Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-κB pathway.

Alterations in mitochondria and increased oxidative stress are associated with the disease progression in Huntington's disease (HD). Endoplasmic reticulum (ER) stress and oxidative damage are linked through the close communication between the ER and mitochondria. Sigma-1 receptor (Sig-1R) is a chaperone protein in the ER that is involved in ER stress regulation, but little is known about its role in HD or the mechanisms for cell protection. Here we show that the Sig-1R agonist, PRE084 increases cell survival and counteracts the deleterious effects caused by N-terminal mutant huntingtin proteins in neuronal PC6.3 cells. Particularly, PRE084 increased the levels of cellular antioxidants by activating the NF-κB pathway that is compromised by the expression of mutant huntingtin proteins. These results show that the Sig-1R agonist has beneficial effects in models of HD and that compounds affecting the Sig-1R may be promising targets for future drug development in HD.

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice.

AIMS/HYPOTHESIS: NOD.Igmicro ( null ) mice lacking mature B cells are highly resistant to diabetes and display poor CD4 T cell responses to autoantigens. Nevertheless, the degree to which different B cell subsets contribute to diabetes in NOD mice remains unresolved. Due to their role in the recognition of microbial and autoantigens, peritoneal B cell characteristics were examined in NOD mice to see if they differ developmentally, phenotypically or functionally in aspects relevant to diabetogenesis. METHODS: The population dynamics, activation state, migratory behaviour and antigen presentation function were investigated in NOD peritoneal B cells. RESULTS: NOD peritoneal B cells were found to express abnormally high levels of co-stimulatory molecules (CD40, CD86 and CD69). In contrast, the expression of L-selectin and integrin alpha4beta1 was markedly reduced in NOD mice compared with BALB/c and C57BL/6 mice. The number of B cells in the peritoneum was lower in NOD than in control mice throughout development; migration of B cells from the peritoneum to the pancreatic lymph nodes in NOD mice was enhanced tenfold. NOD B cells showed no chemotactic response to sphingosine-1-phosphate, which normally acts to retain B cells in the peritoneum. Peritoneal B cells of NOD mice also presented insulin autoantigen to CD4 T cells, inducing T cell proliferation. CONCLUSIONS/INTERPRETATION: NOD peritoneal B cells are hyperactivated, migrate to the pancreatic lymph nodes and are capable of driving insulin-specific CD4 T cell activation. These characteristics could make them important for inducing or amplifying T cell responses against islet-antigens.

Evaluation of screening procedures for congenital cataracts.

AIM: To evaluate the efficacy of two different Swedish screening procedures for early detection of congenital cataracts in comparison with no screening. METHODS: Children born between January 1992 and December 1998 in Swedish regions with an established eye-screening routine procedure, diagnosed with congenital cataract, and operated on before 1 y of age, were included in a retrospective study. Age at referral and age at time of the operation were compared between regions using different screening procedures: screening in the maternity wards (Region 1), at the well-baby clinics (Region 2) and one region without any screening (Region 3). RESULTS: Seventy-two children were included in the study. Concerning early diagnosis and surgery, Region 1 differed significantly from Regions 2 and 3, which were more similar and were combined for further analysis. The difference in detected cases was greatest at 21 d of age (55% vs 18%; p < 0.001), but persisted even at 100 d of age (78% vs 64%; p < 0.02). Region 1 screening resulted in more and earlier cases detected than the other two regions (22 vs 15 per 100,000 births). In 72% of all cases, surgery was performed in response to referrals from either the maternity wards (36%), or the well-baby clinics (36%). However, half of the cases from the well-baby clinics were detected too late, i.e. at > 100 d. CONCLUSION: Eye screening in the maternity ward is preferable to well-baby clinic screening and to no screening at all, since it leads to early detection. Screening should also be performed routinely at well-baby clinics within the period when successful treatment is possible.

Association between visual impairment and functional and morphological cerebral abnormalities in full-term children.

