Oral ribose supplementation in dystroglycanopathy: A single case study.

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein (ISPD), fukutin-related protein (FKRP), and fukutin (FKTN) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation (p < 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects.

A reduced size of the ovarian follicle pool is associated with an increased risk of a trisomic pregnancy in IVF-treated women.

BACKGROUND: The increased risk of a trisomic pregnancy with a woman's age arises from an increased rate of meiotic non-disjunction in the oocytes. It has been hypothesized that the increase in meiotic errors is related to the decreasing number of oocytes with age. Our aim was to assess the relation between trisomic pregnancy and three parameters of oocyte quantity. METHODS: In a Dutch nationwide database on in vitro fertilization (IVF) treatment from 1983 to 1995, we identified 28 women with a trisomic pregnancy conceived via or within 1 year from IVF treatment. We selected five age-matched controls with a healthy child for each trisomy case. We performed a case-control study to examine whether trisomy cases more often had a history of ovarian surgery and a lower response to ovarian hyperstimulation than controls. Subsequently, cases and controls were followed to compare the incidence of signs of menopause at the end of the study period as self-reported by questionnaire. RESULTS: Logistic regression analysis showed an association between trisomic pregnancy and a history of ovarian surgery [odds ratio (OR) 3.3; 95% confidence interval (CI): 1.0-10.5; P = 0.04] and between trisomic pregnancy and retrieval of < or = 4 oocytes during IVF treatment (OR 4.0; 95% CI: 1.4-11.5; P = 0.01). The adjusted OR for signs of menopause associated with trisomic pregnancy was 5.7 (95% CI: 1.1-29.9; P = 0.04). CONCLUSIONS: Our results suggest that IVF-treated women with a reduced ovarian follicle pool are at increased risk of a trisomic pregnancy, independent of their age. Our findings support the hypothesis that follicle pool size and not chronological age determines a woman's trisomy risk. Since a questionnaire was used, we cannot fully exclude the possibility of selection bias in this study.

[Management of pregnancy and childbirth in carriers of haemophilia]. / Begeleiding van de zwangerschap en de partus bij draagsters van hemofilie.

3 pregnant women, aged 27, 33 and 31 years respectively, were carriers of haemophilia A. The first patient had a caesarean section without prior measurement or substitution of factor VIII. She gave birth to a healthy boy, but developed severe diffuse abdominal bleeding after a few hours. The second patient had a normal level of factor VIII, and lived 100 km away from the nearest haemophilia treatment centre. Ultrasound investigation revealed a female foetus. She gave birth in the local hospital. The third patient was pregnant with a male foetus, but refused further prenatal investigation. Contrary to medical advice she gave birth at home. For carriers of haemophilia, there are several options for prenatal diagnosis and managing labour and delivery. Early referral is advised and the need for adequate counselling is explained. It is important to have an experienced haemophilia treatment centre nearby, where haematologists, gynaecologists, geneticists and paediatricians cooperate in caring for pregnant carriers of haemophilia.

Perinatal death investigations: What is current practice?

Perinatal death (PD) is a devastating obstetric complication. Determination of cause of death helps in understanding why and how it occurs, and it is an indispensable aid to parents wanting to understand why their baby died and to determine the recurrence risk and management in subsequent pregnancy. Consequently, a perinatal death requires adequate diagnostic investigation. An important first step in the analysis of PD is to identify the case circumstances, including relevant details regarding maternal history, obstetric history and current pregnancy (complications are evaluated and recorded). In the next step, placental examination is suggested in all cases, together with molecular cytogenetic evaluation and fetal autopsy. Investigation for fetal-maternal hemorrhage by Kleihauer is also recommended as standard. In cases where parents do not consent to autopsy, alternative approaches such as minimally invasive postmortem examination, postmortem magnetic resonance imaging, and fetal photographs are good alternatives. After all investigations have been performed it is important to combine findings from the clinical review and investigations together, to identify the most probable cause of death and counsel the parents regarding their loss.

Three cases of mosaicism for balanced reciprocal translocations.

