Henrik Arnell

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.

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

Abstract 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.

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.

Follow-up in children with progressive familial intrahepatic cholestasis after partial external biliary diversion.

Objectives: The aim of this study was to examine whether reversion of histological fibrosis followed partial external biliary diversion (PEBD) in patients with progressive familial intrahepatic cholestasis (PFIC); whether the duration of cholestatic episodes after PEBD influenced the evolution of fibrosis; and whether genotyping was helpful in predicting outcome of PEBD. Patients and Methods: Children with PFIC who underwent PEBD were investigated with genetic, biochemical, and anthropometric standard methods. Serial liver specimens were assessed histologically without knowledge of genotype and outcome. Findings were evaluated in the contexts of the total duration of cholestasis and the clinical outcome after PEBD. Results: From a total of 18 children with PFIC, 13 underwent PEBD, and 12 of these (among them 10 with identified ABCB11 mutations) were amenable for clinical and histological follow-up. When compared with baseline at PEBD, statistically significant reductions were found in histological cholestasis 1 and 3 years after PEBD, and in fibrosis 5 and >10 years after PEBD. The relative duration of cholestatic episodes after PEBD was positively correlated with the severity of fibrosis. Children homozygous for the missense mutation c.890A>G in ABCB11 responded well to PEBD. Conclusions: Biliary diversion should be regarded as the first choice of surgical treatment in noncirrhotic patients with severe ABCB11 disease and may also be efficacious in other forms of PFIC.

Impact of parenteral fat composition on cholestasis in preterm infants.

Objectives: Parenteral nutrition–associated liver disease (PNALD) is frequently detected in neonatal intensive care units. Parenteral lipid emulsion (PLE) content has been implicated in its pathogenesis. We aimed to study the effect on incidence and outcome of PNALD by replacing soy-based PLE with olive oil–based PLE in a population-based group of preterm infants. Methods: All infants in Stockholm County with gestational age (GA) <30 weeks were included (nu200a=u200a615). Infants who died before 28 days of age or were referred to or from other regions were excluded (nu200a=u200a97). PNALD was defined as conjugated serum bilirubin ≥30 &mgr;mol/L and exceeding 20% of the total fraction on at least 2 occasions. Two different 2-year time periods were compared: before (SOY period) and after (OLIVE period) switching PLE. For each PNALD case, 2 GA-matched controls were randomly identified. Results: PNALD incidence was 14.8% (37/250) in the SOY period and 12.7% (34/268) in the OLIVE period (Pu200a=u200a0.52). The OLIVE infants with PNALD had more risk factors, such as lower GA and longer periods of parenteral nutrition, for developing PNALD than the SOY infants. Nevertheless, treatment during the SOY period was an independent risk factor for PNALD in logistic regression analysis. Conclusions: Population-based incidence of PNALD is 1 of 7 in preterm infants with GAu200a<u200a30 weeks. Changing from soy oil to olive oil–based PLE did not decrease the incidence of PNALD significantly. Olive oil–based PLE carries an equal or slightly decreased risk to develop PNALD compared with soy oil–based PLE.

Omitting control biopsy in paediatric coeliac disease: a follow‐up study

Aim: To evaluate the practice of diagnosing coeliac disease with only one small‐bowel mucosal biopsy in a selected group of children with suspected coeliac disease.

The genetics of nocturnal enuresis: a simple question of complexity.

