Motor Responses in Pediatric Pompe Disease in the ADVANCE Participant Cohort.

Background: ADVANCE (NCT01526785) presented an opportunity to obtain a more nuanced understanding of motor function changes in treatment-experienced children with Pompe disease receiving 4000L-production-scale alglucosidase alfa for 52 weeks.

Objective: To estimate minimal detectable change (MDC) and effect size on Gross Motor Function Measure-88 (GMFM-88) after 52 weeks of 4000L alglucosidase alfa (complete data N =  90).

Methods: The GMFM-88 mean total % score changes, MDC, and effect size were analyzed post hoc by Pompe Motor Function Level at enrollment, age groups at enrollment, and fraction of life on pre-study 160L-production-scale alglucosidase alfa.

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.

Background: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31.

Objective: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia.

Methods: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family.

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 This article presents unpublished cardiac findings, concomitant medications, and cardiac efficacy and safety outcomes from the ADVANCE study; trajectories of patients with abnormal left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).

Participant choices for return of genomic results in the eMERGE Network.

Purpose: Secondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium.

Methods: Within the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel.

Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease.

Purpose: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.

Methods: Patients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment.

Tertiary Pediatric Academic Institution's Experience With Intraoperative Neuromonitoring for Nonspinal Surgery in Children With Mucopolysaccharidosis, Based on a Novel Evidence-Based Care Algorithm.

Background: Musculoskeletal deformities in mucopolysaccharidoses (MPSs) patients pose unique challenges when patients present for surgery, especially nonspinal surgery. MPS patients have developed postsurgical neurological deficits after nonspinal surgery. While the incidence of neurological deficits after nonspinal surgery under anesthesia is unknown, accumulating evidence provides impetus to change current practice and increased neurological monitoring in these patients.

Acquired ornithine transcarbamylase deficiency in pediatric and adolescent patients with fibrolamellar hepatocellular carcinoma.

Ornithine transcarbamylase deficiency (OTCD) disrupts the metabolic pathway responsible for converting nitrogenous waste to urea, allowing for excretion. When impaired, ammonia levels accumulate in the blood resulting in severe, sometimes life-threatening toxicities. Abnormalities of the urea cycle are often inherited, though there are some rarer acquired forms.

Efficacy, safety profile, and immunogenicity of alglucosidase alfa produced at the 4,000-liter scale in US children and adolescents with Pompe disease: ADVANCE, a phase IV, open-label, prospective study.

Purpose: Pompe disease results from lysosomal acid α-glucosidase (GAA) deficiency and its associated glycogen accumulation and muscle damage. Alglucosidase alfa (recombinant human GAA (rhGAA)) received approval in 2006 as a treatment for Pompe disease at the 160 L production scale. In 2010, larger-scale rhGAA was approved for patients up to 8 years old without cardiomyopathy.

Ethical Considerations Related to Return of Results from Genomic Medicine Projects: The eMERGE Network (Phase III) Experience.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants.

Inborn Errors of Metabolism Collaborative: large-scale collection of data on long-term follow-up for newborn-screened conditions.

Purpose: The Inborn Errors of Metabolism Information System (IBEM-IS) collects data on the clinical history of inborn errors of metabolism (IBEMs). The IBEM-IS is accessible to metabolic clinics nationwide and seeks to (i) influence clinical management of affected individuals and (ii) provide information to support public health decision making.

Methods: Thirty centers in 21 states are enrolling persons with newborn-screened conditions, collecting information on diagnosis and treatment at the time of enrollment and all subsequent visits.

Bilateral cataracts in a 6-yr-old with new onset diabetes: a novel presentation of a known INS gene mutation.

The prevalence of diabetes-related cataracts during childhood is less than 1%. When cataracts occur, it is often in adolescent females with prolonged symptoms and significant hyperglycemia. Cataracts are not a classic feature of monogenic diabetes.

Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening.

Purpose: We evaluated the clinical outcome in homocysteine remethylation disorders following newborn screening (NBS) and initiation of early specific treatment.

Methods: Five patients with remethylation disorders were included in this study.

Results: Two asymptomatic patients (one with cblG and one with cblE) were identified by NBS using an approach that combines a postanalytical interpretive tool (available on the Region 4 Stork (R4S) collaborative project website, http://www.

Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy.

Malonyl coenzyme A (CoA) decarboxylase (MCD) deficiency is a rare autosomal recessive organic acidemia characterized by varying degrees of organ involvement and severity. MCD regulates fatty acid biosynthesis and converts malonyl-CoA to acetyl-CoA. Cardiomyopathy is 1 of the leading causes of morbidity and mortality in this disorder.

Recurrent pancreatitis in ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is a urea cycle defect with varying frequency and severity of episodes of hyperammonemia. We report three patients with OTC deficiency with recurrent pancreatitis. The pathogenesis of acute pancreatitis in this patient population requires further elucidation.

Evidence-based path to newborn screening for Duchenne muscular dystrophy.

Objective: Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing.

Cardiac disease in methylmalonic acidemia.

Methylmalonic acidemia (MMA) is a heterogeneous disorder, with onset from infancy to adulthood and varying degrees of organ involvement and severity. Cardiac disease is a known lethal complication of other organic acidemias, but has not been associated with MMA. We identified 3 patients with MMA and cardiac disease.

The effects of gestational age and birth weight on false-positive newborn-screening rates.

Objective: Newborn-screening false-positive rates (FPRs) are disproportionately increased in preterm infants. The objective of this study was to determine variation in newborn screening FPRs according to birth weight and gestational age. Our secondary objective was to examine the effect of postnatal age on FPRs in preterm infants.

Intellectual disability, midface hypoplasia, facial hypotonia, and Alport syndrome are associated with a deletion in Xq22.3.

Alport syndrome with intellectual disability (ID) is a contiguous gene deletion syndrome involving several genes on Xq22.3 including COL4A5 and ACSL4. We report on a family with two males with this disorder and a Xq22.

Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease.

In a previous 52-wk trial, treatment with alglucosidase alpha markedly improved cardiomyopathy, ventilatory function, and overall survival among 18 children <7 mo old with infantile-onset Pompe disease. Sixteen of the 18 patients enrolled in an extension study, where they continued to receive alglucosidase alpha at either 20 mg/kg biweekly (n = 8) or 40 mg/kg biweekly (n = 8), for up to a total of 3 y. These children continued to exhibit the benefits of alglucosidase alpha at the age of 36 mo.

A novel hereditary spastic paraplegia with dystonia linked to chromosome 2q24-2q31.

Spastic paraplegias (HSPs) and dystonias (DYTs) typically localize to different neuroanatomic systems. We report clinical and genetic data from large Ohio kindred with autosomal dominant (AD) HSP and DYT. Single and multipoint linkage using microsatellite and single nucleotide polymorphism array genotyping were performed on a large, multigenerational family with a novel, AD, highly penetrant neurological disease causing spasticity and DYT.

Review of the use of idursulfase in the treatment of mucopolysaccharidosis II.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a heterogeneous, progressive X-linked recessively inherited lysosomal storage disease that is caused by a deficiency of the enzyme iduronate-2-sulfatase, resulting in abnormal tissue accumulation of the glycosaminoglycans, dermatan sulfate and heparan sulfate. The disorder results from mutations in IDS, which is located at Xq28. Over 300 pathogenic mutations have been identified to date.