PURPOSE: To characterise the nature and degree of ocular disorders and cerebral morphological and functional abnormalities in a population-based group of visually impaired full-term pre-school children. METHODS: Forty-five children who were born at full-term between 1989 and 1995 in Värmland, Sweden, were reported as being visually impaired. An ophthalmological examination was performed and clinical data regarding mental development and neurological disease were obtained for all children. Cerebral imaging was performed in 35 children. RESULTS: Twenty-six per cent of the children were found to have ocular disorders only. Forty-two per cent had cerebral morphological abnormalities, verified by cerebral imaging, and 65% had signs of cerebral functional abnormalities. In total, 74% were found to have cerebral morphological and/or cerebral functional abnormalities. CONCLUSION: The majority of children with visual impairment, including children with ocular disorders, were found to have cerebral morphological and/or cerebral functional abnormalities. We suggest that any child with visual impairment should therefore undergo cerebral imaging and be examined by a paediatrician in order to establish the correct diagnosis.

Visually impaired Swedish children. The 1980 cohort study--a 19-year ophthalmological follow-up.

PURPOSE: To assess the ophthalmological outcome in a cohort of visually impaired children in a geographically defined area. METHODS: A 19-year follow-up of medical records, interview and, if needed, re-examination of the initial 128 patients, born 1962-1976. RESULTS AND CONCLUSION: Follow-up was possible in 123 patients (96%); 76 (59%) were still visually impaired, 17 (13%) were deceased, while 30 (23%) had acquired a visual function > or = 0.3. The chances of gaining a visual function outside the WHO limits for visual impairment was significantly higher for patients without additional impairments (p=0.0023). The initial ophthalmologic diagnosis remained unchanged in 88%. The diagnoses with improved visual development included albinism and congenital nystagmus, while retinal diseases showed poorer results. An increase in visual function could be seen even in the initially older age-groups, indicating a maturation of visual function beyond what is usually considered the limit of plasticity of the visual system.

Visually impaired Swedish children. The 1980 cohort study--aspects on mortality.

PURPOSE: Assessment of the burden of mortality in a cohort of visually impaired children in a geographically defined area. METHODS: A 19-year follow-up of medical records and death certificates. RESULTS AND CONCLUSIONS: Of the initial 128 patients, born 1962-76, 17 (13%) had died, giving a highly significant increase in mortality compared to the equivalent age-specific Swedish population (p-value <0.000001). All deceased had additional impairments. Respiratory causes of death were found in 12/17 cases. The primary ophthalmological diagnosis was cerebral visual impairment in 8 cases, optic atrophy in 6 cases, one each of congenital cataract, microphthalmus and chorioretinitis. A more pronounced level of visual impairment gave an increased risk of mortality. A significantly higher mortality rate among multiply impaired was seen in the combined group with 'childhood blindness' (visual acuity <0.05) and 'visual impairment, undetermined or unknown' opposed to the group with 'low vision' (visual acuity 0.05-<0.3) (p=0.047).

Visually impaired Swedish children. Longitudinal comparisons 1980-1999.

PURPOSE: To produce the background to a pilot-study of the visual and social outcome of visually impaired children. A study, originally including 219 individuals, done in 1980 in the county of Malmöhus in southern Sweden, was revisited. METHODS: A revision according to current WHO classification led to a cohort of 128 individuals. This was compared to the corresponding group, comprising 2048 individuals, of the total Swedish registration of visually impaired children of today. RESULTS AND CONCLUSION: The two groups were mostly similar as regards male/ female distribution, additional impairments, etiological factors and diagnoses. The prevalence of visual impairment due to peri-/neonatal influence had increased (p=0.038; odds ratio (OR): 1.61, 95% confidence interval (CI): 1.04-2.61), while visual impairment due to prenatal infections had decreased (p = 0.0001; OR: 0.26, 95%CI: 0.15-0.49). Regarding diagnoses we saw a significant decrease in chorioretinitis, as well as in microphthalmus and Stargardt's disease, while hypoplasia of the optic nerve increased. In all these, except chorioretinitis, the changes are probably due to altered diagnostic classification.

Intrafamilial variation of the phenotype in Bardet-Biedl syndrome.

