Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades

Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in \u3e 80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006-2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg*day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989-2018) were identified by NBS and treated with natural protein restriction (1.0-1.3 g/kg*day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973-2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p \u3c .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain

Branched-chain alpha-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes

Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain alpha-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing

Abnormal hypermethylation at imprinting control regions in patients with S-adenosylhomocysteine hydrolase (AHCY) deficiency

S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity

Clinical trial and postmarketing safety of onasemnogene abeparvovec therapy

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity

Extragalactic Science, Cosmology and Galactic Archaeology with the Subaru Prime Focus Spectrograph (PFS)

The Subaru Prime Focus Spectrograph (PFS) is a massively-multiplexed fiber-fed optical and near-infrared 3-arm spectrograph (N_fiber=2400, 380<lambda<1260nm, 1.3 degree diameter FoV), offering unique opportunities in survey astronomy. Here we summarize the science case feasible for a survey of Subaru 300 nights. We describe plans to constrain the nature of dark energy via a survey of emission line galaxies spanning a comoving volume of 9.3 (Gpc/h)^3 in the redshift range 0.8<z<2.4. In each of 6 redshift bins, the cosmological distances will be measured to 3% precision via BAO, and redshift-space distortions will be used to constrain structure growth to 6% precision. In the GA program, radial velocities and chemical abundances of stars in the Milky Way and M31 will be used to infer the past assembly histories of spiral galaxies and the structure of their dark matter halos. Data will be secured for 10^6 stars in the Galactic thick-disk, halo and tidal streams as faint as V~22, including stars with V < 20 to complement the goals of the Gaia mission. A medium-resolution mode with R = 5000 to be implemented in the red arm will allow the measurement of multiple alpha-element abundances and more precise velocities for Galactic stars, elucidating the detailed chemo-dynamical structure and evolution of each of the main stellar components of the Milky Way Galaxy and of its dwarf spheroidal galaxies. For the extragalactic program, our simulations suggest the wide avelength range will be powerful in probing the galaxy population and its clustering over a wide redshift range. We propose to conduct a color-selected survey of 1<z<2 galaxies and AGN over 16 deg^2 to J~23.4, yielding a fair sample of galaxies with stellar masses above ~10^{10}Ms at z~2. A two-tiered survey of higher redshift LBGs and LAEs will quantify the properties of early systems close to the reionization epoch.Comment: This document describes the scientific program and requirements for the Subaru Prime Focus Spectrograph (PFS) project. Made significant revision based on studies for the Preliminary Design Review (PRD) held in Feb 2013. The higher-resolution paper file is available from http://member.ipmu.jp/masahiro.takada/pfs_astroph_rv.pd

Backsplash galaxies in isolated clusters

At modest radii from the centre of galaxy clusters, individual galaxies may be infalling to the cluster for the first time, or have already visited the cluster core and are coming back out again. This latter population of galaxies is known as the backsplash population. Differentiating them from the infalling population presents an interesting challenge for observational studies of galaxy evolution. To attempt to do this, we assemble a sample of 14 redshift- and spatially-isolated galaxy clusters from the Sloan Digital Sky Survey. We clean this sample of cluster-cluster mergers to ensure that the galaxies contained within them are (to an approximation) only backsplashing from the centre of their parent clusters and are not being processed in sub-clumps. By stacking them together to form a composite cluster, we find evidence for both categories of galaxies at intermediate radii from the cluster centre. Application of mixture modelling to this sample then serves to differentiate the infalling galaxies (which we model on galaxies from the cluster outskirts) from the backsplash ones (which we model on galaxies in the high density core with low velocity offsets from the cluster mean). We find that the fraction of galaxies with populations similar to the low velocity cluster core galaxies is f = -0.052R/R_virial + 0.612 +/- 0.06 which we interpret as being the backsplash population fraction at 1<R/R_virial<2. Although some interlopers may be affecting our results, the results are demonstrated to be in concordance with earlier studies in this area that support density-related mechanisms as being the prime factor in determining the star formation rate of a galaxy.Comment: Accepted for publication in MNRA

Two Rare Magnetic Cataclysmic Variables with Extreme Cyclotron Features Identified in the Sloan Digital Sky Survey

Two newly identified magnetic cataclysmic variables discovered in the Sloan Digital Sky Survey (SDSS), SDSSJ155331.12+551614.5 and SDSSJ132411.57+032050.5, have spectra showing highly prominent, narrow, strongly polarized cyclotron humps with amplitudes that vary on orbital periods of 4.39 and 2.6 hrs, respectively. In the former, the spacing of the humps indicates the 3rd and 4th harmonics in a magnetic field of ~60 MG. The narrowness of the cyclotron features and the lack of strong emission lines imply very low temperature plasmas and very low accretion rates, so that the accreting area is heated by particle collisions rather than accretion shocks. The detection of rare systems like these exemplifies the ability of the SDSS to find the lowest accretion rate close binaries.Comment: Accepted for publication in the Astrophysical Journal, vol. 583, February 1, 2003; slight revisions and additions in response to referee's comments; 17 pages, 6 figures, AASTeX v4.

Hyper-luminous Dust Obscured Galaxies discovered by the Hyper Suprime-Cam on Subaru and WISE

We present the photometric properties of a sample of infrared (IR) bright dust obscured galaxies (DOGs). Combining wide and deep optical images obtained with the Hyper Suprime-Cam (HSC) on the Subaru Telescope and all-sky mid-IR (MIR) images taken with Wide-Field Infrared Survey Explorer (WISE), we discovered 48 DOGs with $i - K_\mathrm{s} > 1.2$ and $i - [22] > 7.0$, where $i$, $K_\mathrm{s}$, and [22] represent AB magnitude in the $i$-band, $K_\mathrm{s}$-band, and 22 $\mu$m, respectively, in the GAMA 14hr field ($\sim$ 9 deg$^2$). Among these objects, 31 ($\sim$ 65 %) show power-law spectral energy distributions (SEDs) in the near-IR (NIR) and MIR regime, while the remainder show a NIR bump in their SEDs. Assuming that the redshift distribution for our DOGs sample is Gaussian, with mean and sigma $z$ = 1.99 $\pm$ 0.45, we calculated their total IR luminosity using an empirical relation between 22 $\mu$m luminosity and total IR luminosity. The average value of the total IR luminosity is (3.5 $\pm$ 1.1) $\times$ $10^{13}$ L$_{\odot}$, which classifies them as hyper-luminous infrared galaxies (HyLIRGs). We also derived the total IR luminosity function (LF) and IR luminosity density (LD) for a flux-limited subsample of 18 DOGs with 22 $\mu$m flux greater than 3.0 mJy and with $i$-band magnitude brighter than 24 AB magnitude. The derived space density for this subsample is log $\phi$ = -6.59 $\pm$ 0.11 [Mpc$^{-3}$]. The IR LF for DOGs including data obtained from the literature is well fitted by a double-power law. The derived lower limit for the IR LD for our sample is $\rho_{\mathrm{IR}}$ $\sim$ 3.8 $\times$ 10$^7$ [L$_{\odot}$ Mpc$^{-3}$] and its contributions to the total IR LD, IR LD of all ultra-luminous infrared galaxies (ULIRGs), and that of all DOGs are $>$ 3 %, $>$ 9 %, and $>$ 15 %, respectively.Comment: 15 pages, 15 figures, and 3 tables, accepted for publication in PASJ (Subaru special issue