Characterization of the first supernumerary tricentric ring chromosome 1 mosaicism by conventional and molecular cytogenetic techniques.

We report on the conventional cytogenetic and fluorescence in situ hybridization (FISH) results obtained for a 3.5-year-old girl with developmental and language delay and a supernumerary ring chromosome mosaicism in 8% of T-lymphocytes analyzed. Using different conventional and molecular cytogenetic techniques as YAC hybridization and comparative genomic hybridization, we could show that the extra tricentric ring chromosome consists of three heterochromatic blocks with inserted euchromatic material. Additionally, chromosome microdissection followed by FISH analysis demonstrated that the small tricentric ring chromosome consisted of material from the pericentromeric region of chromosome 1q21. Thus, the patient has a mosaic of normal cells and cells with partial pentasomy of the pericentromeric region of chromosome 1. So far, 19 cases with single supernumerary marker chromosome 1 have been published, but no tricentric ring chromosome 1 is, to our knowledge, reviewed in the literature. In this study, we compare the clinical features of our patient with cytogenetically comparable cases described in the literature. We introduce a hypothesis for the formation of a tricentric ring chromosome: starting with a monocentric ring, sister chromatid exchange leading to the formation of a tetracentric ring, which underwent intrastrand recombination generating the tricentric ring.

Long-term follow-up study of vigabatrin in pretreated children with West syndrome.

A multicentre, long-term, open-label, add-on study of vigabatrin was undertaken in 23 pretreated children with infantile spasms. After 3 months of vigabatrin therapy 11 of the 23 patients had become seizure-free. At this time two-thirds of these 11 children still received other antiepileptic drugs (AEDs) in addition to vigabatrin (mostly valproic acid and/or dexamethasone). After a mean follow-up time of 5 1/4 years (range: 4 1/4-6 1/2) 72% of 18 evaluable patients (two children died, three were lost to follow-up) revealed seizure freedom for at least 1 year. The mean duration of vigabatrin therapy had been 2 1/2 years (range: 2 weeks to 4 3/4 years). Two-thirds of the 18 children continued to take AEDs, three of them undergoing vigabatrin monotherapy. Relapses of infantile spasms had occurred in 14% of the children. The rate of vigabatrin side effects (10%) was low. At follow-up, the EEG of 13 and the 18 patients demonstrated focal or multifocal epileptic discharges. Fifty-five percent had developed another epilepsy (focal epilepsy, secondary generalized epilepsy or myoclonic-astatic epilepsy). With respect to mental functions, three children were normal or slightly retarded, four showed moderate retardation and 11 revealed severe or very severe retardation. This long-term result is comparable to that in ACTH studies with unselected patients. The conclusions are: (1) vigabatrin is an effective drug for the short-term and long-term treatment of refractory infantile spasms; (2) the relapse rate is low; (3) vigabatrin is well tolerated; (4) with respect to secondary epilepsies and mental functions the long-term outcome in these pretreated children is similar to that in earlier studies with ACTH or corticosteroids.

Long-term outcome of children with fetal alcohol syndrome: psychopathology, behavior, and intelligence.

Within an interdisciplinary research project, the long-term outcome of children with fetal alcohol syndrome was studied. Methods for the assessment of psychopathology, behavior, and intelligence included psychiatric interviews, behavior checklists for parents and teachers, and intelligence tests. The children were assessed during preschool age, early school age (6 to 12 years), and late school age (> or =13 years). An excess of psychopathology, (including hyperkinetic disorders, emotional disorders, sleep disorders, and abnormal habits and stereotypes) with a strong persistence over time was found. Cognitive functioning was marked by a large proportion of mentally retarded children and also did not change considerably over time. This long-term outcome study reflects the handicapping effects of fetal alcohol syndrome.

Antiepileptic drugs alter endogenous retinoid concentrations: a possible mechanism of teratogenesis of anticonvulsant therapy.

