Evolution of epilepsy and EEG findings in Angelman syndrome.

PURPOSE: To evaluate the evolution of epileptic seizures and EEG features in a large group of patients with Angelman syndrome (AS). METHODS: Thirty-six patients with AS with a proven chromosome 15q11-13 deletion were retrospectively analyzed with regard to their epilepsy and EEG findings by examination of patient files and EEGs. AIJ EEGs were reviewed by one of the authors. A logistic regression model, with a follow-up from 1 to 39 years (mean, 15 years), was used for statistical analysis. RESULTS: Epileptic seizures had occurred in 30 (83%) patients. In 43% of them, the initial symptoms of epilepsy were febrile convulsions in infancy. In childhood, epilepsy could start with almost any type of seizure. Atypical absences and myoclonic seizures prevailed in adulthood. Epileptic seizures were present in 92% of the adult patients. The most typical EEG findings were rhythmic triphasic delta waves of high amplitude with a maximum over the frontal regions, identified in 99 (66%) of 150 EEGs, and continuously or intermittently, in 30 (83%) of 36 patients with AS. In 47% it was present even before a clinical diagnosis of AS was considered. High-amplitude rhythmic 4-6/s slow activity, seen in 44 (29%) of 150 EEGs, was not present after the age of 12 years. CONCLUSIONS: In contrast to previous reports suggesting a decreasing frequency of epileptic seizures with age, we found that 92% of the adult patients with AS continued to have epileptic seizures. The most typical EEG finding in AS, in both children and adults, was the presence of frontal triphasic delta waves. In mentally retarded patients, this EEG pattern should point the physician in the direction of AS.

Acute and chronic effect of molsidomine extended release on exercise capacity in patients with stable angina, a double-blind cross-over clinical trial versus placebo.

A double-blind, placebo-controlled, cross-over study was performed in 50 patients with ischemic heart disease and stable angina to determine the duration of efficacy of 8 mg molsidomine in extended-release form. Exercise testing was performed at baseline and 2, 4, 6, 8, and 10 h after intake of either the medication or the placebo. Total duration of exercise (in minutes) and total work performance (workload x min) was significantly improved in the molsidomine retard group, not only compared with baseline but also with placebo for all time-points. ST segment depression at 60 W and at maximal exercise improved similarly until 10 h after molsidomine retard treatment. The rate-pressure product (heart rate x systolic blood pressure) showed significant improvement only at 60 W. No attenuation of the obtained effects was observed after 14 days of treatment. The number of anginal attacks and the consumption of sublingual nitroderivates were significantly reduced with molsidomine retard 8 mg as compared with placebo. Molsidomine retard 8 mg is effective until at least 10 h after oral (p.o.) intake. A dose schedule of molsidomine retard 8 mg twice daily definitely reduces anginal symptoms.

Acrofacial dysostosis of unknown type: nosology of the acrofacial dysostoses.

We describe a stillborn girl with an unclassified form of mandibulofacial dysostosis, a postaxial defect of the right, and a preaxial defect of the left hand. The Nager syndrome is characterized by preaxial limb defects, whereas the Genée-Wiedemann syndrome (= Miller syndrome) by postaxial limb defects. We briefly review the established acrofacial dysostoses (AFD) and discuss the position of our case in the current classification.

Clinical profile of Angelman syndrome at different ages.

We describe 47 patients with Angelman syndrome (AS) from Belgium and the Netherlands, including the anamnestic data, the clinical and the behavioral attributes at different ages. The clinical picture of AS is most distinct between the ages of 2-16 years. Most patients of this age group show at least 8 of the major characteristics (bursts of laughter, happy disposition, hyperactive behaviour, microcephaly, brachycephaly, macrostomia, tongue protrusion, mandibular prognathism, widely spaced teeth, stiff and puppetlike movements, typical stature, wide based gait) beside the mental retardation and (almost) absence of speech, which is a universal trait. The diagnosis in infants is based on only a limited number of clinical characteristics or on anamnestic data. However, if these occur in combination, they are indicative of AS. In older patients, the diagnosis may be hampered in part because of the changing behavioral characteristics and the decreasing frequency of fits. Other manifestations, such as scoliosis, may become more pronounced with age.

Localization of a gene responsible for nonspecific mental retardation (MRX9) to the pericentromeric region of the X chromosome.

Nonspecific X-linked mental retardation (MRX) includes several distinct entities with mental retardation but without additional distinguishing features. The MRX family reported here has been classified previously as MRX9. In this study, we performed linkage analysis of MRX9 with a panel of 43 polymorphic DNA markers dispersed over chromosome X. Two-point linkage analysis revealed lod scores of 3.52 and 3.82 at 0% recombination for OATL1 and MAOA, both located in Xp11.2-p11.4. Lod scores for linkage with PGK1P1, DXS106, and DXS132, all located in Xq11-q13, were 3.83, 3.82, and 3.52, respectively, all at 0% recombination. Multipoint linkage analysis showed two peaks with MAOA and DXS132/DXS106, respectively. Analysis of recombinational events indicated a position of the MRX9 gene between DXS164 and DXS453. These findings are compatible with a location of the MRX9 gene in the pericentromeric region of the X chromosome at Xp21-q13.

