Expanding the genotypic spectrum of Perrault syndrome.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.

Familial adenomatous polyposis: mental health, psychosocial functioning and reactions to genetic risk in adolescents.

Familial adenomatous polyposis (FAP) in a parent requires diagnostic follow-up and treatment from adolescence in possible gene carriers in order to prevent cancer development. A nationwide sample (n = 22) of adolescent FAP offspring including 85% of eligible individuals aged 11-20 years and their parents were interviewed with regard to adolescent mental health, psychosocial functioning, knowledge about FAP and genetic risk, and experiences with testing and surgery. Thirty-six percent of the FAP offspring fulfilled criteria for a psychiatric diagnosis. For adolescents older than 15 years, this was increased relative to a comparison group with Hirschprung's disease and a general population sample. Neither genetic testing nor FAP diagnosis in adolescent FAP-offspring differentiated significantly between those who fulfilled the criteria and those who did not for psychiatric diagnosis, while a global score of chronic family difficulties did. This may imply that experiencing parental illness more than inheriting FAP is a perceived stressor for adolescent FAP offspring.

High prevalence of Leptospira spp. in sewer rats (Rattus norvegicus).

Earlier studies on the ecology of leptospirosis in temperate regions focused mainly on free-ranging rats in rural areas. Here we report on the occurrence of Leptospira spp. in Rattus norvegicus living in sewers in a suburban area in Copenhagen, Denmark. In 2006-2007, about 30 rats were captured in sewers at each of six different locations. Rat kidneys were screened by PCR for pathogenic Leptospira spp. In one location no infected rats were found, whereas the prevalence in the remaining five locations ranged between 48% and 89%. Micro-agglutination tests showed that serogroup Pomona, Sejroe, and Icterohaemorrhagiae were the most common. Infection was related to age with the highest prevalence observed for adult rats but there was no difference in infection rate between sexes, suggesting primarily environmental transmission. Since most reported rat problems in urban areas are related to sewer rats, the surprisingly high level of infection calls for an increased public health concern.

Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.

The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. The protein truncation test (PTT), fragment length and heteroduplex analyses of large (0.8-1.2 kb) cDNA fragments were used. In total, 67 of 82 (82%) of the disease-causing alleles were characterized. Thirty-seven unique mutations were detected of which 25 have not previously been reported. The mutations had five different consequences for the ATM transcript: mutations affecting splicing (43%); frameshift mutations (32%); nonsense mutations (16%); small in-frame deletions (5%); and one double substitution (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands. One-third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygote with at least one identified allele. Ten alleles were found more than once; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disease-causing. Some of them even involved partial skipping of exons, leading to subsequent truncation of the ATM protein.

Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect.

The ATM gene is responsible for the autosomal recessive disorder Ataxia-Telangiectasia (AT). Many different mutations, located all across the gene, have been reported with a predominance of truncating mutations. By using PTT (protein truncation test) a mutation was found in one Norwegian AT family. Sequencing revealed that the mutation affected nucleotides 3245-3247, codon 1082, and changed the sequence from ATC to TGAT, inducing a stop codon downstream at codon 1095 and leading to early truncation of the ATM protein. Perpendicular DGGE (denaturing gradient gel electrophoresis) was used to screen 10 additional families for this mutation. The 3245 delATC insTGAT mutation was found in 12 of 22 proband alleles: five patients were homozygotes and two heterozygotes. Haplotype analyses were performed using eight microsatellite markers, within and flanking the ATM gene. All carriers of the mutation described were found to have a common haplotype of the five closest CA-repeat microsatellite markers. Genealogical investigations of the families identified a common ancestor for three of the families. The common ancestor was a woman born in 1684 in the area from which these families originate. The prevalence of this mutation in Norwegian patients now allows a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cancer risk can be evaluated.

The use of polymorphic DNA and protein markers for the third complement component for determining linkage of familial hypercholesterolaemia.

We have used DNA and protein polymorphisms for the third complement component (C3) to assess the potential of DNA markers in the diagnosis and study of familial hypercholesterolaemia (FH), and to confirm the reported linkage between FH and C3. The inheritance of FH and the C3 gene has been studied in 10 families by combining information from both the protein and DNA polymorphisms. Our results confirm that the C3 gene is loosely linked to the gene causing FH (lod score maximum of 2.0) at a recombination distance of 0.15. When these results are combined with previously published data the overall lod score maximum is 4.75 at a recombination distance of 0.2, meaning that the two genes will be inherited together in only about 80% of children. These results confirm that the gene that causes familial hypercholesterolaemia is linked to C3 and is therefore on chromosome 19, but C3 is not close enough to be used as a diagnostic marker.

Tentative assignment of a locus for Rubinstein-Taybi syndrome to 16p13.3 by a de novo reciprocal translocation, t(7;16)(q34;p13.3).