Mosaicism for a balanced reciprocal translocation (BRTM) is rare. As far as we know only 26 cases of BRTM, demonstrated in lymphocyte cultures, have been described, five of which had an abnormal phenotype. Prenatally three confirmed cases with a normal phenotypic outcome have been described. Here we present three further cases of BRTM in lymphocyte cultures. The first was detected during a family study, the second after an abnormal karyotype in chorionic villus sampling, and the third because of a history of stillborn children. All three carriers have normal phenotypes. An inventory of the BRTM cases reported so far is made.

Tetrasomy 9p due to an intrachromosomal triplication of 9p13-p22.

To date, approximately 30 patients have been described with a tetrasomy 9p, all being caused by the presence of an isochromosome 9p. We now report on a 3-year-old boy with a de novo intrachromosomal triplication of 9p13-p22, resulting in partial tetrasomy 9p. We compared his phenotype with cases of tetrasomy 9p caused by the presence of an extra isochromosome 9p. He has facial anomalies similar to those of cases of tetrasomy 9p, central nervous system abnormalities, and severe psychomotor retardation but no other major congenital anomalies. Fluorescence in situ hybridization with region-specific probes showed that the middle repeat of the triplicated part is inverted. Microsatellite analysis demonstrated an involvement of both paternal chromosome 9 homologues in the triplication. This is compatible with either unequal crossing over of three of the four chromatids in paternal meiosis I or with a double crossing over in meiosis I and II (or an early mitotic division).

[Experiences of women who decided to continue the pregnancy after diagnosis of Down's syndrome]. / Ervaringen van vrouwen die besloten de zwangerschap uit te dragen na de diagnose 'Down-syndroom'.

OBJECTIVE: To gain insight into the motives and experiences of women who had decided to continue with the pregnancy after Down's syndrome had been diagnosed in the foetus. DESIGN: In-depth interviews. METHOD: In ten women who had decided to continue her pregnancy after Down's syndrome had been diagnosed in the foetus, qualitative in-depth interviews were held. Four women were pregnant at the time of the interview, the other six were parent of a Down's syndrome child already. One of the women was in her first pregnancy, the other nine had been pregnant once or several times. Four women had problems in their history (subfertility, miscarriage, in-vitro fertilisation). RESULTS: Many pregnant women were confronted with an increased risk as the result of maternal serum testing or nuchal translucency. They hoped to reduce the uncertainty which had arisen by submitting to an amniocentesis or a chorionic villus sampling. The result of this diagnostic test put those concerned in the position of having to make a difficult decision. They had to make the choice between having to bring up a child with intellectual limitations or allowing the termination of an already well-advanced pregnancy. For the ten respondents, the latter proved to be unacceptable. Initially, little understanding was shown for the parent's decision by some social and medical workers; however, sufficient help and support were usually given. The respondents received a lot of support from members of their family, friends and acquaintances, but there were also negative and disapproving reactions. Only one woman regretted the examination. CONCLUSION: As the technological possibilities for determining individual risks during pregnancy increase, it will occur more often that women hesitate to have their pregnancy terminated after diagnostic testing has identified Down's syndrome. Whatever decision is made, those involved should be treated with understanding.

The Tulip classification of perinatal mortality: introduction and multidisciplinary inter-rater agreement.

