Nutritional status of neurologically impaired children: Impact on comorbidity.

BACKGROUND AND AIMS: Malnutrition is common in neurologically impaired (NI) children. It is, however, ill-defined and under-diagnosed. If not recognized and treated, it increases the burden of comorbidities and affects the quality of life of these children. The aim of this study was to characterize the nutritional status of a cohort of children followed up at a reference center for cerebral palsy (CP) in Brussels, Belgium, and to investigate possible links with the occurrence of comorbidities. MATERIAL AND METHODS: We conducted a single-center retrospective study including all the children followed up at the Inter-university Reference Center for Cerebral Palsy ULB-VUB-ULg. The data were obtained by reviewing medical files. Anthropometric measurements as well as the etiology of neurological impairment, comorbidities, feeding patterns, and laboratory test results were collected. The children were assigned a nutritional diagnosis according to the World Health Organization and Waterlow definitions. RESULTS: A total of 260 children with cerebral palsy were included, 148 males and 112 females. Their mean age was 10.9±4.3 years. The gross motor function classification system (GMFCS) level was I for 79 children, II for 63 children, III for 35 children, IV for 33 children, and V for 50 children. Of the children, 54% had a normal nutritional status, 34% showed malnutrition, and 8% were obese; 38% had oropharyngeal dysphagia. The sensitivity of mean upper arm circumference of

Dietary practices in propionic acidemia: A European survey.

BACKGROUND: The definitive dietary management of propionic acidaemia (PA) is unknown although natural protein restriction with adequate energy provision is of key importance. AIM: To describe European dietary practices in the management of patients with PA prior to the publication of the European PA guidelines. METHODS: This was a cross-sectional survey consisting of 27 questions about the dietary practices in PA patients circulated to European IMD dietitians and health professionals in 2014. RESULTS: Information on protein restricted diets of 186 PA patients from 47 centres, representing 14 European countries was collected. Total protein intake [PA precursor-free L-amino acid supplements (PFAA) and natural protein] met WHO/FAO/UNU (2007) safe protein requirements for age in 36 centres (77%). PFAA were used to supplement natural protein intake in 81% (n = 38) of centres, providing a median of 44% (14-83%) of total protein requirement. Seventy-four per cent of patients were prescribed natural protein intakes below WHO/FAO/UNU (2007) safe levels in one or more of the following age groups: 0-6 m, 7-12 m, 1-10 y, 11-16 y and > 16 y. Sixty-three per cent (n = 117) of patients were tube fed (74% gastrostomy), but only 22% received nocturnal feeds. CONCLUSIONS: There was high use of PFAA with intakes of natural protein commonly below WHO/FAO/UNU (2007) safe levels. Optimal dietary management can only be determined by longitudinal, multi-centre, prospective case controlled studies. The metabolic instability of PA and small patient cohorts in each centre ensure that this is a challenging undertaking.

Dietary practices in isovaleric acidemia: A European survey.

BACKGROUND: In Europe, dietary management of isovaleric acidemia (IVA) may vary widely. There is limited collective information about dietetic management. AIM: To describe European practice regarding the dietary management of IVA, prior to the availability of the E-IMD IVA guidelines (E-IMD 2014). METHODS: A cross-sectional questionnaire was sent to all European dietitians who were either members of the Society for the Study of Inborn Errors of Metabolism Dietitians Group (SSIEM-DG) or whom had responded to previous questionnaires on dietetic practice (n = 53). The questionnaire comprised 27 questions about the dietary management of IVA. RESULTS: Information on 140 patients with IVA from 39 centres was reported. 133 patients (38 centres) were given a protein restricted diet. Leucine-free amino acid supplements (LFAA) were routinely used to supplement protein intake in 58% of centres. The median total protein intake prescribed achieved the WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Centres that prescribed LFAA had lower natural protein intakes in most age groups except 1 to 10 y. In contrast, when centres were not using LFAA, the median natural protein intake met WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Enteral tube feeding was rarely prescribed. CONCLUSIONS: This survey demonstrates wide differences in dietary practice in the management of IVA across European centres. It provides unique dietary data collectively representing European practices in IVA which can be used as a foundation to compare dietary management changes as a consequence of the first E-IMD IVA guidelines availability.

Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation.

Mutations affecting splicing underlie the development of many human genetic diseases, but rather rarely through mechanisms of pseudoexon activation. Here, we describe a novel c.1092T>A mutation in the iduronate-2-sulfatase (IDS) gene detected in a patient with significantly decreased IDS activity and a clinical diagnosis of mild mucopolysaccharidosis II form. The mutation created an exonic de novo acceptor splice site and resulted in a complex splicing pattern with multiple pseudoexon activation in the patient's fibroblasts. Using an extensive series of minigene splicing experiments, we showed that the competition itself between the de novo and authentic splice site led to the bypass of the authentic one. This event then resulted in activation of several cryptic acceptor and donor sites in the upstream intron. As this was an unexpected and previously unreported mechanism of aberrant pseudoexon inclusion, we systematically analysed and disproved that the patient's mutation induced any relevant change in surrounding splicing regulatory elements. Interestingly, all pseudoexons included in the mature transcripts overlapped with the IDS alternative terminal exon 7b suggesting that this sequence represents a key element in the IDS pre-mRNA architecture. These findings extend the spectrum of mechanisms enabling pseudoexon activation and underscore the complexity of mutation-induced splicing aberrations. KEY MESSAGE: Novel exonic IDS gene mutation leads to a complex splicing pattern. Mutation activates multiple pseudoexons through a previously unreported mechanism. Multiple cryptic splice site (ss) activation results from a bypass of authentic ss. Authentic ss bypass is due to a competition between de novo and authentic ss.

Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system.

BACKGROUND: Multilevel approaches involving environmental strategies are considered to be good practice to help reduce the prevalence of childhood overweight. OBJECTIVES: The objective of this study was to evaluate the effects of VIASANO, a community-based programme using the EPODE methodology, on the prevalence of overweight in two pilot towns in Belgium. METHODS: We analysed data from a national school health monitoring system to compare changes in the prevalence of overweight and obesity over a 3-year period (2007-2010) in children aged 3-4 and 5-6 years in the pilot towns with those of children of the same ages from the whole French-speaking community of Belgium. Heights and weights of all participants were measured by trained school nurses using a standardized method. RESULTS: The prevalence of overweight (-2.1%) and overweight + obesity (-2.4%) decreased in the pilot towns, but remained stable in the comparison population (+0.1% and +0.2%, respectively). After adjustment for lack of homogeneity between the study populations, there was a trend towards a decrease in overweight (P = 0.054) and overweight + obesity (P = 0.058) in the pilot towns compared with the general population. CONCLUSIONS: These results suggest that a community-based programme, such as VIASANO, may be a promising strategy for reducing the prevalence of childhood overweight even over a short period of time.

[Newborn screening : the point of view of the paediatrician]. / Dépistage néonatal : le point de vue du pédiatre.

Newborn screening is a public health effort that has changed the prognosis of some congenital diseases. Newborn screening programmes differ between countries in which it is organized. Demographic, epidemiological or economic factors play a role in the choice of the screening panel. In the French Community of Belgium, the programme focuses on 13 metabolic and endocrine diseases, hearing loss and hemoglobinopathies (Brussels and Liege). Newborn screening is a complex process that requires the involvement of all stakeholders : parent information, blood sampling or testing, lab analysis, follow-up of the results, initiate adequate care in case of positive test and genetic counselling. Newborn screening programmes will evolve in the next years. New therapeutic and diagnostic methods will make other genetic diseases candidates for screening. Whole genome sequencing may be the next expansion; it will create new opportunities but will pose new ethical dilemmas. We must all prepare now for future challenges.