During a systematic chromosomal survey of 7 unrelated patients with Rubinstein-Taybi syndrome, an apparently balanced de novo reciprocal translocation, t(7;16)(q34;p13.3), was detected in an affected boy. The involvement of the region 16p13.3 coincides with the position of one of the breakpoints in another de novo reciprocal translocation associated with Rubinstein-Taybi syndrome, suggesting that a locus for this syndrome maps to 16p13.3.

Second trimester prenatal diagnosis of the fragile X.

The fra(X) chromosome was detected in 5 samples of amniotic fluid cells in a series of 23 pregnancies at risk. The prenatal results were confirmed in 2 male abortuses, one with a relatively high and one with a very low frequency of expression in both amniocytes and fetal tissue. In a third male fetus with low expression in amniocytes, the fra(X) was not detected in the fetal tissues tested. In another male with low expression in amniocytes the fra(X) was not detected after birth. In one female with a low expression in amniocytes, a very high frequency (28%) was detected in cord blood after birth. Low expression of the fra(X) was found in a 4-year-old normally developed girl, where the prenatal results had been negative. In 4 males and 4 females the negative prenatal diagnoses were confirmed after birth. This study indicates that prenatal diagnosis of the fragile X after amniocentesis may be complicated, either due to technical problems related to the use of amniotic fluid cells, or due to genetic heterogeneity, or both. Part of this heterogeneity could be due to the existence of normal male transmitters. Also, it seems that the frequency of expression in amniocytes from female carriers can not be used for the prediction of the frequency in blood after birth.

Energy and nutrient intakes of disabled children: do feeding problems make a difference?

We examined the effect of feeding problems and alternative feeding practices on the energy and nutrient intakes of disabled children. Subjects were 221 disabled children aged 1 to 16 years from seven diagnostic groups: a 4-day food record was obtained for 166 children. The children's energy and nutrient intakes were examined in relation to the presence or absence of four feeding problems (gross motor/self-feeding impairment, oral-motor dysfunction, lack of appetite, food aversions) and two alternate feeding practices (prolonged assisted feeding and use of pureed foods). Cross-sectional analyses showed that children with feeding problems or alternative feeding practices had lower energy and nutrient intakes than did children without these factors. The presence of oral-motor dysfunction or prolonged assisted feeding significantly reduced relative energy intake. In general, differences in energy and nutrient intakes between children with and without other feeding problems or practices were small, and few statistically significant differences were found. The findings indicate that some feeding problems may reduce food intake in disabled children, although this effect is lessened by the conscientious efforts of parents. Parents and families of disabled children should receive dietary counseling to prevent deteriorative effects on the physical growth and health of children with long-standing feeding problems.

Feeding problems in children with congenital heart disease: the impact on energy intake and growth outcome.

Cross-sectional data on growth outcome, upper-arm measurements and energy intake have been analysed according to the presence or absence of early feeding problems and poor appetite in 40 children (0.9-13 years) with congenital heart disease (CHD). At the time of study, refusal to eat or poor appetite was reported as a significant problem in 19 children and subnormal height and/or weight were recorded in 11 children. The children ate considerably less calories than recommended for healthy children. The cross-sectional analyses showed that children with poor appetite had significantly (P less than 0.05 and P less than 0.01) lower outcome values of growth and upper-arm measurements than their disabled counterparts with no feeding problems and good appetite. Children with feeding problems also tended to eat less than children without feeding problems. For most parents (65%) feeding of infants and children with CHD involves difficulties, time and anxiety. This study has shown that the parents' experience about feeding problems may be a good predictor for low growth outcome and low voluntary food intake of the child. Whenever feeding problems are reported, nutritional intervention should be offered in order to increase the caloric intake of the child and to develop a sound feeding relationship in the family.

The impact of feeding problems on growth and energy intake in children with cerebral palsy.

Retrospective data on growth and cross-sectional data on growth outcome, anthropometric measurements and energy intake have been analysed according to the presence or absence of feeding problems in 42 children with cerebral palsy (CP) between 1 and 13 years of age. The mean age for boys and girls was 5.1 and 5.9 years, respectively. The study revealed a high frequency of feeding problems (50%) and growth retardation (48%) in the group. The results of weight for height, triceps skinfold thickness and energy intake indicate that 15% of the children were undernourished at the time of study. The cross-sectional analyses showed that children with feeding problems at the time of study (n = 22) had significantly lower height for age, weight for height, triceps skinfold thickness and upper-arm circumference than children without problems (P less than 0.05). Children with feeding problems also tended to have lower energy intake, but the differences were not significant. The feeding problems were most frequent among the severely disabled children. This study has shown that the presence of feeding problems is one important predictor of low growth outcome in children with CP. When parents report on feeding problems, feeding evaluation, training and nutritional intervention should be offered immediately. This is important for alleviating the heavy care-load for parents and health-workers and for some children it may be necessary to maintain an acceptable nutritional state.

