title: The M405V allele of the glutaryl-CoA dehydrogenase gene is an important marker for glutaric aciduria type I (GA-I) low excretors.
abstract: Glutaric aciduria type I (GA-I) is an autosomal recessive organic aciduria resulting from a functional deficiency of glutaryl-CoA dehydrogenase, encoded by GCDH. Two clinically indistinguishable diagnostic subgroups of GA-I are known; low and high excretors (LEs and HEs, respectively). Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We report on nine cases of GA-I LE patients all sharing the M405V allele with two cases missed by newborn screening (NBS) using tandem mass spectrometry (MS/MS). We describe a novel case with the known pathogenic M405V variant and a novel V133L variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the M405V allele. Three of the nine patients are of African American ancestry, with two as siblings. GCDH activity was assayed in six of the nine patients and varied from 4 to 25% of the control mean. We support the use of urine glutarylcarnitine as a biochemical marker of GA-I by demonstrating that glutarylcarnitine is efficiently cleared by the kidney (50-90%) and that plasma and urine glutarylcarnitine follow a linear relationship. We report the allele frequencies for three known GA-I LE GCDH variants (M405V, V400M and R227P) and note that both the M405V and V400M variants are significantly more common in the population of African ancestry compared to the general population. This report highlights the M405V allele as another important molecular marker in patients with the GA-I LE phenotype. Therefore, the incorporation into newborn screening of molecular screening for the M405V and V400M variants in conjunction with MS/MS could help identify asymptomatic at-risk GA-I LE patients that could potentially be missed by current NBS programs.
authors.affiliation: Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, OH, United States.
authors.forename: Lori-Anne P
authors.initials: LA
authors.lastname: Schillaci
authors.affiliation: Department of Pediatrics, University of Maryland, Baltimore, MD, United States.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Greene
authors.affiliation: Department of Pediatrics, University of Maryland, Baltimore, MD, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Strovel
authors.affiliation: Department of Pediatrics, University of Maryland, Baltimore, MD, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Rispoli-Joines
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, United States.
authors.forename: Elaine
authors.initials: E
authors.lastname: Spector
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, United States.
authors.forename: Gunter
authors.initials: G
authors.lastname: Scharer
authors.affiliation: Department of Pediatrics, Division of Genetics, Stanford University School of Medicine, Stanford, CA, United States.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States.
authors.forename: Renata
authors.initials: R
authors.lastname: Gallagher
authors.affiliation: Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, OH, United States; Center for Inherited Disorders of Energy Metabolism (CIDEM), University Hospitals Case Medical Center, Cleveland, OH, United States.
authors.forename: Arthur B
authors.initials: AB
authors.lastname: Zinn
authors.affiliation: Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, OH, United States; Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States; Center for Inherited Disorders of Energy Metabolism (CIDEM), University Hospitals Case Medical Center, Cleveland, OH, United States.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: McCandless
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States; Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, United States.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Goodman
authors.affiliation: Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, OH, United States; Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States; Center for Inherited Disorders of Energy Metabolism (CIDEM), University Hospitals Case Medical Center, Cleveland, OH, United States. Electronic address: jirair.bedoyan@uhhospitals.org.
authors.forename: Jirair K
authors.initials: JK
authors.lastname: Bedoyan
mesh_terms: D001741:Black or African American / Q000235:genetics; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D015415:Biomarkers; D001928:Brain Diseases, Metabolic / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency; D005977:Glutarates / Q000378:metabolism; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D010641:Phenotype; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D005977:Glutarates; D050770:Glutaryl-CoA Dehydrogenase
keywords: GCDH; Glutaric aciduria; Glutaryl-CoA dehydrogenase; Low excretor; Newborn screen; Urinary acylcarnitines