Malignant Pleural Mesothelioma : Rationale for a New TNM Classification.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with a poor prognosis. In this regard, a well-defined staging system is of utmost importance in order to correctly diagnose and assign an appropriate treatment to the patient. METHODS: The current TNM-staging system (7th edition) enables to either clinically or pathologically stage the severity of the disease according to extension of the tumor (T), number of nodes (N) and presence of metastases (M). Patients with stage I-III are considered for surgery, while palliative treatment is indicated for stage IV patients according to the current classification. RESULTS: Despite its widespread use, the validity of this staging system is questioned due to the low prevalence, histological variety and retrospective nature of the previous study design. In addition, the role of specific treatment modalities including surgery, has yet to be determined, especially for treatment of early-stage disease. In this regard, the International Association for the Study of Lung Cancer (IASLC) initiated the multi-centre, prospective "Mesothelioma Staging Project" in order to address limitations of the 7th edition and to optimize the staging system in accordance to current needs. CONCLUSIONS: An improved staging system will contribute to the design of prospective multi-institutional clinical trials investigating novel treatment strategies for mesothelioma. In this way comparison of outcome between different medical centres also becomes feasible.

Deficiency of Subunit 6 of the Conserved Oligomeric Golgi Complex (COG6-CDG): Second Patient, Different Phenotype.

We describe a 27-month-old girl with COG6 deficiency. She is the first child of healthy consanguineous Moroccan parents. She presented at birth with dysmorphic features including microcephaly, post-axial polydactyly, broad palpebral fissures, retrognathia, and anal anteposition. The clinical phenotype was further characterised by multiorgan involvement including mild psychomotor retardation, and microcephaly, chronic inflammatory bowel disease, micronodular liver cirrhosis, associated with life-threatening and recurrent infections due to combined T- and B-cell dysfunction and neutrophil dysfunction.Mutation analysis showed the patient to be homozygous for the c.G1646T mutation in the COG6 gene. She is the second reported patient with a deficiency of subunit 6 of the COG complex. Although both patients are homozygous for the same mutation, they present a markedly different clinical picture. Indeed immunodeficiency as well as inflammatory bowel disease has not been described previously in patients with any COG-CDG.

[Alendronate more effective than alfacalcidol in the prevention of osteoporosis in patients with rheumatic disease who are starting glucocorticoid therapy]. / Alendroninezuur effectiever dan alfacalcidol voor preventie van osteoporose bij patiënten met een reumatische ziekte die starten met glucocorticoïdtherapie.

OBJECTIVE: To compare the effects of alendronate and alfacalcidol in the prevention ofglucocorticoid-related osteoporosis in patients with a rheumatic disease. DESIGN: Randomised, double-blind, double-placebo clinical trial (www. clinicaltrials.gov; number: NCT00138983). METHODS: A total of 201 patients with rheumatic disease who were starting glucocorticoid treatment at a daily dose that was equivalent to at least 7.5 mg of prednisone were randomised to alendronate (10 mg) and a placebo capsule ofalfacalcidol daily (n = 100) or alfacalcidol (1 microg) and a placebo tablet ofalendronate daily (n = 101) for 18 months. Primary outcome was change in lumbar spine bone mineral density at 18 months. The main secondary outcome was the incidence of morphometrically confirmed vertebral deformities. RESULTS: Overall, 163 patients completed the study. The bone mineral density of the lumbar spine increased by 2.1% (95% CI: 1.1-3.1) in the alendronate group and decreased by 1.9% (95% CI: -3.I--0.7) in the alfacalcidol group. At 18 months the mean difference in change in bone mineral density between the two groups was 4.0% (95% CI: 2.4-5-5). Three patients in the alendronate group had a new vertebral deformity, compared with 8 patients in the alfacalcidol group, including 5 symptomatic vertebral fractures in 3 patients; the hazard ratio was 0.4 (95% CI: 0.1-1.4). CONCLUSION: Alendronate was more effective than alfacalcidol in preventing glucocorticoid-induced bone loss during this 18-month trial in patients with rheumatic diseases who were starting glucocorticoid treatment.

The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women.

UNLABELLED: BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD. METHODS: Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score). RESULTS: CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts. CONCLUSIONS: The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.

[Inborn errors of metabolism: new developments and challenges]. / Les erreurs innées du métabolisme: progrès et défis.