OBJECTIVE: To introduce the pathophysiological Tulip classification system for underlying cause and mechanism of perinatal mortality based on clinical and pathological findings for the purpose of counselling and prevention. DESIGN: Descriptive. SETTING: Tertiary referral teaching hospital. POPULATION: Perinatally related deaths. METHODS: A classification consisting of groups of cause and mechanism of death was drawn up by a panel through the causal analysis of the events related to death. Individual classification of cause and mechanism was performed by assessors. Panel discussions were held for cases without consensus. MAIN OUTCOME MEASURES: Inter-rater agreement for cause and mechanism of death. RESULTS: The classification consists of six main causes with subclassifications: (1) congenital anomaly (chromosomal, syndrome and single- or multiple-organ system), (2) placenta (placental bed, placental pathology, umbilical cord complication and not otherwise specified [NOS]), (3) prematurity (preterm prelabour rupture of membranes, preterm labour, cervical dysfunction, iatrogenous and NOS), (4) infection (transplacental, ascending, neonatal and NOS), (5) other (fetal hydrops of unknown origin, maternal disease, trauma and out of the ordinary) and (6) unknown. Overall kappa coefficient for agreement for cause was 0.81 (95% CI 0.80-0.83). Six mechanisms were drawn up: cardio/circulatory insufficiency, multi-organ failure, respiratory insufficiency, cerebral insufficiency, placental insufficiency and unknown. Overall kappa for mechanism was 0.72 (95% CI 0.70-0.74). CONCLUSIONS: Classifying perinatal mortality to compare performance over time and between centres is useful and necessary. Interpretation of classifications demands consistency. The Tulip classification allows unambiguous classification of underlying cause and mechanism of perinatal mortality, gives a good inter-rater agreement, with a low percentage of unknown causes, and is easily applicable in a team of clinicians when guidelines are followed.

Necrotizing sarcoid granulomatosis with uveitis: a variant of sarcoidosis?

A patient with malaise, uveitis and a nodular infiltrate in the left lower lobe of the lung is described. An open lung biopsy established the diagnosis of necrotizing sarcoid granulomatosis. The differential diagnosis of necrotizing sarcoid granulomatosis with sarcoidosis and angiocentric granulomatosis (Wegener's disease) is extensively discussed. Our case illustrates that NSG and sarcoidosis could be pathogenetically related.

Age at postnatal diagnosis of down syndrome in the northern Netherlands for the period 1981-2000.

BACKGROUND: In live-born children with Down syndrome it may be very difficult for the clinician or midwife assisting at the delivery to recognise Down syndrome in newborn babies due to varying physical appearances. Meanwhile more and more therapeutical interventions become available that should start early in life. We were interested in the age at the postnatal diagnosis of Down syndrome, and found no literature on the subject. METHODS: We studied the age at the diagnosis of Down syndrome for live-born babies born in the period of 1981-2000 and registered by the European Registration of Congenital Anomalies in the northern part of The Netherlands. RESULTS: For 289 children, data on the age at the postnatal diagnosis were available, in 70.8% of whom there was suspicion of DS on the day of birth. In 1.7% of the cases, the diagnosis was made after 1 year. Place of birth and the specialty of the health worker assisting at the delivery were associated with age at diagnosis. When the child was delivered at hospital, 96.4% of the Down syndrome cases had been diagnosed within 1 month compared to 81.3% following home delivery. CONCLUSION: In some cases of Down syndrome in live-born babies, the diagnosis is made only after months or a year. The diagnosis was made faster in babies born in hospital compared to those born at home.

Fluticasone propionate in children with moderate asthma.

Inhaled corticosteroids are considered to be effective and safe to treat children with asthma. These drugs, often used as maintenance treatment, can, however, influence the HPA-axis, which might be reflected by the serum and urine cortisol concentration. The aim of the present study was to investigate the efficacy and safety of fluticasone propionate (FP) 100 microg administered twice a day via a Diskhaler for 3 mo. FP was tested in a double-blind randomized placebo-controlled parallel trial in a group of 34 children with moderate asthma who did not use inhaled steroids for at least 4 wk prior to the study. At home, symptoms and peak flow recordings (PEFR) were noted in a diary. At each visit lung function was measured, and serum and urinary cortisol were determined. During treatment, wheezing decreased and PEFR values increased in the FP group. FEV1 and PC20-histamine increased and the reversibility decreased in the FP group. All changes were significant, with the exception of the change in nocturnal PEFR. Four weeks after cessation of FP all parameters returned to pretreatment values. Serum cortisol did not change significantly in either treatment group. The decrease in urinary cortisol in the FP group was significant only if it was compared with the increase in urinary cortisol in the placebo group. We conclude that FP 100 microg given twice a day is effective in children with moderate stable asthma. Suppression of the HPA-axis by FP 100 microg given twice daily, although not likely, cannot be ruled out by this study since the absence of a significant decrease in urinary cortisol in the FP group could be due to an insufficient number of patients. Additional studies are required to solve this problem.

