Tetrasomy 18p de novo: parental origin and different mechanisms of formation.

We have used eight PCR-based DNA polymorphisms to determine the parental origin and mechanisms of formation in 9 patients with de novo nonmosaic tetrasomy 18p. The 9 patients, 4 girls and 5 boys, had clinical features characteristic of i(18p) syndrome. The supernumerary marker chromosome was identified by fluorescence in situ hybridization (FISH) analysis using centromeric probes and a flow-sorted 18p-specific library.

Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland.

The incidence of phenylketonuria (PKU) in Finland is extremely low, probably below 1 in 100,000. We describe the mutations and haplotypes in all four presently known patients. Mutation R408W was found on four mutant chromosomes (all haplotype 2), and IVS7nt1, R261Q, and IVS2nt1 were each found on a single chromosome.

A 10-year survey, 1980-1990, of prenatally diagnosed small supernumerary marker chromosomes, identified by FISH analysis. Outcome and follow-up of 14 cases diagnosed in a series of 12,699 prenatal samples.

A cytogenetic survey and follow-up studies were made of 14 cases with supernumerary marker chromosomes, identified among 12,699 prenatal samples, investigated at our institution over a 10-year period from 1980 to 1990. FISH (fluorescence in situ hybridization) techniques were employed to identify the chromosomal origin of the marker chromosomes. Five cases were familial, all derived from acrocentric chromosomes, and all without apparent phenotypic effects in the children.

In vivo assessment of mutations in the phenylalanine hydroxylase gene by phenylalanine loading: characterization of seven common mutations.

Unlabelled: Mutations in the gene encoding phenylalanine hydroxylase (PAH) cause persistent hyperphenylalaninaemia. To date, more than 200 point mutations and microdeletions have been characterized. Each mutation has a particular quantitative effect on enzyme activity and recessive expression of different mutant alleles results in a marked interindividual heterogeneity of metabolic and clinical phenotypes.

Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders.

We have isolated and chromosomally fine-mapped 16 novel genes belonging to the human zinc finger Krüppel family (ZNF131-140, 142, 143, 148, 151, 154, and 155), including 1 of the GLI type (ZNF143) and 3 containing a KRAB (Krüppel-associated box) segment (ZNF133, 136, and 140). Based on their map position, several of these ZNF genes are putative candidate genes for both developmental and malignant disorders: ZNF138, ZNF139, and ZNF143 were localized to 7q11.2, 7q21.

Characterization of the exon structure of the Menkes disease gene using vectorette PCR.

The gene defective in Menkes disease, an X-linked recessive disturbance of copper metabolism, has been isolated and predicted to encode a copper-binding P-type ATPase. We determined the complete exon-intron structure of the Menkes disease gene, which spans about 150 kb of genomic DNA. The gene contains 23 exons, and the ATG start codon is in the second exon.

Analysis of a whole arm translocation between chromosomes 18 and 20 using fluorescence in situ hybridization: detection of a break in the centromeric alpha-satellite sequences.

Using classical cytogenetic techniques, we detected a male patient with monosomy 18p/trisomy 20p, originating from a paternal reciprocal translocation of the short arms of chromosomes 18 and 20. To characterize the breakpoints further and to determine the centromeric origin of the chromosomes involved, we analyzed the metaphase chromosomes by fluorescence in situ hybridization using alpha-satellite DNA probes specific to chromosomes 18 and 20. With this approach, we showed that alpha-satellite centromeric fragments were involved in the translocation event and that the chromosome-18-specific centromeric sequences were split into two.

Dopamine precursors and brain function in phenylalanine hydroxylase deficiency.

Phenylalanine and tyrosine constitute the two initial steps in the biosynthesis of dopamine, which, in its turn, is the metabolic precursor of noradrenaline and adrenaline. The extracellular phenylalanine concentration influences brain function in phenylalanine deficiency (PHD) by decreased dopamine synthesis. It has been shown to induce EEG slowing, and prolonged the performance time on neuropsychological tests.

Mutations in the phenylalanine hydroxylase gene: genetic determinants for the phenotypic variability of hyperphenylalaninemia.