Two siblings with midline field defects and Hirschsprung disease: variable expression of Toriello-Carey or new syndrome?

We describe 2 sibs with multiple congenital anomalies. The main manifestations include hypoplasia of the corpus callosum and/or cerebellar hypoplasia, Robin sequence, pharyngeal and laryngeal hypoplasia, abnormal ears, excessive neck skin, cardiac defect, and Hirschsprung disease. The presence in 2 sibs born to healthy, consanguineous parents suggests autosomal recessive inheritance. These anomalies must have arisen during blastogenesis; the syndrome resembles most the condition described in 1988 by Toriello and Carey.

Molecular study of chromosome 15 in 22 patients with Angelman syndrome.

DNA studies in 22 families with Angelman syndrome (AS) were performed using the chromosome 15 marker loci D15S9, D15S10, D15S11, D15S12, D15S13, D15S18, D15S24, D15S86, the alpha-actin gene and the GABA beta 3 receptor gene (GABRB3). Uniparental disomy of chromosome 15 was excluded in all patients. Eighteen AS patients (82%) showed a molecular deletion of chromosome 15q11-q13 with one or more of these markers. No duplications of junction fragments, bridging deletions or duplication breakpoints were observed. The GABRB3 gene was deleted in all deletion-positive patients tested. Analysis of maternal DNA indicated that each deletion was a de novo event. All deletions were of maternal origin; this is in agreement with genomic imprinting in AS.

Reciprocal translocation between the proximal regions of the long arms of chromosomes 13 and 15 resulting in unbalanced offspring: characterization by fluorescence in situ hybridization and DNA analysis.

We describe two female siblings with similar clinical features consisting of hydrocephalus, scaphocephaly, hypotonia, mongoloid eye slant, blepharophimosis, micrognathia, supernumerary mouth frenula and mental retardation. Routine cytogenetic studies in the elder patient did not reveal any abnormality, and initially it was assumed that the syndrome had an autosomal recessive inheritance. However, a slightly larger chromosome 13 was seen in routine G-banded metaphases of the mother and the youngest of the two siblings. A shorter chromosome 15 was detected in the mother only. High resolution banding showed that the abnormal chromosome 13 contained an extra G-positive band at 13q12. The short chromosome 15 in the mother appeared to have a deletion of band q12. Fluorescence in situ hybridization using DNA markers specific to chromosomes 13 and 15 unequivocally showed that the mother was a carrier of a balanced reciprocal translocation t(13;15)(q12;q13), whereas the youngest sibling's karyotype was 46,XX,-13,+der(15)t(13;15)(q12;q13)mat, resulting in partial monosomy 13pter----q12 and partial trisomy 15pter----q13. The proband is thus trisomic for the critical region responsible for Prader-Willi syndrome and Angelman syndrome; this was confirmed by DNA analysis demonstrating one paternal and two maternal alleles from multiallelic marker loci mapping to 15q11-q13. This report illustrates the sensitivity and specificity offered by fluorescence in situ hybridization and its usefulness in the diagnosis and delineation of subtle chromosomal rearrangements.

Acardiac amorphous twin with prune belly sequence in the co-twin.

We describe a twin with acardia acephalus or "Twin Reversed Arterial Perfusion Sequence" and prune belly sequence in the co-twin. In a former quite similar case a prune belly appearance of the co-twin of an acardiac fetus was found to be secondary to the ascites caused by cardiac failure. In the present case, we are dealing with the prune belly sequence as a separate condition, given the fact there were no signs of ascites or cardiac failure. We also found associated anomalies: agenesis of the left ureter and kidney, dysplastic right kidney and anal atresia. Urinary tract obstruction has never been described in the co-twin of an acardiac amorphous fetus.

Neonatal Marfan syndrome with congenital arachnodactyly, flexion contractures, and severe cardiac valve insufficiency.

We describe a male neonate with severe arachnodactyly, hypermobility of the fingers, flexion contractures of elbows, wrists, hips, and knees, micrognathia, crumpled ears, rockerbottom feet, loose redundant skin, and ocular abnormalities. Severe cardiac valve insufficiency and aortic dilatation resulted in cardiac failure and death 20 hours after birth. This case represents the severe end of the clinical spectrum of Marfan syndrome. As similar patients have been reported, they may represent a separate mutation.

[Angelman's happy puppet syndrome]. / Het 'happy puppet' syndroom van Angelman.

The Angelman ('happy puppet') syndrome is clinically characterized by severe mental retardation without any development of speech, a happy disposition with paroxysms of laughter, a stiff-atactic gait with arms in flexion and abduction, epileptic seizures, EEG-abnormalities, and some dysmorphic features like prognathism, macrosomia, tongue protrusion and brachycephaly and/or microcephaly. The genetic background is still obscure, but in some patients with this syndrome small deletions in the long arm of chromosome 15 have been found. So further investigation of this probably rather frequent syndrome seems appropriate.

A single maxillary incisor as a manifestation of an ectodermal dysplasia.

A single, central, maxillary incisor was found in a patient with an ectodermal dysplasia.