title: Diagnosis of adenylosuccinate lyase deficiency by metabolomic profiling in plasma reveals a phenotypic spectrum.
abstract: Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive neurometabolic disorder that presents with a broad-spectrum of neurological and physiological symptoms. The ADSL gene produces an enzyme with binary molecular roles in de novo purine synthesis and purine nucleotide recycling. The biochemical phenotype of ADSL deficiency, accumulation of SAICAr and succinyladenosine (S-Ado) in biofluids of affected individuals, serves as the traditional target for diagnosis with targeted quantitative urine purine analysis employed as the predominate method of detection. In this study, we report the diagnosis of ADSL deficiency using an alternative method, untargeted metabolomic profiling, an analytical scheme capable of generating semi-quantitative z-score values for over 1000 unique compounds in a single analysis of a specimen. Using this method to analyze plasma, we diagnosed ADSL deficiency in four patients and confirmed these findings with targeted quantitative biochemical analysis and molecular genetic testing. ADSL deficiency is part of a large a group of neurometabolic disorders, with a wide range of severity and sharing a broad differential diagnosis. This phenotypic similarity among these many inborn errors of metabolism (IEMs) has classically stood as a hurdle in their initial diagnosis and subsequent treatment. The findings presented here demonstrate the clinical utility of metabolomic profiling in the diagnosis of ADSL deficiency and highlights the potential of this technology in the diagnostic evaluation of individuals with neurologic phenotypes.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Taraka R
authors: TR
authors: Donti
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States; Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy.
authors: Gerarda
authors: G
authors: Cappuccio
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Leroy
authors: L
authors: Hubert
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Juanita
authors: J
authors: Neira
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Paldeep S
authors: PS
authors: Atwal
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Marcus J
authors: MJ
authors: Miller
authors: Section of Pediatric Neurology and Neuroscience, Baylor College of Medicine, Houston, TX, United States.
authors: Aaron L
authors: AL
authors: Cardon
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: V Reid
authors: VR
authors: Sutton
authors: Stanford Medical School, Stanford, CA, United States.
authors: Brenda E
authors: BE
authors: Porter
authors: Stanford Medical School, Stanford, CA, United States.
authors: Fiona M
authors: FM
authors: Baumer
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Michael F
authors: MF
authors: Wangler
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Qin
authors: Q
authors: Sun
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States; Section of Pediatric Neurology and Neuroscience, Baylor College of Medicine, Houston, TX, United States.
authors: Lisa T
authors: LT
authors: Emrick
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
authors: Sarah H
authors: SH
authors: Elsea
keywords: ADSL deficiency; ADSL, adenylosuccinate lyase; AICAR, aminoimidazole carboxamide ribotide; Global MAPSSM, Global Metabolomic Assisted Pathway Screen; IEM, inborn errors of metabolism; Intellectual disability; Metabolomic profiling; SAICAR, succinylaminoimidazole carboxamide ribotide; Succinyladenosine