The concept "inborn error of metabolism" (IEM) arose from the observations of Sir A. Garrod at the beginning of the XXth century. The exponential development, during the last decades, of our knowledge in cellular biology and molecular genetics, and the availability of increasingly more precise diagnostic tools, allow the identification of a still growing number of inborn errors of metabolism. Their physiopathology is better understood. Treatments have considerably improved: more specific diets, new medical treatments, enzyme replacement therapy, organ transplantation, hepatocyte or stem cell transplantation... New techniques are under development, including various strategies of gene therapy. Improved therapeutic efficacy combined with earlier diagnosis have dramatically changed the prognosis of many disorders. As a consequence, new challenging questions have to be answered. Today, patients with an IEM, because of the extreme complexity of their management, need to be looked after by a multidisciplinary team of physicians (pediatricians and internists), dieticians, social workers, psychologists... It is essential, in this complex and rapidly expanding field, that experiences should be shared at national and international level, in order to provide the most adequate care for patients.

[Dietetic and nutritional management in a university children's hospital]. / Diététique et nutrition dans un hôpital pédiatrique universitaire.

Dietetics and nutrition are new, expanding disciplines. Feeding man's cub to ensure the best physical, brain and psychic growth to reach the adult age in a "sane" state is the daily challenge of pediatric dieteticians. The role of dieteticians in a pediatric hospital is essential: optimizing sick children's nutrition. A child is highly vulnerable, above all when he is sick. Unappropriate feeding can put his growth and development, as well as his healing at stake. Numerous studies believe that denutrition in pediatric hospitals prevail by 7 to 45%. A survey has been carried out in two care units in the University Children's Hospital Queen Fabiola in Brussels. For one month, the nutritional hazard has been evaluated in every children admitted in these units. One observes that one third of these children shows a high nutritional hazard, and another third a moderate nutritional hazard. The tracking of the nutritional hazard and the appropriate nutritional care must be an integral part of the care given to any child admitted in hospital. A nutrition unit, with all the attending people involved (doctor, dietician, chemist, nurse), is necessary to improve the nutritional care of the patients.

Assessment of fracture risk: who should be treated for osteoporosis?

The clinical significance of osteoporosis arises from the fractures that occur. Of these, the hip fracture in particular is associated with high morbidity, mortality and socio-economic costs. The primary goal of osteoporosis treatment is fracture prevention. In this chapter we try to answer the question of how to assess fracture risk and how to identify those above a given risk threshold so that treatment can be given to those in whom fractures can be prevented (cost-) effectively. At first, the two main strategies for fracture prevention--population screening and case finding--are discussed. Then a fracture risk assessment score, based on easily identifiable clinical risk factors, is proposed. This clinical risk factor analysis can guide the decisions whether additional bone assessment is relevant and whether treatment should be started. Finally, we advocate that absolute fracture risk is important for communication with the patient about the decision whether or not to initiate treatment.

Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study.

The aim of this study was to determine the association between type-2 diabetes mellitus (DM), BMD and fractures in 6,655 men and women aged 55 years and over from the Rotterdam Study. We compared subjects with type-2 DM to subjects without DM. Additionally, subset analyses were performed, dividing subjects on the basis of the glucose tolerance test into already treated DM, newly diagnosed DM, impaired glucose tolerance (IGT) and normal glucose tolerance (NGT, reference). Femoral neck and lumbar spine BMD were measured using DEXA. Nonvertebral fracture ascertainment was performed using an automated record system involving GPs and local hospitals. Although subjects with DM had higher BMD, they had an increased nonvertebral fracture risk: hazard ratio (HR) 1.33 (1.00-1.77). In subset analysis, the increased fracture risk appeared restricted to treated DM subjects only: HR 1.69 (1.16-2.46). Subjects with IGT had a higher BMD, but contrary to treated DM, they had a lower fracture risk: HR 0.80 (0.63-1.00). In conclusion, subjects with type-2 DM and IGT both have a higher BMD. Whereas, subjects with IGT have a decreased fracture risk, subjects with DM (primarily those with already established and treated DM) had an increased fracture risk, probably due to long-term complications associated with DM.

Body mass index as a predictor of fracture risk: a meta-analysis.

Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.