AIMS: To describe the variation of the phenotype within families with several individuals with Bardet-Biedl syndrome. METHODS: The phenotypes of affected siblings in 11 Scandinavian families with two or more members who had at least three of the features: retinal dystrophy, polydactyly, obesity, hypogenitalism, and mental retardation, were compared [corrected]. Individuals without retinal dystrophy were excluded. RESULTS: Intrafamilial variation of expressivity of the features obesity, polydactyly, abnormal radiograms of the extremities, hypogenitalism, short stature, paraplegia, and dental abnormalities was found. The retinal dystrophy varied with respect to both the onset of symptoms and the course of the disease. The morphology of the fundus, however, was consistent within the families. The disorder showed statistically significant genetic linkage to the BBS4 locus on chromosome 15 in the affected siblings in two of the families, but the clinical features in these patients did not differ from the other cases of Bardet-Biedl syndrome. CONCLUSION: Comparison of siblings with the Bardet-Biedl syndrome showed variation of the typical features. In addition, the course of retinal dystrophy varied. No distinctive clinical features were found to separate the BBS4 phenotype from the remaining patients.

Visual impairment in Swedish children. I. Register and prevalence data.

Knowledge of the epidemiology of visual impairment in children forms one of the cornerstones of pediatric ophthalmology. In contrast to e.g. the other Nordic countries, Sweden has had no efficient and continuous registration of visually impaired children. An epidemiological study on this subject has now been done, collecting data on all children and adolescents registered at the Low Vision Clinics throughout Sweden. In this work data on 2373 visually impaired children, 0-19 years of age and living throughout Sweden are presented. Data collected in the study include sex, date of birth, county, ocular diagnosis, systemic diagnosis, classification of visual impairment, aetiology and possible additional impairments. The prevalence of visual impairment as defined by WHO was 10.9/10,000 inhabitants in the current age group. A slight male preponderance was seen compared to the total population 0-19 years. This was not reduced when only non-genetic aetiological factors were taken into consideration. A total of 45% of the children had only a moderate visual impairment (WHO category 1), whereas approximately 25% were found in WHO categories 3,4 and 5, i.e. fulfilled the requirements for blindness. Additional impairments were found in 60% of the children. Mental impairment in combination with motor impairment or mental impairment exclusively were the most common ones seen.

Visual impairment in Swedish children. II. Etiological factors.

The analysis of etiological factors in a group of visually impaired children is of considerable importance when trying to find guidelines for possible preventive work. In this study we present etiological data on 2373 Swedish children. Data have been obtained by reviewing medical records on all known children with visual impairment throughout the country. In accordance with similar studies from industrialised countries, the group with prenatal etiology was the predominant, comprising 64% of the material. Within this group, half the patients had a disease of genetic origin. A total of 50% of all patients with prenatal etiology had an additional impairment, but in the group with diseases of genetic origin this proportion was smaller, only 40%. On the other hand, many children with additional impairments were found among those with an unspecified prenatal influence. Peri-/neonatal etiologies were found in 20% of the patients. In this group as many as 83% had additional impairments. This was even more pronounced among children delivered at term. The group with infantile/juvenile etiologies was small, 7%, with additional impairments in 66%. In 9% of all patients the etiology was classified as unknown. Among these, 80% had additional impairments. The visual impairment tended to be more pronounced, the later the disease was acquired. A male preponderance was seen in most etiological subgroups and in the material as a whole.

Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21.

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous autosomal recessive disorder characterized by retinitis pigmentosa, polydactyly, obesity, hypogenitalism, mental retardation, and renal anomalies. To detect linkage to BBS loci, 29 BBS families, of mixed but predominantly European ethnic origin, were typed with 37 microsatellite markers on chromosomes 2, 3, 11, 15, 16, and 17. The results show that an estimated 36-56% of the families are linked to the 11q13 chromosomal site (BBS1) previously described by M. Leppert et al. (1994, Nature Genet. 7, 108-112), with the gene order cen-D11S480-5 cM-BBS1-3 cM-D11S913/D11S987-qter. A further 32-35% of the families are linked to the BBS4 locus, reported by R. Carmi et al. (1995, Hum. Mol. Genet. 4, 9-13) in chromosomal region 15q22.3-q23, with the gene order cen-D15S125-5 cM-BBS4-2 cM-D15S131/D15S204-qter. Three consanguineous BBS families are homozygous for three adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis supports a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to the 16q21 (BBS2) region reported by A. E. Kwitek-Black et al. (1993, Nature Genet. 5, 392-396) was observed in 24-27% of families with the gene order cen-D16S408-2 cM-BBS2-5 cM-D16S400. A fourth group of families, estimated at 8%, are unlinked to all three of the above loci, showing that at least one other BBS locus remains to be found. No evidence of linkage was found to markers on chromosome 3, corresponding to the BBS3 locus, reported by V. C. Sheffield et al. (1994, Hum. Mol. Genet. 3, 1331-1335), or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with a t(2;17) translocation.

