2. Academic Validation
  3. The role of orotic acid measurement in routine newborn screening for urea cycle disorders

The role of orotic acid measurement in routine newborn screening for urea cycle disorders

  • J Inherit Metab Dis. 2021 May;44(3):606-617. doi: 10.1002/jimd.12331.
Orna Staretz-Chacham 1,  Suha Daas 2,  Igor Ulanovsky 2,  Ayala Blau 2 3,  Nira Rostami 2,  Talya Saraf-Levy 2,  Nasser Abu Salah 4 5,  Yair Anikster 6 7,  Ehud Banne 8,  Dalit Dar 9,  Elena Dumin 9 10,  Aviva Fattal-Valevski 7 11,  Tzipora Falik-Zaccai 12 13,  Eli Hershkovitz 14 15,  Sagi Josefsberg 8,  Hatem Khammash 16,  Rimona Keidar 17,  Stanley H Korman 18 19,  Yuval Landau 20,  Tally Lerman-Sagie 7 21,  Dror Mandel 7,  Hanna Mandel 10 19,  Ronella Marom 22,  Iris Morag 17,  Erez Nadir 10 23,  Naama Yosha-Orpaz 21,  Ben Pode-Shakked 6 7,  Elon Pras 24 25,  Haike Reznik-Wolf 24,  Ann Saada 25 26,  Reeval Segel 26 27,  Avraham Shaag 25,  Nava Shaul Lotan 25,  Ronen Spiegel 10 28,  Galit Tal 19,  Taly Vaisid 29,  Avi Zeharia 20,  Shlomo Almashanu 2
Affiliations

Affiliations

  • 1 Metabolic Clinic, Pediatric Division, Soroka University Medical Center, Ben Gurion University, Beer Sheva, Israel.
  • 2 National Newborn Screening Program, Ministry of Health, Tel-HaShomer, Ramat Gan, Israel.
  • 3 Nursing Department, School of Health Sciences, Ariel University, Ariel, Israel.
  • 4 Department of Neonatology, Red Crescent Society Hospital, Jerusalem, Israel.
  • 5 Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel.
  • 6 Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
  • 7 Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.
  • 8 Genetics Institute, Kaplan Medical Center, Rehovot, Israel.
  • 9 Department of Clinical Biochemistry, Rambam Health Care Campus, Haifa, Israel.
  • 10 Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • 11 Pediatric Neurology Unit, Dana Children Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
  • 12 Institute of Human Genetics, The Galilee Medical Center, Naharia, Israel.
  • 13 The Azrieli Faculty of Medicine, Bar Ilan, Israel.
  • 14 Pediatric D Department, Soroka Medical Center, Beer Sheva, Israel.
  • 15 Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.
  • 16 Department of Neonatology, Makassed Islamic Hospital, Jerusalem, Israel.
  • 17 Pediatric Department, Shamir Medical Center (Assaf Harofeh), Zerifin, Israel, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 18 Wilf Children's Hospital, Shaare Zedek Medical Center, Jerusalem, Israel.
  • 19 Metabolic Unit, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel.
  • 20 Metabolic Disease Unit, Schneider Children's Medical Center of Israel, Tel Aviv University, Israel.
  • 21 Pediatric Neurology Unit, Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel.
  • 22 Department of Neonatology, Dana Dwek Children's Hospital, Tel Aviv Medical Center, Affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • 23 Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel.
  • 24 The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.
  • 25 Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 26 Hebrew University School of Medicine, Jerusalem, Israel.
  • 27 Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
  • 28 Department of Pediatrics B, Metabolic Service, Emek Medical Center, Afula, Israel.
  • 29 Metabolic Laboratory, Sheba Medical Center, Tel-HaShomer, Ramat Gan, Israel.
PMID: 33190319 DOI: 10.1002/jimd.12331
Abstract

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a Newborn Screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.

Keywords

citrulline; newborn screening; ornithine transcarbamylase deficiency; orotic acid; urea cycle disorders.

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