue protocol at three different knee joint angles, 90°, 150°, 175° of knee extension, on three occasions. In response to randomly triggered light signals, the subjects performed three isometric maximal voluntary contraction (IMVC) that lasted for 4 to 8 s. This was then followed by the fatigue protocol which consisted of six bursts of contractions fixed at 30 s on and 10 s off. Immediately after the exercise to fatigue, the subjects performed another three IMVC in response to the light signals. Repeated measures ANOVA were performed to examine the effects of fatigue at these three positions on the electromechanical delay (EMD), median frequency (f _med), peak force (F _peak) and root mean square (rms)-EMG:F _peak quotient of VMO and VL. The results revealed a significant effect of the three knee joint angles on the EMD before the fatigue (P < 0.05). The fatigue protocol induced a significant decrease in F _peak at all the three positions (P < 0.01). However, the fatigue induced a significant decrease of f _med at only 90° and 150° of knee extension (P < 0.01). This occurred in parallel with the lengthening of EMD at these two joint angles (P < 0.01 and P < 0.05). The effects of fatigue on the f _med and EMD were not significant between VMO and VL at all three angles. The insignificant difference in f _med and EMD between VMO and VL at the three knee positions before and after fatigue indicated that no preferential onset activation between VMO and VL had occurred. Accepted: 1 September 2000     

Is MED13L-related intellectual disability a recognizable syndrome?

Introduction

MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.

Assessment of cancer immunotherapy outcome in terms of the immune response time features.

A cytokine-based periodic immunotherapy treatment is included in a model of tumour growth with a delay. The effects of dose schedule are studied in the case of a weak immune system and a growing tumour. We find the existence of 'metastable' states (that may last for tens of years) induced by the treatment and also potentially adverse effects of the dosage frequency on the stabilization of the tumour. These two effects depend on the delay between the tumour growth and the immune system response, the cytokine dose burden, and other parameters considered in the model.     

Wiedemann‐Steiner syndrome in two patients from Portugal

Wiedemann‐Steiner syndrome (WSS) is a rare genetic disorder characterized by growth retardation, facial dysmorphism, hypertrichosis cubiti and neurodevelopment delay. It is caused by pathogenic variants in the KMT2A gene. This report describes two unrelated Portuguese patients, age 11 and 17 years, with a phenotype concordant with WSS and clinical and molecular diagnosis of WSS by the identification of two novel frameshift variants in the KMT2A gene. This work also highlights the presence of certain clinical features in patients with growth retardation and development delay and should draw attention to the diagnosis of WSS, when hirsutism, particularly hypertrichosis cubiti is present.     

Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene

Around 6% of infants born to mothers taking anticonvulsants have malformations, including neural tube defects, and a further proportion show developmental delay in later childhood. Three commonly used anticonvulsants, carbamazepine, phenytoin and sodium valproate, interfere with folic acid metabolism. We investigated the common 677 C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in samples from 57 patients and their parents and 152 controls to determine its contribution to the risk of fetal anticonvulsant syndrome. The 677 C>T mutation frequency was significantly higher in the mothers than in the controls, but there was no significant difference in 677 C>T frequency in the patients or in the fathers. Genotype frequencies in the mothers were significantly different from controls, there being an excess of 677 C>T homozygotes. Amongst the patients, there was an apparent excess of heterozygotes (not statistically significant), and the fathers were not significantly different from controls. Mutation in the MTHFR gene in a mother taking sodium valproate, phenytoin or carbamazepine during pregnancy is associated with fetal anticonvulsant syndrome in her offspring. The skewed distribution of genotypes in the affected children probably reflects the association of fetal anticonvulsant syndrome with the maternal genotype.     

Sonic phase delay from trachea to chest wall: spatial and inhaled gas dependency

A parametric phase delay estimation technique is used to determine the spatial and inhaled gas composition dependencies of sound propagation time through an intact human lung at frequencies of 150–1200 Hz. Noise transmission measurements from the mouth to the extrathoracic trachea and six sites on the posterior chest wall are performed in 11 healthy adult subjects at resting lung volume after equilibration with air, an 80% helium-20% oxygen mixture, and an 80% sulfurhexafluoride-20% oxygen mixture. The phase delay, τ(f), exhibits a bilateral asymmetry with relatively decreased delays to the left posterior chest as compared with the right. The phase delay to lower lung sites is greater than to upper sites at frequencies below 300 Hz; yet the opposite is found at higher frequencies, indicating changing propagation pathways with frequency. There is no measurable effect of inhaled gas composition on τ(f) below 300 Hz. At higher frequencies, changes in τ(f) that reflect the relative sound speed of the particular inhaled gas are observed. These findings support and extend previous measurements and hypotheses concerning the strong frequency dependence of the acoustical properties of the intact respiratory system.     

Long‐term observation of a Japanese mucolipidosis IV patient with a novel homozygous p.F313del variant of MCOLN1

Mucolipidosis type IV (MLIV) is an autosomal recessively inherited lysosomal storage disorder characterized by progressive psychomotor delay and retinal degeneration that is associated with biallelic variants in the MCOLN1 gene. The gene, which is expressed in late endosomes and lysosomes of various tissue cells, encodes the transient receptor potential channel mucolipin 1 consisting of six transmembrane domains. Here, we described 14‐year follow‐up observation of a 4‐year‐old Japanese male MLIV patient with a novel homozygous in‐frame deletion variant p.(F313del), which was identified by whole‐exome sequencing analysis. Neurological examination revealed progressive psychomotor delay, and atrophy of the corpus callosum and cerebellum was observed on brain magnetic resonance images. Ophthalmologically, corneal clouding has remained unchanged during the follow‐up period, whereas optic nerve pallor and retinal degenerative changes exhibited progressive disease courses. Light‐adapted electroretinography was non‐recordable. Transmission electron microscopy of granulocytes revealed characteristic concentric multiple lamellar structures and an electron‐dense inclusion in lysosomes. The in‐frame deletion variant was located within the second transmembrane domain, which is of putative functional importance for channel properties.