Nicolle Quinn

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

The adult galactosemic phenotype

BackgroundClassic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression.MethodsThirty-three adults (mean age = 32.6 ± 11.7 years; range = 18–59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures.ResultsThe sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55–122). All subjects followed a dairy-free diet and 75–80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression.ConclusionsTaken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.

Impact of Carbohydrate Counting on Glycemic Control in Children With Type 1 Diabetes

OBJECTIVE To study the association between parent carbohydrate counting knowledge and glycemic control in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS We assessed 67 youth ages 4–12 years with type 1 diabetes (duration ≥1 year). Parents estimated carbohydrate content of childrens meals in diet recalls. Ratios of parent estimates to computer analysis defined carbohydrate counting knowledge; the mean and SD of these ratios defined accuracy and precision, respectively. A1C defined glycemic control. RESULTS Greater accuracy and precision were associated with lower A1C in bivariate analyses (P < 0.05). In a multivariate analysis (R2= 0.25, P = 0.007) adjusting for child age, sex, and type 1 diabetes duration, precision (P = 0.02) and more frequent blood glucose monitoring (P = 0.04), but not accuracy (P = 0.9), were associated with lower A1C. A1C was 0.8% lower (95% CI −0.1 to −1.4) among youth whose parents demonstrated precision. CONCLUSIONS Precision with carbohydrate counting and increased blood glucose monitoring were associated with lower A1C in children with type 1 diabetes.

Treatment of Vitamin D Insufficiency in Children and Adolescents with Inflammatory Bowel Disease: A Randomized Clinical Trial Comparing Three Regimens

CONTEXT Vitamin D insufficiency [serum 25-hydroxyvitamin D (25OHD) concentration less than 20 ng/ml] is prevalent among children with inflammatory bowel disease (IBD), and its treatment has not been studied. OBJECTIVE The aim of this study was to compare the efficacy and safety of three vitamin D repletion regimens. DESIGN AND SETTING We conducted a randomized, controlled clinical trial from November 2007 to June 2010 at the Clinical and Translational Study Unit of Childrens Hospital Boston. The study was not blinded to participants and investigators. PATIENTS Eligibility criteria included diagnosis of IBD, age 5-21, and serum 25OHD concentration below 20 ng/ml. Seventy-one patients enrolled, 61 completed the trial, and two withdrew due to adverse events. INTERVENTION Patients received orally for 6 wk: vitamin D(2), 2,000 IU daily (arm A, control); vitamin D(3), 2,000 IU daily (arm B); vitamin D(2), 50,000 IU weekly (arm C); and an age-appropriate calcium supplement. MAIN OUTCOME MEASURE We measured the change in serum 25OHD concentration (Δ25OHD) (ng/ml). Secondary outcomes included change in serum intact PTH concentration (ΔPTH) (pg/ml) and the adverse event occurrence rate. RESULTS After 6 wk, Δ25OHD ± se was: 9.3 ± 1.8 (arm A); 16.4 ± 2.0 (arm B); 25.4 ± 2.5 (arm C); P (A vs. C) = 0.0004; P (A vs. B) = 0.03. ΔPTH ± SE was -5.6 ± 5.5 (arm A); -0.1 ± 4.2 (arm B); -4.4 ± 3.9 (arm C); P = 0.57. No participant experienced hypercalcemia or hyperphosphatemia, and the prevalence of hypercalciuria did not differ among arms at follow-up. CONCLUSIONS Oral doses of 2,000 IU vitamin D(3) daily and 50,000 IU vitamin D(2) weekly for 6 wk are superior to 2,000 IU vitamin D(2) daily for 6 wk in raising serum 25OHD concentration and are well-tolerated among children and adolescents with IBD. The change in serum PTH concentration did not differ among arms.

Hutchinson-gilford progeria is a skeletal dysplasia

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare segmental premature aging disorder that affects bone and body composition, among other tissues. We sought to determine whether bone density and structural geometry are altered in children with HGPS and whether relationships exist among these parameters and measures of skeletal anthropometry, body composition, and nutrition. We prospectively enrolled 26 children with HGPS (ages 3.1 to 16.2 years). Outcomes included anthropometric data; bone age; areal bone mineral density (aBMD) and body composition by dual‐energy X‐ray absorptiometry (DXA); volumetric bone mineral density (vBMD), strength‐strain index (SSI), and bone structural rigidity calculated from radial transaxial peripheral quantitative computed tomographic (pQCT) images; serum bone biomarkers and hormonal measures; and nutrition assessments. Children with HGPS had low axial aBMD Z‐scores by DXA, which improved after adjustment for height age, whereas differences in radial vBMD by pQCT were less striking. However, pQCT revealed distinct abnormalities in both novel measures of bone structural geometry and skeletal strength at the radius compared with healthy controls. Dietary intake was adequate, confirming that HGPS does not represent a model of malnutrition‐induced bone loss. Taken together, these findings suggest that the phenotype of HGPS represents a unique skeletal dysplasia.

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.