A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids.

BACKGROUND: Previous analyses of risk factors for glucocorticoid (GC)-induced osteoporosis have focused on the estimation of relative rather than absolute fracture probability. AIM: To estimate risk scores for the individual probability of fracture in GC users. DESIGN: Retrospective data analysis. METHODS: We evaluated all patients aged 40 years or older with a prescription for oral GCs in the General Practice Research Database (GPRD), which comprises the computerized medical records of around 7 million UK subjects. Individual risk factors for osteoporotic fractures were identified, and combined in a predictive model for 10-year absolute fracture risk. RESULTS: Of 191 752 oral GC users aged > or =40 years, 7412 experienced an osteoporotic fracture. Several characteristics independently contributed to the fracture risk score (GC therapy, age, gender, fall history, fracture history, body mass index, smoking, previous diagnoses, use of medication, recent hospitalization and indication for GC treatment). Scores of 30, 40 and 50 corresponded to absolute 5-year fracture risks of 6.2%, 15.3% and 35.2%, respectively. A woman aged 65 years with RA, low BMI, and a previous history of fracture and falls, who used 15 mg GC daily (total risk score 54) would have a 5-year fracture risk of 47% (a man with similar history, 30.1%). Short-term use of high-dose GC therapy (> or =30 mg) was associated with only a small increased risk of osteoporotic fracture (RR 1.21, 95%CI 1.04-1.42) in patients with a history of GC use. DISCUSSION: This risk score helps to predict an individual's risk of fracture during GC use. Decisions about bone protection treatment could be based on long-term risks of fracture.

Smoking and fracture risk: a meta-analysis.

Smoking is widely considered a risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex and bone mineral density (BMD). We studied 59,232 men and women (74% female) from ten prospective cohorts comprising EVOS/EPOS, DOES, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, Hiroshima and two cohorts from Gothenburg. Cohorts were followed for a total of 250,000 person-years. The effect of current or past smoking, on the risk of any fracture, any osteoporotic fracture and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex and BMD. The results of the different studies were merged using the weighted beta-coefficients. Current smoking was associated with a significantly increased risk of any fracture compared to non-smokers (RR=1.25; 95% Confidence Interval (CI)=1.15-1.36). Risk ratio (RR) was adjusted marginally downward when account was taken of BMD, but it remained significantly increased (RR=1.13). For an osteoporotic fracture, the risk was marginally higher (RR=1.29; 95% CI=1.13-1.28). The highest risk was observed for hip fracture (RR=1.84; 95% CI=1.52-2.22), but this was also somewhat lower after adjustment for BMD (RR=1.60; 95% CI=1.27-2.02). Risk ratios were significantly higher in men than in women for all fractures and for osteoporotic fractures, but not for hip fracture. Low BMD accounted for only 23% of the smoking-related risk of hip fracture. Adjustment for body mass index had a small downward effect on risk for all fracture outcomes. For osteoporotic fracture, the risk ratio increased with age, but decreased with age for hip fracture. A smoking history was associated with a significantly increased risk of fracture compared with individuals with no smoking history, but the risk ratios were lower than for current smoking. We conclude that a history of smoking results in fracture risk that is substantially greater than that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies.

The burden of hospitalised fractures in Sweden.

The aim of this study was to characterise the hospital burden of fractures in the Swedish population by age and gender. The number of patients and number of fractures were documented according to site of fracture, age, sex and duration of hospital stay for the whole population of Sweden in 1996. Fractures were additionally classified as osteoporotic according to fracture site. In 1996 there were 54,000 admissions for fracture in men and women aged 50 years or more, accounting for 600,000 hospital-bed days. Hip fractures accounted for 63% of admissions for fracture in men and 72% in women, for 69% and 73% of hospital-bed days, respectively. Fractures considered to be osteoporotic accounted for 84% of all hospital-bed days due to fracture in men, and 93% in women. More hospital-bed days were due to osteoporotic fracture than to breast cancer and prostate cancer combined. The number of hospital-bed days due to osteoporotic fracture was between the amount due to ischaemic heart disease and the amount due to stroke.