Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM).

Background: Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU.

Methods: Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU.

Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial.

Introduction: Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU.

Methods: PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study).

Scrambler Therapy for the Treatment of Chronic Central Pain: A Case Report.

Central pain syndromes affect several million people worldwide. A 52-year-old woman had central pain manifest as burning pain from her left foot to the knee for 12 years after treatment for a medullary cavernoma diagnosed after a right-sided brainstem bleeding episode. All this time, her baseline pain was 5-6/10 with spikes to 9-10/10 during activity.

Whole Brain Imaging with Serial Two-Photon Tomography.

Imaging entire mouse brains at submicron resolution has historically been a challenging undertaking and largely confined to the province of dedicated atlasing initiatives. This has limited systematic investigations into important areas of neuroscience, such as neural circuits, brain mapping and neurodegeneration. In this article, we describe in detail Serial Two-Photon (STP) tomography, a robust, reliable method for imaging entire brains with histological detail.

Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK.

Traf2- and Nck-interacting kinase (TNIK) is a serine/threonine kinase highly expressed in the brain and enriched in the postsynaptic density of glutamatergic synapses in the mammalian brain. Accumulating genetic evidence and functional data have implicated TNIK as a risk factor for psychiatric disorders. However, the endogenous substrates of TNIK in neurons are unknown.

Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.

Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.

Resveratrol up-regulates AMPA receptor expression via AMP-activated protein kinase-mediated protein translation.

Resveratrol is a phytoalexin that confers overall health benefits including positive regulation in brain function such as learning and cognition. However, whether and how resveratrol affects synaptic activity remains largely unknown. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are glutamatergic receptors that mediate the majority of fast excitatory transmission and synaptic plasticity, and thus play a critical role in higher brain functions, including learning and memory.

Microplastic pollution in the surface waters of the Laurentian Great Lakes.

Neuston samples were collected at 21 stations during an ~700 nautical mile (~1300 km) expedition in July 2012 in the Laurentian Great Lakes of the United States using a 333 μm mesh manta trawl and analyzed for plastic debris. Although the average abundance was approximately 43,000 microplastic particles/km², station 20, downstream from two major cities, contained over 466,000 particles/km², greater than all other stations combined. SEM analysis determined nearly 20% of particles less than 1 mm, which were initially identified as microplastic by visual observation, were aluminum silicate from coal ash.

NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits.

We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs).

AMPK signaling in neuronal polarization: Putting the brakes on axonal traffic of PI3-Kinase.

Neuronal polarization, the process by which neurons form multiple dendrites and an axon from the soma, is the first critical step in the formation and function of neural networks. Polarization begins with the rapid extension of a single neurite to produce an axon of impressive size and complex geometry, while the remaining sister neurites differentiate into dendrites. The extensive biosynthesis required to produce an axon therefore necessitates coordination with cellular energy status to ensure an ample energy supply.

Bioenergy sensing in the brain: the role of AMP-activated protein kinase in neuronal metabolism, development and neurological diseases.

Bioenergy homeostasis constitutes one of the most crucial foundations upon which other cellular and organismal processes may be executed. AMP-activated protein kinase (AMPK) has been shown to be the key player in the regulation of energy metabolism, and thus is becoming the focus of research on obesity, diabetes and other metabolic disorders. However, its role in the brain, the most energy-consuming organ in our body, has only recently been studied and appreciated.

AMPK links cellular bioenergy status to the decision making of axon initiation in neurons.

Neuronal polarization begins by the selection of a single minor neurite that subsequently undergoes rapid extension until reaching a formidable length. To ensure that the highly active growth can be sustained by a sufficient energy supply, neurons are supposed to sense their energy status prior to initiating polarization. Our recent work shows that the bioenergy sensor, AMPK, plays a crucial role in the regulation of axon initiation.

AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization.

Axon-dendrite polarization is crucial for neural network wiring and information processing in the brain. Polarization begins with the transformation of a single neurite into an axon and its subsequent rapid extension, which requires coordination of cellular energy status to allow for transport of building materials to support axon growth. We found that activation of the energy-sensing adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway suppressed axon initiation and neuronal polarization.

Compound heterozygous polymerase gamma gene mutation in a patient with Alpers disease.

Alpers disease is a mitochondrial depletion syndrome characterized by psychomotor retardation, intractable epilepsy, and liver failure. Polymerase gamma (POLG) gene mutations are a known cause of the disease. We describe a case in which a 14-month-old female presented with epilepsia partialis continua evolving into generalized status epilepticus.

Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.

NRXN1 is highly expressed in brain and has been shown recently to be associated with ASD, schizophrenia, cognitive and behavioral abnormalities, and alcohol and nicotine dependence. We present three families, in whom we identified intragenic rearrangements within NRXN1 using a clinical targeted oligonucleotide array CGH. An approximately 380 kb deletion was identified in a woman with Asperger syndrome, anxiety, and depression and in all four of her children affected with autism, anxiety, developmental delay, and speech delay but not in an unaffected child.

Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size.

Background: Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.

Method: We indentified 27 deletions and 18 duplications of 16p11.

Improving genetic health care: a Northern New England pilot project addressing the genetic evaluation of the child with developmental delays or intellectual disability.

In 2006, all clinical genetics practices in Northern New England (Vermont, New Hampshire, and Maine) formed a learning collaborative with the purpose of improving genetic health care and outcomes. This article describes the current status of this effort. The methodology is based on our own modifications of the Institute of Healthcare Improvement "Breakthrough Series" and the Northern New England Cystic Fibrosis Consortium.

Increased LIS1 expression affects human and mouse brain development.

Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3epsilon) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.

Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.

Regulation of AMPA receptor localization in lipid rafts.

Lipid rafts are special microdomains enriched in cholesterol, sphingolipids and certain proteins, and play important roles in a variety of cellular functions including signal transduction and protein trafficking. We report that in cultured cortical and hippocampal neurons the distribution of lipid rafts is development-dependent. Lipid rafts in mature neurons exist on the entire cell-surface and display a high degree of mobility.

22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome.

Microdeletions within chromosome 22q11.2 cause a variable phenotype, including DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). About 97% of patients with DGS/VCFS have either a common recurrent approximately 3 Mb deletion or a smaller, less common, approximately 1.

A de novo complex karyotype with two independent balanced translocations and a double inversion of chromosome 6 presenting with multiple congenital anomalies.

We report a 4-year-old female with a de novo complex karyotype with multiple chromosomal rearrangements and a distinctive phenotype. Her medical history is significant for having been a twin born at 35 weeks gestation, breech presentation, with feeding problems and poor growth as an infant, gastroesophageal reflux disease, peripheral pulmonic stenosis, omphalocele, high myopia, and severe mental retardation. She is small for her age with microcephaly, posteriorly sloping forehead, shallow orbits, long palpebral fissures, prominent nose, wide mouth, absent uvula, kyphosis, brachydactyly, bridged palmar crease, and hypertonia.

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing.

Purpose: Hearing loss is a common congenital disorder that is frequently associated with mutations in the GJB2 gene encoding the connexin 26 protein (Cx26). We sought to evaluate the effectiveness of direct DNA sequencing for detection of Cx26 mutations as a clinical diagnostic test.

Methods: We designed a clinical assay using a three-step polymerase chain reaction (PCR)-based DNA sequencing strategy to detect all possible mutations in the open reading frame and flanking sequences of Cx26.