De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown.

Protein and calorie intakes in adult and pediatric subjects with urea cycle disorders participating in clinical trials of glycerol phenylbutyrate.

Background: Little prospectively collected data are available comparing the dietary intake of urea cycle disorder (UCD) patients to UCD treatment guidelines or to healthy individuals.

Objective: To examine the protein and calorie intakes of UCD subjects who participated in clinical trials of glycerol phenylbutyrate (GPB) and compare these data to published UCD dietary guidelines and nutritional surveys.

Design: Dietary data were recorded for 45 adult and 49 pediatric UCD subjects in metabolic control during participation in clinical trials of GPB.

Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials.

Background: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes.

Methods: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire.

Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.

Purpose: The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.

Methods: The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.

Results: Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.

Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements.

Whole-genome oligonucleotide single-nucleotide polymorphism (oligo-SNP) arrays enable simultaneous interrogation of copy number variations (CNVs), copy neutral regions of homozygosity (ROH) and uniparental disomy (UPD). Structural variation in the human genome contributes significantly to genetic variation, and often has deleterious effects leading to disease causation. Co-occurrence of CNV and regions of allelic homozygosity in tandem involving the same chromosomal arm are extremely rare.

Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation.

Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and genetic heterogeneity. CIII comprises 11 subunits encoded by one mitochondrial and 10 nuclear genes. Abnormalities of the nuclear genes such as BCS1L and TTC19 encoding mitochondrial assembly factors are well known, but an explanation of the majority of CIII deficiency remains elusive.

Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.

Unlabelled: Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively.

Correlation of nasal morphology to air-conditioning and clearance function.

Nasal morphology plays an important functional role in the maintenance of upper airway health. Identification of functional regions, based on morphological attributes, assists in correlating location to primary purpose. The effects of morphological variation on heat and water mass transport in congested and patent nasal airways were investigated by examining nasal cross-sectional MRI images from 8 healthy subjects.

Nasal levels of nitric oxide as an outcome variable in allergic upper respiratory tract disease: Influence of atopy and hayfever on nNO.

Background: The role of nasal levels of nitric oxide (nNO) as noninvasive marker of inflammation and as an outcome variable in allergic upper respiratory tract disease has not been defined. Our aim is to determine in patients with perennial allergic rhinitis (i) whether nNO is elevated, (ii) whether increased nNO is correlated with upper respiratory tract symptoms (discrimination), and (iii) whether changes in symptom scores are associated with changes in nNO levels (responsiveness).

Methods: Subjects (n = 38) with perennial rhinitis were studied weekly for 3 weeks.

Partial hexasomy of chromosome 15.

Marker chromosomes originating from chromosome 15, often referred to as inv dup(15), is the most common marker chromosome found in humans. The large marker 15 that contains the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) chromosome region is usually associated with an abnormal phenotype of moderate to severe mental retardation, seizures, poor motor coordination, behavioral problems, and mild dysmorphic features. We report here an infant boy with two copies of the large inv dup(15).