A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.

The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and gamma-glutamyltranspeptidase (gammaGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP).

An echocardiographic study comparing male Swedish elite orienteers with other elite endurance athletes.

Between 1979 and 1992, there were 16 known cases of sudden unexpected cardiac death among young Swedish orienteers, whose autopsies showed myocarditis to be a common finding. Therefore, 96 elite orienteers and 47 controls underwent echocardiography, showing left ventricular wall motion abnormalities in 9% of the orienteers compared with 4% in the controls.

Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children.

OBJECTIVE: To determine the extent of use of unlicensed and off label drugs in children in hospital in five European countries. DESIGN: Prospective study of drugs administered to children in general paediatric medical wards over four weeks. SETTING: Children's wards in five hospitals (one each in the United Kingdom, Sweden, Germany, Italy, and the Netherlands). SUBJECTS: Children aged 4 days to 16 years admitted to general paediatric medical wards. MAIN OUTCOME MEASURE: Proportion of drugs that were used in an unlicensed or off label manner. RESULTS: 2262 drug prescriptions were administered to 624 children in the five hospitals. Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. Over half of the patients (421; 67%) received an unlicensed or off label drug prescription. CONCLUSIONS: Use of off label or unlicensed drugs to treat children is widespread. This problem is likely to affect children throughout Europe and requires European action.

Growth and pubertal development in Down syndrome.

Growth retardation and gonadal insufficiency are well-known features of Down syndrome. In this longitudinal study, 44 home-reared children and adolescents with Down syndrome, aged 10-24 years, living in the county of Uppsala, were followed yearly. The male patients had a mean final height above that reported previously, and a close correlation between target and final heights was found. The mean final height in the female patients was below that reported earlier. Mean peak height velocities in males and females were 8.5 and 7.3 cm year-1, respectively, significantly lower than in healthy children. The mean ages at peak height velocity were 12.3 and 10.8 years, respectively, indicating early growth spurts. The serum follicle-stimulating hormone concentrations, the small testes and the negative correlation between luteinizing hormone and testicular volume in the males may indicate some primary gonadal insufficiency. For the girls, mean menarcheal age corresponded closely to that of their mothers.

Progressive familial intrahepatic cholestasis (PFIC): evidence for genetic heterogeneity by exclusion of linkage to chromosome 18q21-q22.

Progressive familial intrahepatic cholestasis (PFIC) is the second most common form of familial intrahepatic cholestasis. The genes for PFIC and for a milder form of the disease, benign recurrent intrahepatic cholestasis (BRIC), were recently mapped to a 19-cM region on chromosome 18q21-q22. The results suggest that PFIC and BRIC are allelic diseases. We have studied 11 Swedish patients from eight families with clinical and biochemical features consistent with PFIC. The families were genotyped for markers D18S69, D18S64, D18S55 and D18S68, spanning the PFIC candidate region. Unexpectedly, the segregation of haplotypes excluded the entire region in three families, and no indications for shared haplotypes were found in the patients of the six remaining families. A four-point linkage analysis of all families excluded linkage from D18S69 to D18S55 (Zmax < -5). Thus, our data strongly suggest the presence of a second, yet unknown, locus for PFIC. The results indicate that great care should be taken when using 18q markers for prenatal diagnosis and genetic counseling for the disease.

Stargardt disease: linkage to the ABCR gene region on 1p21-p22 in Scandinavian families.

UNLABELLED: Stargardt disease (STGD) or fundus flavimaculatus (FFM) is one of the most frequent causes of macular degeneration in childhood. The disease is inherited as an autosomal recessive trait and the corresponding gene has been localized to chromosome 1p21-22 and subsequently identified as the ATP-binding cassette transporter (ABCR) gene. PURPOSE: To characterize Finnish and Swedish STGD families genetically, with special reference to chromosome region 1p21-22. METHODS: We performed genetic linkage and haplotype analyses in five families of Finnish and Swedish origin with members affected by STGD or FFM. RESULTS: Evidence for linkage between STGD and the ABCR gene region on chromosome 1p was found with a maximum cumulative two-point lod score for marker D1S188 (Z=4.04, theta=0.001). The affected individuals of all families, including the offspring of a consanguineous family, were found heterozygous for haplotypes spanning the ABCR gene. CONCLUSION: The results support genetic homogeneity for a STGD/FFM gene defect on chromosome 1p21-22. A variety of haplotypes tightly linked to the ABCR gene region were found among affected individuals which indicate the presence of several independent STGD mutations in the Scandinavian population.