The major antiepileptic drugs used for the control of seizures can induce developmental toxicity when administered during pregnancy. Vitamin A and retinoids are thought to control many processes of embryonic development including growth, differentiation and morphogenesis. We have therefore studied if the teratogenic action of antiepileptic agents could be mediated via alteration of the endogenous vitamin A--retinoid metabolism. Retinol and its oxidative metabolites all-trans-, 13-cis- and 13-cis-4-oxo-retinoic acid were measured in the plasma of 75 infants and children treated with various antiepileptic drugs for the control of seizures, and in 29 untreated controls of comparable age. Retinol levels increased with age, while the concentrations of retinoic acid compounds did not exhibit age-dependency. Valproic acid monotherapy increased retinol levels in the young age group and a trend toward increased retinol concentrations was also observed in all other patient groups. The plasma levels of the oxidative metabolites 13-cis- and 13-cis-4-oxo-retinoic acids were strongly decreased in all patient groups treated with phenytoin, phenobarbital, carbamazepine and ethosuximide, in combination with valproic acid, to levels which were below 1/3rd and 1/10th of corresponding control values, respectively. Little changes were observed with all-trans-retinoic acid except in one patient group treated with valproic acid/ethosuximide cotherapy where increased levels of this retinoid were found. Our study indicates that therapy with antiepileptic agents can have a profound effect on the endogenous retinoid metabolism. Because of the importance of retinoids for the signaling of crucial biological events during embryonic development, such altered retinoid metabolism may be highly significant in regard to antiepileptic drug teratogenesis.

The fetal alcohol syndrome in adolescence.

At present, alcohol is recognized as the leading teratogenic agent in long-lasting CNS dysfunction. Little is known about the long-term development and outcome of children with fetal alcohol syndrome (FAS). Forty-four FAS patients who were diagnosed in early childhood were followed up for 10-14 years. This study documents the developmental changes of the manifestations of FAS from childhood to adolescence and describes a characteristic "juvenile" pattern of FAS, which may help to identify this syndrome even in adolescence. This is especially relevant for patients who were not diagnosed earlier.

Correlates of psychopathology and intelligence in children with fetal alcohol syndrome.

After documenting the wide range of psychopathology and impairment of intellectual functioning in earlier contributions, the present report from long-term observations of an extended cohort of children with Fetal Alcohol Syndrome (FAS) deals with correlates of psychopathology and intelligence in these children. At preschool age, severity of morphological damage, the type of milieu, sex and IQ were significant predictors of psychopathology. In another subgroup of school-aged children, these associations were less strong; only severity of morphological damage and IQ still correlated to some extent significantly with psychopathology. Intelligence was significantly impaired in those children with severe morphological damage who were raised in institutions.

Long-term psychopathological and cognitive outcome of children with fetal alcohol syndrome.

OBJECTIVE: The long-term outcome of a large cohort of children suffering from fetal alcohol syndrome was studied. METHOD: Structured psychiatric interviews, behavior checklists for parents and teachers, and intelligence tests were used. Assessments took place during preschool age, early school age (6 to 12 years), and late school age (> or = 13 years). RESULTS: There was an excess of psychopathology with a wide variety of psychiatric syndromes in this cohort. Hyperkinetic disorders, emotional disorders, sleep disorders, and abnormal habits and stereotypes persisted over time. Interview findings were largely in accordance with parents' and teachers' questionnaire findings. Intelligence test findings included a large proportion of mentally retarded children and displayed high stability at follow-up. CONCLUSIONS: The development of children suffering from fetal alcohol syndrome is jeopardized by a high rate of persistent psychiatric and cognitive impairments.

Prenatal alcohol exposure and long-term developmental consequences.

Fetal alcohol syndrome (FAS) is a leading cause of congenital mental retardation but little is known about the long-term development and adolescent outcome of children with FAS. In a 10-year follow-up study of 60 patients diagnosed as having FAS in infancy and childhood, we investigated the long-term sequelae of intrauterine alcohol exposure. We found that the characteristic craniofacial malformations of FAS diminish with time, but microcephaly and, to a lesser degree, short stature and underweight (in boys) persist; in female adolescents body weight normalises. Persistent mental retardation is the major sequela of intrauterine alcohol exposure in many cases, and environmental and educational factors do not have strong compensatory effects on the intellectual development of affected children.