Background: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. Methods: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. Results: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001–0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. Conclusions: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

Comparison of Body Composition Assessment Methods in Pediatric Intestinal Failure

Objectives: The aim of the study was to examine the agreement of multifrequency bioelectric impedance analysis (BIA) and anthropometry with reference methods for body composition assessment in children with intestinal failure (IF). Methods: We conducted a prospective pilot study in children 14 years or younger with IF resulting from either short bowel syndrome or motility disorders. Bland-Altman analysis was used to examine the agreement between BIA and deuterium dilution in measuring total body water (TBW) and lean body mass (LBM), and between BIA and dual-energy x-ray absorptiometry (DXA) techniques in measuring LBM and fat mass (FM). FM and percent body fat (%BF) measurements by BIA and anthropometry were also compared in relation to those measured by deuterium dilution. Results: Fifteen children with IF, median (interquartile range) age 7.2 (5.0, 10.0) years, and 10 (67%) boys, were studied. BIA and deuterium dilution were in good agreement with a mean bias (limits of agreement) of 0.9 (−3.2 to 5.0) for TBW (L) and 0.1 (−5.4 to 5.6) for LBM (kg) measurements. The mean bias (limits) for FM (kg) and %BF measurements were 0.4 (−3.8 to 4.6) kg and 1.7 (−16.9 to 20.3)%, respectively. The limits of agreement were within 1 standard deviation of the mean bias in 12 of 14 (86%) subjects for TBW and LBM, and in 11 of 14 (79%) for FM and %BF measurements. Mean bias (limits) for LBM (kg) and FM (kg) between BIA and DXA were 1.6 (−3.0 to 6.3) kg and −0.1 (−3.2 to 3.1) kg, respectively. Mean bias (limits) for FM (kg) and %BF between anthropometry and deuterium dilution were 0.2 (−4.2 to 4.6) and −0.2 (−19.5 to 19.1), respectively. The limits of agreement were within 1 standard deviation of the mean bias in 10 of 14 (71%) subjects. Conclusions: In children with IF, TBW and LBM measurements by multifrequency BIA method were in agreement with isotope dilution and DXA methods, with small mean bias and clinically acceptable limits of agreement. In comparison with deuterium dilution, BIA was comparable to anthropometry for FM and %BF assessments with small mean bias, but the limits of agreement were large. BIA is a reliable method for TBW and LBM assessments in population studies; however, its reliability in individual patients, especially for FM assessments, cannot be guaranteed.

Intensively managed young children with type 1 diabetes consume high-fat, low-fiber diets similar to age-matched controls

Despite significant emphasis on nutrition, older children with diabetes demonstrate poor dietary quality. We tested the hypothesis that dietary quality in young children with type 1 diabetes (T1D) would be better than age-matched children in the US population. Dietary data from children with T1D (n = 67) aged 2 to 12 years attending a pediatric diabetes clinic were compared with a nationally representative, age-matched sample from the National Health and Nutrition Examination Survey (NHANES; n = 1691). Multiple 24-hour dietary recalls were used. Recommended intakes were based on national guidelines, and dietary quality was assessed using the Healthy Eating Index-2005. More children with T1D were overweight or obese compared with children participating in NHANES (42% vs 30%, P = .04). Greater proportions of children with T1D met daily recommendations for vegetables (22% vs 13%, P = .03), whole grains (12% vs 5%, P = .005), and dairy (55% vs 36%, P = .001) compared with NHANES children, whereas similar proportions met daily fruit recommendations (40% vs 33%, P = .2). Less than one-third of all children limited total fat to recommended levels; children with T1D consumed more saturated fat than did NHANES children (14% vs 12% total energy intake, P = .0009). Fiber intakes were very low in both groups. Compared with NHANES children, children with T1D had higher Healthy Eating Index-2005 scores (59.6 vs 49.7, P = .0006) primarily because of lower intakes of added sugars. The nutritional intake of young children with T1D remains suboptimal in the contemporary era of diabetes management. Despite focused nutrition management, young children with T1D consume high-fat, low-fiber diets comparable with youth in the general population.

Body Composition in Children with Chronic Illness: Accuracy of Bedside Assessment Techniques

Objective To evaluate the accuracy of estimated fat mass and fat‐free mass from bedside methods compared with reference methods in children with chronic illnesses. Study design Fat mass and fat‐free mass values were obtained by skinfold, bioelectrical impedance analysis (BIA), dual‐energy x‐ray absorptiometry (DXA), and deuterium dilution method in children with spinal muscular atrophy, intestinal failure, and post hematopoietic stem cell transplantation (HSCT). Spearmans correlation and agreement analyses were performed between (1) fat mass values estimated by skinfold equations and by DXA and (2) fat‐free mass values estimated by BIA equations and by DXA and deuterium dilution methods. Limits of agreement between estimating and reference methods within ±20% were deemed clinically acceptable. Results Fat mass and fat‐free mass values from 90 measurements in 56 patients, 55% male, and median age of 11.6 years were analyzed. Correlation coefficients between the skinfold‐estimated fat mass values and DXA were 0.93‐0.94 and between BIA‐estimated fat‐free mass values and DXA were 0.92‐0.97. Limits of agreement between estimated and DXA values of fat mass and fat‐free mass were greater than ±20% for all equations. Correlation coefficients between estimated fat‐free mass values and deuterium dilution method in 35 encounters were 0.87‐0.91, and limits of agreement were greater than ±20%. Conclusion Estimated body composition values derived from skinfold and BIA may not be reliable in children with chronic illnesses. An accurate noninvasive method to estimate body composition in this cohort is desirable.

Providing Food to Treat Adolescents at Risk for Cardiovascular Disease

Diet modification is recommended to treat childhood cardiovascular (CV) risk factors; however, the optimal dietary strategy is unknown.