Phenylalanine hydroxylase (PAH) deficiency is a heterogeneous disease at the phenotype level. The spectrum of clinical and metabolic phenotypes spans from the potential pathogenic disease classical phenylketonuria (PKU) to the benign condition non-PKU hyperphenylalaninemia (non-PKU HPA). This review provides an introduction to the clinical variants of PAH deficiency, and summarizes our attempts to define the disease at the molecular level and to relate mutation genotype to clinical outcome.

Mutations in the phenylalanine hydroxylase gene: methods for their characterization.

Mutations in the phenylalanine hydroxylase (PAH) gene represent the root cause of PAH-deficient hyperphenylalaninemia. To date, more than 160 different mutations have been reported. Single-base substitutions and microdeletions account for the majority of molecular defects.

Hypoxic-hemodynamic pathogenesis of brain lesions in the newborn.

For more than a century two opposing views on the pathogenetic mechanisms and the timing of the origin of cerebral palsy (CP) have prevailed: the idea first formulated by Little attributing CP to "difficult deliveries" has been opposed by the view by Freud recognizing fetal influences, and the issue seems to be unsettled. The present review seeks to bridge the gap by recognizing that late prenatal or perinatal hypoxic-hemodynamic insult is a dominating final common path in the pathogenesis of static encephalopathies during development, in particular in premature infants. In turn, however, such lesions are determined by early genetic and environmental influences.

Prenatal stressors of human life affect fetal brain development.

In a population-based study, 3021 women in a central Copenhagen district received a questionnaire on environmental and psychological factors during mid-gestation. Of these, 70 women were selected consecutively on the basis of moderate to severe stressful life-events (DSM-III-R categories 3 to 5), in combination with an inadequate social network. They were compared with 50 non-stressed women with an intact social network.

Monozygotic twins discordant for gastroschisis: case report and review of the literature of twins and familial occurrence of gastroschisis.

We describe a pair of monozygotic (MZ) female twins discordant for gastrochisis. To our knowledge, this is the first such case reported. The zygosity was verified by DNA analysis using highly polymorphic microsatellites.

First trimester prenatal diagnosis of Menkes disease by DNA analysis.

Menkes disease is an X linked recessive disorder of copper metabolism characterised by neurological symptoms and connective tissue manifestations. The defective gene in Menkes disease has recently been isolated and the gene product is predicted to be a copper transporting ATPase. The diagnosis of Menkes disease has hitherto been performed by biochemical analysis, based on intracellular accumulation of copper.

Toward a functional analysis of self-injury.

This study describes the use of an operant methodology to assess functional relationships between self-injury and specific environmental events. The self-injurious behaviors of nine developmentally disabled subjects were observed during periods of brief, repeated exposure to a series of analogue conditions. Each condition differed along one or more of the following dimensions: (1) play materials (present vs absent), (2) experimenter demands (high vs low), and (3) social attention (absent vs noncontingent vs contingent).

Brain magnetic resonance imaging in children with optimally controlled hyperphenylalaninaemia.

This study was undertaken to investigate whether the white-matter changes on MRI and the EEG abnormalities detectable in treated adolescents and adults with hyperphenylalaninaemia (HPA) can be detected in younger children on an optimally controlled diet. The study included 17 children, 7-12 years of age, with HPA. The MRI of five healthy children were included in the blind evaluation of the MR images.

Mutation analysis in families with discordant phenotypes of phenylalanine hydroxylase deficiency. Inheritance and expression of the hyperphenylalaninaemias.

Neonatal hyperphenylalaninaemia caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) represents a wide spectrum of metabolic phenotypes, ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). The marked interindividual heterogeneity is due to the expression of multiple PAH mutations in genetic compounds. We have investigated four unusual families in which both PKU and MHP were present.

Sex dependent transmission of Beckwith-Wiedemann syndrome associated with a reciprocal translocation t(9;11)(p11.2;p15.5).

Beckwith-Wiedemann syndrome (BWS), a disorder associated with neonatal hypoglycaemia, increased growth potential, and predisposition to Wilms's tumour (WT) and other malignancies, has been mapped to 11p15. The association with 11p15 duplications of paternal origin, of balanced translocations and inversions with breakpoints within 11p15.4-p15.