Visual impairment in Swedish children. III. Diagnoses.

PURPOSE: To gain an overview of the spectrum of diagnoses among Swedish visually impaired children. METHODS: An epidemiological study of all known visually impaired children was made by review of medical records. RESULTS AND CONCLUSION: In all we found 2373 children, 0-19 years of age, with an age-specific prevalence of 10.9/10,000. The two largest diagnostic groups included neuro-ophthalmological and retinal diseases. The most frequent disorders were cerebral visual impairment, non-hereditary optic atrophy, retinal dystrophy (when regarded as a general entity), congenital hypoplasia of the optic nerve and congenital cataract. Nystagmus secondary to brain disorder, albinism, congenital nystagmus, retinopathy of prematurity and high myopia were also found in a considerable number of patients. The leading diagnoses in children with WHO-defined childhood blindness were non-hereditary optic atrophy, cerebral visual impairment and retinopathy of prematurity. A large proportion of the children, especially in the groups with neuro-ophthalmological disorders and malformations of the posterior segment had additional impairments, emphasizing the importance of a multi-disciplinary approach when assessing multi-handicapped children.

Ocular findings in the Laurence-Moon-Bardet-Biedl syndrome.

PURPOSE: To improve the description of the ocular part of the Laurence-Moon-Bardet-Biedl syndrome. METHODS: We examined 44 Scandinavian individuals who all had retinal dystrophy plus at least 2 more of the traditional cardinal signs of the syndrome: obesity, hypogenitalism, polydactyly and mental retardation. RESULTS: Full-field electroretinograms were obtained in 36 of the individuals and were abnormal in all. The dark adaptation thresholds were elevated by on average 3.5 log units. Symptoms of night blindness were observed at a mean age of 4 years and visual problems at daytime at 6-7 years. No one exceeding the age of 16 had a best corrected visual acuity of more than 0.1. In the fundus attenuated vessels were noted at all ages while macular pigmentations and a wax-pale optic disc appeared at age 6-7 years. Pigmentary changes in the midperiphery were noted at the earliest at 13 years of age and appeared mainly as bone spicules, however, in a minority of cases the pigmentations were atypical. Ten of the participants had been followed through a period of 9 years. Their visual acuity was reduced by on average 0.3 line (decimals) and the angle of visual fields by approximate 3 degrees (Goldmann standard object V:4e) per year through the adolescence. CONCLUSION: The ocular disease in Laurence-Mood-Bardet-Biedl syndrome presents early, the prognosis for visual function is poor and the fundus features are atypical and varying.

Full-field electroretinograms in individuals with the Laurence-Mood-Bardet-Biedl syndrome.

PURPOSE: To evaluate rod and cone function in individuals with the Laurence-Moon-Bardet-Biedl syndrome. METHODS: We obtained a full-field electroretinograms in 36 patients. If responses less than 10 microV were recorded with single white flashes a special techniques with narrow band filter and computer averaging was used. RESULTS: No rod responses to dim blue light could be obtained in any of the patients. Residual cone flicker responses were measurable in 28 of the individuals. Those with amplitudes < 0.05 microV were significantly older than those with amplitudes > 1.00 microV. The ERG pattern was consistent within affected pairs of siblings in 8 families. CONCLUSION: The retinal dystrophy in Laurence-Moon-Bardet-Biedl syndrome is primarily a rod-cone dystrophy, but even cone flicker amplitudes are severely reduced with further progression with age. There is no intrafamilial variability of the electroretinograms in affected siblings.

Skeletal abnormalities of hands and feet in Laurence-Moon-Bardet-Biedl (LMBB) syndrome: a radiographic study.

