ABSTRACT
Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.
ABSTRACT
BACKGROUND: In adults with Prader-Willi syndrome (PWS), limited information is available about pituitary function, more specifically the prevalence of growth hormone deficiency (GHD). The aim of this study was to gain more insight into endocrine function in PWS adults, with emphasis on GH secretion. METHODS: 15 randomly selected adult PWS individuals were included and 14 healthy brothers and sisters served as a control group. Main outcome measures were IGF-I, IGFBP-3 and peak GH level after a combined GHRH-arginine test. Other pituitary hormone deficits are diagnosed based on serum levels of the concerning hormones. The size of the pituitary gland was measured on MRI images. RESULTS: In PWS adults, IGF-I levels were low and IGFBP-3 levels normal when compared to healthy controls. GHD was diagnosed in 8-38% of the PWS patients, depending on the criteria used. Hypogonadism was present in 87% of the patients. Hypothyroidism and adrenal insufficiency could also be demonstrated. Anterior pituitary size was lower in PWS individuals when compared to healthy controls. CONCLUSION: In this study, pituitary hormone deficiencies are demonstrated in a considerable number of adults with PWS, hypogonadism and GHD being most prominent. Furthermore, the anterior pituitary is smaller in comparison with healthy controls.
Subject(s)
Human Growth Hormone/metabolism , Pituitary Gland/metabolism , Prader-Willi Syndrome/physiopathology , Adiposity , Adolescent , Adult , Arginine , Case-Control Studies , Endocrine Glands/physiopathology , Female , Growth Hormone-Releasing Hormone , Human Growth Hormone/deficiency , Humans , Insulin-Like Growth Factor I/metabolism , Male , Organ Size , Pituitary Gland/pathology , Pituitary Gland/physiopathology , Pituitary Hormones/deficiency , Prader-Willi Syndrome/pathology , Young AdultABSTRACT
BACKGROUND: Individuals with Prader-Willi syndrome (PWS) are at risk of sleep disturbances, such as excessive daytime sleepiness (EDS) and sleep apnoea, and behavioural problems. Sleep disturbances and their relationship with other variables had not been researched extensively in adults with PWS. METHOD: Sleep disturbances and behavioural problems were investigated in adults with genetically confirmed PWS using standardised questionnaires. Results of adults with paternal deletion (n=45) were compared with those of adults with maternal uniparental disomy (n=33). RESULTS: Eleven adults with PWS (i.e. 15%) had a current sleep problem, mostly night waking problems. Twenty-six adults with PWS (i.e. 33%) suffered from severe EDS. No differences in prevalence of sleep disturbances between genetic subtypes were found. Seventeen adults with deletion (i.e. 38%) and 17 adults with maternal uniparental disomy (i.e. 52%) had behavioural problems. No significant relationships were found between sleep disturbances and behavioural problems. CONCLUSIONS: In adults with PWS, EDS is the most common type of sleep disturbance. Men and individuals with relative high body mass index are at increased risk for EDS. More research, aimed at developing a suitable screening instrument for sleep apnoea in adults with PWS, is necessary. Clinical implications of the findings are discussed.
Subject(s)
Mental Disorders/epidemiology , Prader-Willi Syndrome/epidemiology , Sleep Apnea Syndromes/epidemiology , Surveys and Questionnaires , Adolescent , Adult , Aged , Female , Humans , Logistic Models , Male , Mental Disorders/diagnosis , Middle Aged , Prader-Willi Syndrome/genetics , Risk Factors , Sleep Apnea Syndromes/diagnosis , Sleep Stages , Young AdultABSTRACT
An inventory was made of 5 substitute care projects in old people's homes, performed by the nursing home in Geertruidenberg. Data were gathered by semi-structured interviews and enquiries. The general goal of substitution of nursing home care for outdoor patients is to provide complementary outreaching nursing home services, by which real nursing home admittance can be postponed or avoided. In fact, in many cases substitution care appears to avoid nursing home admittance. In 1991-1993 there were 144 participants in these projects, from which only 11 at least were admitted to the nursing home. In the near future however, the quality of these outreaching nursing home projects has to be improved, especially on aspects as: continuity and methodology of care and with respect to the multidisciplinary approach. At last the financial support of these projects appears to be complicated and uncertain. A structural solution for this problem is urgent too.