Relationship between sociomedical factors and TMJ-symptoms in Norwegians with myofascial pain-dysfunction syndrome.

The relationship between background characteristics, stress, reported symptoms and clinical findings was studied in a group comprising 333 patients with Myofascial Pain Dysfunction Syndrome (MPD). Three-quarters of this clientele were women, most of them of young or middle age. The stressors most frequently reported were pressed working conditions, anxiety and frustration deriving from disease, and family problems. Of the symptoms, pain was reported by 78 percent of the patients, clicking by 53 percent, limitation of movement by 44 percent and feeling of stiffness and fatigue of masticatory muscles by 41 percent. Significant correlations were found between a number of variables, of which the close relationship between perceived pressors and muscle groups painful to palpation was considered to be a paramount importance. The data were combined into a hypothetic model postulating causal relations. The model was intended for testing and modification in coming studies.

Myofascial pain dysfunction (MPD) syndrome in twins.

The Myofascial Pain Dysfunction Syndrome (MPD) was investigated in 94 twin pairs (21 male pairs and 73 female pairs), who had not been selected with respect to MPD. The frequency of past and/or present symptoms was found to be 10% in males and 27% in females. No differences between monozygous (identical) and dizygous (non-identical) female twins was found in pair-wise concordance rates, the concordance rate being higher than expected to occur by chance in both twin types. The findings are compatible with the view that environmental influences give rise to this specific stress-reaction pattern.

Social-medical aspects of cystic fibrosis in Norway. I. Characterization of the material.

The families of 90 children with cystic fibrosis and the families of 1977 control children have answered extensive questionnaires, which are the basis for this study. In the first part of the study the two groups are compared for some important factors, to detect differences that would make further analysis of the material questionable. The two groups were commensurable concerning their economic situation, standard of housing, ages of children, and the family situation in general. The educational level of the parents in the two groups did differ, the parents of children with cystic fibrosis having less education. The parents of children with cystic fibrosis were more dissatisfied with their situation than those in the control group. These differences are probably a result of having cystic fibrosis in the family; consequently, it is concluded that the two groups can well be compared.

Correlation between prenatal ultrasound and autopsy findings: A study of second-trimester abortions.

OBJECTIVE: To evaluate discrepancies between sonographic and autopsy findings following termination of pregnancy (TOP) in the second trimester. METHODS: This retrospective report is based on 288 consecutive second-trimester abortions carried out because of fetal malformations diagnosed by ultrasound examination at a tertiary referral center. The correlation between the results from the ultrasound and autopsy examinations was evaluated. RESULTS: Autopsy was performed in 274 cases. In 160 of the 274 pregnancies (58.4%) there was full agreement between the two examination methods. Findings detected by autopsy (in addition to those leading to termination) were not observed by ultrasonography in 86 (31.4%) of the pregnancies; of the 64 malformations that occurred, 30 (46.9%) were judged as 'detectable'. In 27 (9.9%) pregnancies, observations made by ultrasound (in addition to those leading to termination) were not confirmed at autopsy. In one pregnancy, postmortem radiology examination-but not autopsy-confirmed the ultrasound observations. No pregnancies were terminated because of false positive ultrasound observations. The correlation between ultrasound and autopsy findings was evaluated by three investigators; the inter-rater agreement was high (kappa = 0.85). CONCLUSION: Discrepancies between ultrasound and autopsy findings were observed in about 40% of the pregnancies. These discrepancies confirm the need for autopsy following TOP.

[Frambu Health Center: information to families with functionally impaired members]. / Frambu Helsesenter: informasjon til familier med funksjonshemmede medlemmer.

Frambu Health Centre is an information and treatment centre serving many different categories of disabled children and their families, primarily Norwegian but also from the other Scandinavian countries. The aim is to support the family in their task of caring for the disabled person, and to improve the handicapped person's ability to function despite the disablement both in the home and at school or at work. The staff at the centre are specialised in the management of rare and poorly understood conditions, and work in cooperation with the appropriate services in the person's home town. A certain amount of research is also carried out at the centre into the life situation of handicapped people.

Indications for psychotherapy in a psychiatric clinic population. A survey.

As a part of a larger project of trying to differentiate the therapies for inpatients in a psychiatric clinic, we have made a half year's survey of the patients' needs for short-term dynamic psychotherapy. Our findings point to less than 10% of the inpatients being able to profit from this kind of therapy. These findings and their implications are discussed briefly.

Indications for psychotherapy in a psychiatric clinic population. Reliability and validity of evaluations.

A half-year survey was made on an in-patient clinic population as to a specific kind of short-term dynamic psychotherapy. The reliability and validity of the evaluations are discussed. It was found that a moderate accordance in evaluations could be found between the evaluators, with a high degree of reliability.