Four years' cytogenetic experience with the culture of chorionic villi.

In 1958 chorionic villus samples, investigated by culture method, we found 137 (7%) abnormalities. The abnormal results were classified in certain abnormal (generalised abnormal at high probability) and uncertain abnormal (potentially confined to the placenta) results. Certain abnormal were 73 cases (3.7%). Uncertain abnormal were 64 cases (3.3%), in which confirmation studies were done in 47 cases. In 12 cases of these 47, the abnormality was confirmed and in 35 cases (1.8%) the abnormality was confined to the placenta. Among the latter cases, poor pregnancy outcome [16% intrauterine death (IUD), 6% intrauterine growth retardation (IUGR)] was increased. Total maternal cell contamination was not seen. The positive predictive value of all confirmed abnormal cases was 66%. The positive predictive value was 100% for indications 'ultrasound abnormalities' and 'carrier' and between 50 and 60% for all other indications. Predictive value among uncertain abnormal cases was low (26%). However, the positive predictive value depends of the type of abnormality. Therefore we conclude that the culture method for chorionic villi is a good test for indications 'ultrasound abnormalities' and 'carrier' and reliable for all other indications. Whether or not follow-up investigations should be offered to the parents depends of the type of abnormality. We conclude that the culture method is reliable for prenatal diagnosis and can be used as the sole investigative method.

Eosinophil and mast cell parameters in children with stable moderate asthma.

UNLABELLED: Mast cells and eosinophils are important cells that contribute to the process of inflammation in asthma either by activating other cells or by secreting products which are potentially toxic to the respiratory epithelium. The influx of these cells in the airways and the secretion of toxic products by these cells is abrogated by inhaled corticosteroids. METHODS: In a double blind randomised, placebo controlled, study in children with stable moderate asthma (N = 34, 15 children received fluticasone propionate (FP), an inhaled corticosteroid, and 19 children used a placebo), we investigated the influence of treatment with FP 100 microg b.d. on various parameters of inflammation: number of eosinophils, secretory products of eosinophils i.e. ECP and EDN (in serum and urine) and a secretory product of mast cells, histamine, which is determined as the compound to which histamine is converted and excreted by the human body: NT-methyl-histamine. RESULTS: Previously we reported that lung function increased and bronchial hyperresponsiveness decreased in the 30 children that completed the study during treatment with FP. In these children we found that none of the laboratory parameters of inflammation changed significantly during treatment with either FP or placebo. However, the decrease in urinary EDN almost reached significance (P = 0.07). CONCLUSIONS: Our results indicate that the number of eosinophils, serum ECP and EDN and urinary EDN as well as urinary NT-methyl-histamine do not reflect asthma disease activity in children with stable moderate asthma. Our data on urinary EDN warrant further study of the use of this parameter to monitor asthma in children.

Identification of a nonsense mutation at the 5' end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disease with a high mutation rate. It is clinically a very variable disorder and hamartomas can occur in many different organs. TSC shows genetic heterogeneity; one gene, TSC1, is on chromosome 9q34, and the second gene, TSC2, on chromosome 16p13.3. Clinical criteria for diagnosis have been established, but diagnosis of patients with minimal expression of the disease can be very difficult. In children the phenotype is often incomplete or not fully assessable. Hence mildly affected subjects, at risk for severely affected offspring, may remain undiagnosed. The detection of (small) mutations in the tuberous sclerosis gene located on chromosome 16 (TSC2) has recently become possible and may be helpful in the diagnosis of ambiguous cases. To our knowledge, this is the first report of a point mutation in the TSC2 gene in a familial case of tuberous sclerosis. A nonsense mutation was detected in a family in which the father had only minor signs hinting at tuberous sclerosis. The son had multiple cardiac tumours and white patches, but full clinical investigation was impossible in this child. This case illustrates that mutation analysis can contribute to a diagnosis of tuberous sclerosis in families with an incomplete phenotype.