[Alcohol drinking and intrauterine dystrophia. Effects and significance in infancy]. / Alkoholkonsum und intrauterine Dystrophie. Auswirkungen und Bedeutung im Säuglingsalter.

In a prospective study intrauterine growth retardation (IUGR) (less than 10. growth percentile at birth) was used as a predictor to diagnose intrauterine alcohol exposure. An interview about maternal alcohol consumption was performed prenatally--when IUGR was diagnosed by ultrasound--or postnatally. The children were followed up to 18 months of age. In 6/47 children we diagnosed various degrees of the Fetal Alcohol Syndrome FAS, with only one patient showing a full blown syndrome at birth. 5 patients could not be identified until the pediatric reexamination at the age of 8-18 months. IUGR and a maternal history of even moderate drinking during pregnancy should emphasize the possibility of an intrauterine alcohol damage, even in a normal child at birth.

[GM2 gangliosidosis, O variant (Sandhoff disease): suspected diagnosis of a storage disease by ultrasound]. / GM2-Gangliosidose, Variante O (M. Sandhoff): Verdachtsdiagnose einer Speicherkrankheit durch Ultraschall.

We report on a 3.6 year old boy who suffers from Sandhoff disease. The diagnosis was suspected because of striking ultrasound findings: Parts of the thalamus were more echogenic, the cortical gyri were sharp and accentuated. The CT- and MRI features were similar to the US-findings. The diagnosis was confirmed by demonstrating the typical enzyme deficiency in leucocytes.

Angelman ("happy puppet") syndrome--seven new cases documented by cerebral computed tomography: review of the literature.

We report on seven children with Angelman syndrome presenting with psychomotor retardation during the 1st year of life. Seizures developed in six patients, and computed tomography (CT) scanning showed diffuse atrophy of the brain in five patients. We conclude that diagnosis is difficult in the first years of life. A review of the literature is given.

Therapy of infantile spasms with valproate: results of a prospective study.

In a prospective study, 22 children with recently manifested infantile spasms (18 patients with symptomatic and 4 with idiopathic infantile spasms) were treated with sodium valproate (VPA). Before VPA was instituted, a loading test was performed to exclude abnormal patterns of VPA metabolites by gas chromatography and mass spectroscopy of serum and urine. This test was repeated during VPA therapy; an abnormal pattern of VPA metabolites was not observed. VPA was started in increasing dosage until infantile spasms were controlled or a maximum dose of 100 mg/kg/day was reached. If VPA did not control seizures or at least reduce frequency significantly after a trial of 4-6 weeks, dexamathasone was added to VPA. If focal seizures occurred in association with localized epileptogenic EEG discharges, carbamazepine (CBZ) was added to VPA. After 4 weeks of VPA monotherapy, infantile spasms were controlled in 11 children. After 3 months of therapy, 16 children were free of seizures (14 patients VPA monotherapy), and 4 children had reduction of seizure frequency to less than 25%. VPA doses varied between 40 and 100 mg/kg/day (mean 74). The mean plasma concentration was 113 micrograms/ml (range 46-177). After 6 months of therapy, total seizure control was achieved in 20 of 22 patients (16 children VPA monotherapy). The mean observation time was 16 1/2 months (range 6-36 months). There were seven relapses in six children during the first 7 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Follow-up studies of children with fetal alcohol syndrome.

Data coming from a prospective multidisciplinary study with repeated examinations of children with fetal alcohol syndrome (FAS) are reported. These patients underwent pediatric, neurological and psychiatric assessment, EEG-recordings and psychological testing. After a period of 3-4 years various subgroups of these children were re-examined. Follow-up examinations revealed that with increasing age dysmorphic signs became less apparent in children with FAS. Furthermore, neurologic performance improved and EEG-recordings revealed less pathological patterns. These positive findings were confirmed by the observation that these patients also experienced an improvement with regard to psychiatric status and cognitive functions. But it must be stated that the affected children did not become normal in all psychiatric areas. Hyperactivity and distractibility seem to be the major handicap for a normal school career of these children. In general biological maturation seems to be the main factor responsible for the outcome of FAS.