During the last decade of medical research, new methods for the study of molecular mechanisms of a variety of diseases have been introduced. Progress in this and other fields has led to new insights of underlying causes of disease and improved treatment modalities. The increasing interest of nocturnal enuresis in many of its aspects is a good example of this development. Being a complex disease with a high prevalence among children, a large number of non-familial cases and a high spontaneous cure rate, it is a very inspiring challenge for genetic research. Although evidence for a genetic component in enuresis was shown much earlier (1, 2), the last years’ rapid evolution of genotyping techniques and the use of powerful statistical tools have made it possible to open the black box of genetics and to further dissect the enuretic trait. Until recently, genetic disease mapping was mainly focused on the less common monogenic diseases, such as diastrophic dysplasia (3), caused by a point mutation in a single gene. A genetic linkage analysis is performed by comparing the genome of affected members in a number of families with unaffected close relatives. The signal of interest is the small part of the genome that is commonly shared by the affected individuals, but not by their healthy relatives. This signal of ‘‘true’’ linkage is generally relatively strong in a monogenic disease, compared to the background noise of ‘‘false’’ linkages occurring by chance in some of the affected individuals at different chromosomal regions. This signal-to-noise ratio (i.e. the lod score) increases in the chromosomal region harbouring the gene. This is the case for genetically homogenous diseases, caused by a single gene defect. For diseases with a more complex inheritance pattern, such as asthma bronchiale, diabetes mellitus, schizophrenia—and nocturnal enuresis, the search for genes is more complicated. The mode of inheritance is less evident and the presumed number of diseasepredisposing genes to look for is higher. Thus, these linkage studies need much larger family materials, which leads to a higher genetic variation. The signal-to-noise ratio therefore becomes lower, which makes it more difficult to distinguish true linkage from ‘‘linkage’’ occurring by chance. In order to minimize false-positive results without excluding falsely negative regions, the need for thorough statistical evaluation is of utmost importance, as pointed out a few years ago by Lander and Kruglyak (4). In this issue of Acta Paediatrica, von Gontard et al. present results from a clinical and genetic study in accordance with the generally accepted idea of nocturnal enuresis as a clinically and genetically heterogeneous disease, with a normal incidence of behavioural problems in the affected children (5). The present study of 42 children with different types of voiding difficulties includes cases of primary and secondary monoand non-monosymptomatic nocturnal enuresis, as well as combined dayand night-time-wetting. The children, selected from a larger group of 167 children with enuresis, underwent a thorough clinical investigation including behavioural tests and a parents’ questionnaire. G notyping of the probands and their families was performed and the segregation of five polymorphic loci on chromosomes 8, 12 and 13 was investigated. Linkage in some of the families to one or more loci is reported, but no clear phenotype–genotype association is found. The authors emphasize that the linkage results should be interpreted with care, since the results are not statistically significant. However, it has to be kept in mind that the results could be due to random assortment. The present study clearly depicts some of the problems that need to be handled accurately in order to get closer to t e enigma of nocturnal enuresis. This has also been ddressed in similar complex diseases: In schizophrenia, twin studies revealed a significantly higher concordance in monozygotic as compared to dizygotic twins (6), claiming an important genetic contribution to development of this disease. Most genetic linkage studies have been performed on large families with the disease in at least two, sometimes three generations. Different degrees of mental illness have been included by using a rather wide (and variable) disease definition. To this date, at least a dozen different chromosomal loci have been claimed to host major or minor genes predisposing to schizophrenia. The majority of these findings has not been possible to reproduce, or to r ject (7, 8). The need is growing for studies with sufficient statistical power to exclude some of the proposed regions, leaving a reasonable number for closer investigation. Recently, a multicentre consortium was established to address this problem. So far, reanalyses on collaborative basis of linkage to some of the chromosomes have been inconclusive (9). The first human whole genome scan for a complex disease was performed in Oxford, UK, mapping susceptibility genes in type I (insulin-dependent) diabetes (10). For the linkage analysis three independent groups of families with affected siblings were used. Each group had a well defined ethnical origin in order to reduce genetic heterogeneity, thus increasing the power of the study. In the first step, indications of linkage to no less than 18 different chromosomal regions were found. In the second Acta Pædiatr 87: 487–8. 1998

Hepatic Glycogen Storage Diseases: Toward One Global Collaborative Network

The third international meeting of the Scandinavian Association for Glycogen Storage Disease focused on hepatic glycogen storage disease and was organized for health-care professionals, patient representatives, and representatives from the industry. This report highlights dilemmas in dietary management, differences in monitoring strategies, and challenges with rare disease care, research, and patient participation.