Echocardiographic right and left ventricular measurements in male elite endurance athletes.

Echocardiography was used to assess normal values in the right and left ventricular cavity and wall in 127 male elite endurance athletes. M-mode and two dimensional measurements of left ventricle and left and right atria were also obtained. All subjects were high-performance orienteers, cross-country skiers and middle-distance runners. They all had a normal electrocardiogram at rest and no echocardiographic evidence of heart disease. With the use of multiple right ventricular cross-sections and two-dimensional measurements, we found a significantly greater right ventricular inflow tract and right and left atrial measurements in endurance athletes compared with earlier studies of normal, active subjects. The right ventricular free wall was slightly thicker than reported in normal active subjects but the differences were small. Left ventricular diastolic diameter was consistent with previous reports of endurance athletes. Of the 127 subjects, 13% had left ventricular wall thickness above 13 mm but none of the athletes had wall thickness above 15 mm. These data suggest that cardiac enlargement occurs symmetrically in both right and left cavities, probably reflecting increased haemodynamic loading, a mechanism by which athletes sustain a high cardiac output during exercise.

The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q.

Primary nocturnal enuresis (PNE), or bedwetting at night, affects approximately 10% of 6 year old children. Genetic components contribute to the pathogenesis and recently one locus was assigned to chromosome 13q. We evaluated the genetic factors and the pattern of inheritance for PNE in 392 families. Dominant transmission was observed in 43% and an apparent recessive mode of inheritance was observed in 9% of the families. Among the 392 probands the ratio of males to females was 3:1 indicating sex linked or sex influenced factors. Linkage to candidate regions was tested in 16 larger families segregating for autosomal dominant PNE. A gene for PNE was excluded from chromosome 13q in 11 families, whereas linkage to the interval D13S263-D13S291 was suggested (Zmax = 2.1) in three families. Further linkage analyses excluded about 1/3 of the genome at a 10 cM resolution except the region around D12S80 on chromosome 12q that showed a positive two point lod score in six of the families (Zmax = 4.2). This locus remains suggestive because the material was not sufficiently large to give evidence for heterogeneity. Our pedigree analysis indicates that major genes are involved in a large proportion of PNE families and the linkage results suggest that such a gene is located on chromosome 12q.

Anticipation of autosomal dominant progressive external ophthalmoplegia with hypogonadism.

A large Swedish family with members affected by progressive external ophthalmoplegia with hypogonadism were followed-up and reviewed. Hypogonadism included delayed sexual maturation, primary amenorrhea, early menopause, and testicular atrophy. Cataracts, cerebellar ataxia, neuropathy, hypoacusia, pes cavus, tremor, parkinsonism, depression, and mental retardation were other features observed in this family. Muscle biopsy samples of advanced cases showed ragged-red fibers, focal cytochrome c oxidase deficiency, and multiple mtDNA deletions by Southern blot analysis. An autosomal dominant mode of inheritance was evident with anticipation in successive generations. Linkage analysis excluded the chromosome 10q23.3-q24.3 region reported as being linked to the disease in a Finnish family with autosomal dominant progressive external ophthalmoplegia. We report for the first time clinical evidence for anticipation in a family with autosomal dominant progressive external ophthalmoplegia. We hypothesize that the nuclear gene causing this enigmatic disorder may be directly influenced by an expansion of an unstable DNA sequence and that the resulting phenotype is caused by a concerted action with multiple deletions of mtDNA.