OBJECTIVE: To identify radiological changes of the hands and feet in a large group of patients with Laurence-Moon-Bardet-Biedl syndrome. DESIGN: Postero-anterior views of hands and feet were obtained and analysed. PATIENTS: The material consists of 43 Scandinavian patients with the syndrome (24 males and 19 females; age 3 weeks to 57 years, median 23 years at the time of radiological examination). RESULTS AND CONCLUSIONS: Polydactyly of the hands and feet is one of the main criteria. This was noted clinically in 33 of 43 patients, but all but 3 had been operated on before this radiological study. Remnants of the extirpated finger or toe noted as exostoses, additional joint surfaces of duplication were found in half the hands and feet, while the remainder showed no radiological changes. Other features found were short, broad bones and flat joint surfaces of the metacarpophalangeal or metatarsophalangeal joints. We also found a high frequency of short or long ulna in relation to the radius and Madelung deformity of the wrist in several patients. Thus, the radiographs showed several non-specific normal variations besides remnants or postoperative changes after polydactyly.

Anomalies in the permanent dentition and other oral findings in 29 individuals with Laurence-Moon-Bardet-Biedl syndrome.

This paper reports a clinical and roentgenological examination of the teeth, jaws and saliva of 29 Scandinavian individuals with Laurence-Moon-Bardet-Biedl (LMBB) syndrome, whose cardinal signs are retinal dystrophy, polydactyly, obesity, hypogenitalism and mental retardation. All subjects had at least three of these signs, including retinal dystrophy. Compared with normal subjects, the group had statistically significantly higher frequencies of hypodontia, small teeth and short roots. In addition, the saliva showed a buffering capacity higher than normal. In conclusion, there seem to exist disturbances of both dental and skeletal formation in the LMBB syndrome.

Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease.

Classical Maple Syrup Urine Disease is a serious, autosomal recessive and rare metabolic disorder due to a completely inactive enzyme complex for metabolizing the branched amino acids leucine, valine and isoleucine. If untreated the disease is lethal. Metabolic control achieved by strict dietary treatment results in normal development. In this paper we describe deepithelialization of the cornea together with skin and intestinal symptoms as the result of isolated deficiency of isoleucine during treatment of a critically ill, newborn infant with this unusual disease.

Incidence of registered visual impairment in the Nordic child population.

A collaborative, population based, prospective register study on the incidence of visual impairment in children during the year 1993 was carried out in five Nordic countries with a total population of 17 million inhabitants. The child population was 3.8 million individuals aged 0-17 years. The following variables were taken into account: nationality, age, sex, diagnoses, aetiology, degree of visual impairment, and additional impairments. Classification routines from an earlier prevalence study were used. The present study included 304 children corresponding to an incidence of notification of 8/100,000 children, varying from 5.7 to 11.1 in the five countries. Fifty per cent of the visually impaired children were reported before they were 3 years of age. In approximately 45% of the children, visual impairment was due to various brain disorders, with cerebral amblyopia and secondary optic atrophy as the two leading causes. The relative impact of retinopathy of prematurity had decreased from the third most frequent cause (10%) in the prevalence study to seventh place (4%) in the incidence study. Two thirds of the children had additional impairments and these children also suffered from the most severe visual impairments. Among aetiological factors the majority (64%) were prenatal. The overall male:female ratio of 1.4:1 was identical to the sex ratio of the prevalence study.

An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the FBN1 polypeptide is connected to a novel variant of Marfan syndrome.

We present here a family with a clinical phenotype resembling Marfan syndrome (MFS), and displaying joint contracture and episodes of knee joint effusions, but lacking the cardiovascular features of the syndrome. The phenotype of this family represents a unique mixture of connective tissue symptoms, some of which are found in classical MFS and some of which are typical of dominant ectopia lentis. Linkage analyses suggested a linkage (LOD score 2.4; theta = 0) between the phenotype of the family and a polymorphic marker in the vicinity of the fibrillin locus on chromosome 15 (FBN1). Furthermore, a novel transition mutation was identified in the FBN1 gene in all the affected members of the family. In contrast to the majority of fibrillin mutations reported so far, this mutation substitutes a cysteine for arginine, producing an extra cysteine in one of the non-calcium-binding EGF-like motifs of the fibrillin polypeptide, most probably disturbing the formation of one of the three disulfide bridges known to be essential for the normal conformation of this motif.