[The course of alcoholic embryopathy]. / Der Verlauf der Alkoholembryopathie.

Pediatric examinations were performed in 71 children with fetal alcohol syndrome (FAS). A subgroup of these patients underwent neurological and psychiatric assessment and psychological testing. Psychopathology was also studied in a matched control group. After a period of 3-4 years various subgroups of these children were re-examined. Follow-up examinations revealed that with increasing age dysmorphic signs became less apparent in children with FAS. Furthermore, neurologic performance improved and EEG-recordings revealed less pathological patterns. These positive findings were confirmed by the observation that these patients also experienced an improvement with regard to psychiatric status and cognitive functions. But it must be stated that the affected children did not become normal in all psychiatric areas. Hyperactivity and distractability seem to be the major handicaps for a normal school career of these children.

Clinical, psychopathological and developmental aspects in children with the fetal alcohol syndrome: a four-year follow-up study.

Paediatric, neurological and psychiatric examinations were done in 71 children with the fetal alcohol syndrome (FAS). A subgroup of these patients underwent psychiatric assessment and psychological testing. Psychopathology was also studied in a matched control group. After three to four years various subgroups were re-examined. With increasing age dysmorphic signs were less apparent. Neurological performance improved and EEG recordings revealed fewer pathological patterns. The psychiatric status and cognitive functions of the patients also improved, but they did not become normal in all psychiatric areas. Hyperactivity and distractibility seem to be the major handicaps preventing these children from having a normal school career.

Fetal alcohol syndrome and mental retardation: spine distribution of pyramidal cells in prenatal alcohol-exposed rat cerebral cortex; a Golgi study.

Among the various possible effects of the fetal alcohol-syndrome (FAS), mental retardation can be considered the most deleterious. In animal studies, prenatal alcohol exposure has been shown to result in increased neonatal mortality, retarded cerebellar development and a significant decrease in neonatal brain weight. In a Golgi study on Wistar rats that were prenatally exposed to alcohol the spine distribution in proximal apical dendrites of layer V pyramidal cells of the parietal cortex was examined. As compared with controls, a distinct spine abnormality could be demonstrated at 12 days and at 40 days of postnatal age: a persistent predominance of long, thin and entangled spines, and a decreased number of normal stubby and mushroom-shaped spines. These abnormal dendritic patterns show a striking resemblance to those described by Purpura in mentally retarded children of normal karyotype.

[The incomplete fetal alcohol syndrome]. / Zum Problem der "abortiven" Alkoholembryopathie.

In contrast to the wellknown picture of the "fetal alcohol syndrome" (FAS), clinical symptoms of the incomplete FAS are less frequently recognized compared to the high incidence of the syndrome as stated in the literature. The diagnostic problem is a clear differentiation between mild forms of the incomplete FAS and clinical normality. Post-natal growth deficiency and microcephaly of unknown aetiology, clinical symptoms of hyperactivity, learning disabilities or mild mental retardation are the main features of the incomplete FAS. The diagnosis is established only by a positive history of maternal alcohol abuse.

Development and psychopathology of children with the fetal alcohol syndrome.

Extended psychiatric and pediatric examinations were performed on patients with the fetal alcohol syndrome (FAS). A subgroup of these patients underwent psychological testing to measure intelligence, visual perception, and psycholinguistic abilities. Psychopathology was also studied in a matched control group. The investigation revealed a broad scale of developmental hazards and psychopathologic symptoms indicating the negative long-range effects of alcohol abuse during pregnancy. The extent of morphologic damage was found to be a good predictor of psychopathology and mental impairment. Social environment and socioeconomic status appear less important as predictors.