Infantile autism—fragile X: Molecular findings support genetic heterogeneity

Twenty-two members of 18 families with autism have been examined for the presence of mutations and abnormal methylation in the FMR-1 region at Xq27.3. All patients fulfilled diagnostic criteria of infantile autism. A characteristic pattern of insertion and methylation were detected after Southern blot analysis in 7 autistic individuals expressing the fragile site at Xq27.3. Normal DNA patterns were observed in 15 autistic boys cytogenetically negative for the fragile site. The results indicate a lack of involvement of the FMR-1 region in infantile autists negative for fragile X expression. © 1992 Wiley-Liss, Inc.     

New type of spinocerebellar degeneration syndrome in a northern Swedish population

A follow-up investigation of 24 patients with hereditary spasticity in a geographically isolated northern Swedish population, first examined by Böök (1953), was performed. Fifteen of them were dead. During the period from 1950–1972 five new cases of spastic syndromes were diagnosed in this population. The patterns of clinical symptoms and the genetic associations between the new and 24 previously reported patients with spastic syndromes were analyzed. Three of the five new cases had a specific syndrome. This starts in the first years of life with ataxia, which is followed by dysarthria, spasticity and jerky intention tremor. Initially the patients are mentally normal, but there seems to be slight mental deterioration through the years. The disorder is a progressive spinocerebellar degeneration with autosomal recessive inheritance.     

Effect of Renal Impairment on the Pharmacokinetics and Tolerability of Tiagabine

Summary: Purpose: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB).
Methods: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4–6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB · HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively.
Results: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t1/2) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 I/h, and from 6.4 to 8.4 h, respectively.
Conclusions: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.     

DNA synthesis of human XYY cells

The autoradiographic YY labelling pattern of the DNA replication in 47, XYY cells of two patients has been studied. Both Y chromosomes began DNA replication simultaneously but later than the rest of the chromosomes. During later stages the YY labelling pattern in both patients was correlated to the position of the cells in S, as indicated by the cell grain count: in cells with more than approximately 500 grains the synchronous labelling of the Y chromosomes was the rule; whereas during later stages in cells with approximately 100–400 grains, synchronous as well as asynchronous labelling in the same patient was found. In cells with less than about 100 grains, both Y chromosomes usually had completed replication. No obvious difference between the labelling pattern of the two Y chromosomes was found when cells from the 2 patients were compared at the same stage of S. Our results demonstrate the importance of analysing cells of comparable developmental stages of S when comparing DNA labelling patterns of different XYY individuals in search of a possible correlation between labelling pattern and phenotypic expression of the syndrome.
In one of the patients the QM fluorescence pattern as well as the autoradiographic pattern of the same cells was studied. The characteristic intense fluorescence pattern of both Y chromosomes was found even in cells where the autoradiographic labelling pattern indicated distinct asynchrony between the two Y chromosomes. The significance of these findings is discussed.     

Methylation and mutation patterns in the fragile X syndrome.

Chromosomes carrying the mutation causing the fragile X [fra(X)] syndrome have been shown to have an unstable DNA sequence close to or within the fragile site. The length variation is located within a DNA fragment containing a CGG trinucleotide repeat which is unstable in both mitosis and meiosis. We have used the probe StB12.3 from the region to analyze the mutations and the methylation patterns in 21 families segregating for the fra(X) syndrome. Among 40 fra(X) males all showed an abnormal pattern. The normal 2.8 kb band was absent in 36 individuals and replaced by a heterogeneous smear of larger size. The remaining four were shown to be "mosaics" with the presence of both mutated, unmethylated and mutated, methylated fragments. We found four normal transmitting males, one which was a great-grandson of another normal transmitting male indicating that the pre-mutation can remain stable through two meioses in the female. In nine fra(X) positive females the abnormal pattern consisted of a smear, usually seen in affected males, in addition to the normal bands. Five of these females were mentally normal. Of clinical importance is the prediction of mental impairment in females. We suggest that this is not made by the detection of the full mutation alone, but rather by the degree of methylation of the normal X chromosome. Our results suggest that difference of clinical expression in monozygotic twins may be correlated with difference in methylation pattern. Six out of 33 fra(X) negative females at risk were diagnosed as carriers. Our observations indicate that molecular heterogeneity is responsible for variable expression of the fra(X) syndrome in both males and females.     

Familial partial trisomy 5p resulting from segregation of an insertional translocation

A case of duplication of segment p13-p15 of the short arm of chromosome 5 as the result of an insertional translocation in a mentally retarded girl with congenital anomalies is reported. Some of the apparently balanced carriers of the inverted insertion showed minor congenital anomalies.     

Catechol-O-methyltransferase activity in erythrocytes in Down''s syndrome: family studies

Catechol-O-methyltransferase (COMT) activity in erythrocytes was measured in six children with Down's syndrome and in their parents to determine if COMT activity is related to a gene on chromosome 21. A gene dosage effect was a possible explanation of the COMT value in three of the children but not in the other three.     

Syndrome characterized by lingual malformation, Polydactyly, tachypnea, and psychomotor retardation (Mohr syndrome)

A 2-year-old girl, who at birth exhibited lingual malformation, Polydactyly, and tachypnea and who subsequently developed severe psychomotor retardation, is described. The syndrome corresponds to the Mohr syndrome and is compared with the oral-facial-digital (OFD) syndrome from a clinical and genetic point of view.     

Platelet monoamine oxidase activity in Down's syndrome

The activity of platelet monoamine oxidase in Down's syndrome cases was significantly lower than that of controls. This difference was found for both males and females, and with tyramine, tryptamine and β-phenethylamine as substrate. The K_m values of the monoamine oxidase towards tryptamine as substrate from controls and Down's syndrome patients were similar.     

Measuring the instructional validity of clinical simulation problems

Written clinical simulation problems in two formats--forced-choiced and essay--were used to test junior and senior medical students at the conclusion of their pediatric rotations. A comparison was made in the performance of students with varying levels of clinical experience. There seemed to be no consistent pattern of improvement with increased instructional time on the forced-choice management problems. Junior students did show improvement over time on the essay management problems, which also seemed to reflect the increased problem-solving and organizational skills of seniors in comparison to juniors. Correlations across problems and correlations between the clinical problem test and other measurement techniques were very weak, partly due to the low sampling reliability of clinical simulation problems. In this study, clinical simulation problems failed to demonstrate responsiveness to development and maturation in the problem-solving approach to patient care.