Cardiac responses in paediatric Pompe disease in the ADVANCE patient cohort.

Pompe disease results from lysosomal acid α-glucosidase deficiency, which leads to cardiomyopathy in all infantile-onset and occasional late-onset patients. Cardiac assessment is important for its diagnosis and management. This article presents unpublished cardiac findings, concomitant medications, and cardiac efficacy and safety outcomes from the ADVANCE study; trajectories of patients with abnormal left ventricular mass z score at enrolment; and post hoc analyses of on-treatment left ventricular mass and systolic blood pressure z scores by disease phenotype, GAA genotype, and "fraction of life" (defined as the fraction of life on pre-study 160 L production-scale alglucosidase alfa). ADVANCE evaluated 52 weeks' treatment with 4000 L production-scale alglucosidase alfa in ≥1-year-old United States of America patients with Pompe disease previously receiving 160 L production-scale alglucosidase alfa. M-mode echocardiography and 12-lead electrocardiography were performed at enrolment and Week 52. Sixty-seven patients had complete left ventricular mass z scores, decreasing at Week 52 (infantile-onset patients, change -0.8 ± 1.83; 95% confidence interval -1.3 to -0.2; all patients, change -0.5 ± 1.71; 95% confidence interval -1.0 to -0.1). Patients with "fraction of life" <0.79 had left ventricular mass z score decreasing (enrolment: +0.1 ± 3.0; Week 52: -1.1 ± 2.0); those with "fraction of life" ≥0.79 remained stable (enrolment: -0.9 ± 1.5; Week 52: -0.9 ± 1.4). Systolic blood pressure z scores were stable from enrolment to Week 52, and no cohort developed systemic hypertension. Eight patients had Wolff-Parkinson-White syndrome. Cardiac hypertrophy and dysrhythmia in ADVANCE patients at or before enrolment were typical of Pompe disease. Four-thousand L alglucosidase alfa therapy maintained fractional shortening, left ventricular posterior and septal end-diastolic thicknesses, and improved left ventricular mass z score.Trial registry: ClinicalTrials.gov Identifier: NCT01526785 https://clinicaltrials.gov/ct2/show/NCT01526785.Social Media Statement: Post hoc analyses of the ADVANCE study cohort of 113 children support ongoing cardiac monitoring and concomitant management of children with Pompe disease on long-term alglucosidase alfa to functionally improve cardiomyopathy and/or dysrhythmia.

Sapropterin dihydrochloride use in pregnant women with phenylketonuria: an interim report of the PKU MOMS sub-registry.

For pregnant women with phenylketonuria (PKU), maintaining blood phenylalanine (Phe)<360µmol/L is critical due to the toxicity of elevated Phe to the fetus. Sapropterin dihydrochloride (sapropterin) lowers blood Phe in tetrahydrobiopterin (BH4) responsive patients with PKU, in conjunction with a Phe-restricted diet, but clinical evidence supporting its use during pregnancy is limited. As of June 3, 2013, the Maternal Phenylketonuria Observational Program (PKU MOMS) sub-registry contained data from 21 pregnancies - in women with PKU who were treated with sapropterin either before (N=5) or during (N=16) pregnancy. Excluding data for spontaneous abortions (N=4), the data show that the mean of median blood Phe [204.7±126.6µmol/L (n=14)] for women exposed to sapropterin during pregnancy was 23% lower, and had a 58% smaller standard deviation, compared to blood Phe [267.4±300.7µmol/L (n=3)] for women exposed to sapropterin prior to pregnancy. Women on sapropterin during pregnancy experienced fewer blood Phe values above the recommended 360µmol/L threshold. When median blood Phe concentration was <360µmol/L throughout pregnancy, 75% (12/16) of pregnancy outcomes were normal compared to 40% (2/5) when median blood Phe was >360µmol/L. Severe adverse events identified by the investigators as possibly related to sapropterin use were premature labor (N=1) and spontaneous abortion (N=1) for the women and hypophagia for the offspring [premature birth (35w4d), N=1]. One congenital malformation (cleft palate) of unknown etiology was reported as unrelated to sapropterin. Although there is limited information regarding the use of sapropterin during pregnancy, these sub-registry data show that sapropterin was generally well-tolerated and its use during pregnancy was associated with lower mean blood Phe. Because the teratogenicity of elevated maternal blood Phe is without question, sapropterin should be considered as a treatment option in pregnant women with PKU who cannot achieve recommended ranges of blood Phe with dietary therapy alone.

Development and validation of a measure of dysmorphology: useful for autism subgroup classification.

Autism spectrum disorders (ASD) comprise a class of neurodevelopmental disorders that can originate from a variety of genetic and environmental causes. To delineate autism's heterogeneity we have looked for biologically-based phenotypes found in consistent proportions of ASD individuals. One informative phenotype is that of generalized dysmorphology, based on whole body examinations by medical geneticists trained in the nuances of anomalous embryologic development. We identified a need for a dysmorphology measure that could be completed by medical clinicians not extensively trained in dysmorphology that would still retain the level of sensitivity and specificity of the comprehensive dysmorphology examination. Based on expert-derived consensus dysmorphology designation of 222 autism patients and a classification validation study of 30 subjects by four dysmorphologists, we determined that dysmorphology designations based on body areas provided superior inter-rater reliability. Using 34 body area designations, we performed a classification and regression tree (CART) analysis to construct a scoring algorithm. Compared to the consensus classification, the model performed with 81% sensitivity and 99% specificity, and classification of a replication dataset of 31 ASD individuals performed well, with 82% sensitivity and 95% specificity. The autism dysmorphology measure (ADM) directs the clinician to score 12 body areas sequentially to arrive at a determination of "dysmorphic" or "nondysmorphic." We anticipate the ADM will permit clinicians to differentiate accurately between dysmorphic and nondysmorphic individuals-allowing better diagnostic classification, prognostication, recurrence risk assessment, and laboratory analysis decisions-and research scientists to better define more homogeneous autism subtypes.

Evidence of common ancestry for the maple syrup urine disease (MSUD) Y438N allele in non-Mennonite MSUD patients.

Maple syrup urine disease (MSUD) is a rare (1/185,000) autosomal recessive inborn error of branched-chain amino acid metabolism characterized by increased plasma leucine, isoleucine, and valine levels. Though, genetically heterogeneous in the worldwide population, MSUD in Old Order Mennonites (1/150-176) is the result of a tyrosine to asparagine substitution (Y438N; previously Y393N) in the E1alpha subunit of the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex. Due to endogamous practices, the presence of Y438N in all reported Mennonite MSUD patients has historically been attributed to a founder effect. However, we have also identified the Y438N defect in eight MSUD patients of non-Mennonite lineage. To evaluate the genetic origin of this defect in these non-Mennonite patients, we examined Mennonite MSUD families and non-Mennonite MSUD families using microsatellite markers located on chromosome 19q13.1-13.2 (location of E1alpha gene, BCKDHA). Haplotype analyses revealed a major and four minor haplotypes that cosegregate with the Y438N allele in the Old Order Mennonite MSUD patients and carrier relatives. Analyses of eight non-Mennonite MSUD patients reveal that three of the non-Mennonite MSUD patients shared common Mennonite Y438N haplotypes, strongly suggesting Mennonite ancestry. However, the remaining non-Mennonite patients carry Y438N haplotypes that are significantly different from the Mennonite Y438N haplotype, suggesting that the occurrence of the defect in these families is due to either pre-Mennonite or de novo events.