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

Orna Staretz-Chacham; Suha Daas; Igor Ulanovsky; Ayala Blau; Nira Rostami; Talya Saraf-Levy; Nasser Abu Salah; Yair Anikster; Ehud Banne; Dalit Dar; Elena Dumin; Aviva Fattal-Valevski; Tzipora Falik-Zaccai; Eli Hershkovitz; Sagi Josefsberg; Hatem Khammash; Rimona Keidar; Stanley H. Korman; Yuval Landau; Tally Lerman-Sagie; Dror Mandel; Hanna Mandel; Ronella Marom; Iris Morag; Erez Nadir; Naama Yosha-Orpaz; Ben Pode-Shakked; Elon Pras; Haike Reznik-Wolf; Ann Saada; Reeval Segel; Avraham Shaag; Nava Shaul Lotan; Ronen Spiegel; Galit Tal; Taly Vaisid; Avi Zeharia; Shlomo Almashanu

doi:10.1002/jimd.12331

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

Orna Staretz-Chacham, Suha Daas, Igor Ulanovsky, Ayala Blau, Nira Rostami, Talya Saraf-Levy, Nasser Abu Salah, Yair Anikster, Ehud Banne, Dalit Dar, Elena Dumin, Aviva Fattal-Valevski, Tzipora Falik-Zaccai, Eli Hershkovitz, Sagi Josefsberg, Hatem Khammash, Rimona Keidar, Stanley H. Korman, Yuval Landau, Tally Lerman-SagieDror Mandel, Hanna Mandel, Ronella Marom, Iris Morag, Erez Nadir, Naama Yosha-Orpaz, Ben Pode-Shakked, Elon Pras, Haike Reznik-Wolf, Ann Saada, Reeval Segel, Avraham Shaag, Nava Shaul Lotan, Ronen Spiegel, Galit Tal, Taly Vaisid, Avi Zeharia, Shlomo Almashanu

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English
Pages (from-to)	606-617
Number of pages	12
Journal	Journal of Inherited Metabolic Disease
Volume	44
Issue number	3
DOIs	https://doi.org/10.1002/jimd.12331
State	Published - 1 May 2021
Externally published	Yes

Keywords

citrulline
newborn screening
ornithine transcarbamylase deficiency
orotic acid
urea cycle disorders

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Staretz-Chacham, O., Daas, S., Ulanovsky, I., Blau, A., Rostami, N., Saraf-Levy, T., Abu Salah, N., Anikster, Y., Banne, E., Dar, D., Dumin, E., Fattal-Valevski, A., Falik-Zaccai, T., Hershkovitz, E., Josefsberg, S., Khammash, H., Keidar, R., Korman, S. H., Landau, Y., ... Almashanu, S. (2021). The role of orotic acid measurement in routine newborn screening for urea cycle disorders. Journal of Inherited Metabolic Disease, 44(3), 606-617. https://doi.org/10.1002/jimd.12331

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title = "The role of orotic acid measurement in routine newborn screening for urea cycle disorders",

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",

author = "Orna Staretz-Chacham and Suha Daas and Igor Ulanovsky and Ayala Blau and Nira Rostami and Talya Saraf-Levy and {Abu Salah}, Nasser and Yair Anikster and Ehud Banne and Dalit Dar and Elena Dumin and Aviva Fattal-Valevski and Tzipora Falik-Zaccai and Eli Hershkovitz and Sagi Josefsberg and Hatem Khammash and Rimona Keidar and Korman, {Stanley H.} and Yuval Landau and Tally Lerman-Sagie and Dror Mandel and Hanna Mandel and Ronella Marom and Iris Morag and Erez Nadir and Naama Yosha-Orpaz and Ben Pode-Shakked and Elon Pras and Haike Reznik-Wolf and Ann Saada and Reeval Segel and Avraham Shaag and {Shaul Lotan}, Nava and Ronen Spiegel and Galit Tal and Taly Vaisid and Avi Zeharia and Shlomo Almashanu",

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year = "2021",

month = may,

day = "1",

doi = "10.1002/jimd.12331",

language = "English",

volume = "44",

pages = "606--617",

journal = "Journal of Inherited Metabolic Disease",

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Staretz-Chacham, O, Daas, S, Ulanovsky, I, Blau, A, Rostami, N, Saraf-Levy, T, Abu Salah, N, Anikster, Y, Banne, E, Dar, D, Dumin, E, Fattal-Valevski, A, Falik-Zaccai, T, Hershkovitz, E, Josefsberg, S, Khammash, H, Keidar, R, Korman, SH, Landau, Y, Lerman-Sagie, T, Mandel, D, Mandel, H, Marom, R, Morag, I, Nadir, E, Yosha-Orpaz, N, Pode-Shakked, B, Pras, E, Reznik-Wolf, H, Saada, A, Segel, R, Shaag, A, Shaul Lotan, N, Spiegel, R, Tal, G, Vaisid, T, Zeharia, A & Almashanu, S 2021, 'The role of orotic acid measurement in routine newborn screening for urea cycle disorders', Journal of Inherited Metabolic Disease, vol. 44, no. 3, pp. 606-617. https://doi.org/10.1002/jimd.12331

TY - JOUR

T1 - The role of orotic acid measurement in routine newborn screening for urea cycle disorders

AU - Staretz-Chacham, Orna

AU - Daas, Suha

AU - Ulanovsky, Igor

AU - Blau, Ayala

AU - Rostami, Nira

AU - Saraf-Levy, Talya

AU - Abu Salah, Nasser

AU - Anikster, Yair

AU - Banne, Ehud

AU - Dar, Dalit

AU - Dumin, Elena

AU - Fattal-Valevski, Aviva

AU - Falik-Zaccai, Tzipora

AU - Hershkovitz, Eli

AU - Josefsberg, Sagi

AU - Khammash, Hatem

AU - Keidar, Rimona

AU - Korman, Stanley H.

AU - Landau, Yuval

AU - Lerman-Sagie, Tally

AU - Mandel, Dror

AU - Mandel, Hanna

AU - Marom, Ronella

AU - Morag, Iris

AU - Nadir, Erez

AU - Yosha-Orpaz, Naama

AU - Pode-Shakked, Ben

AU - Pras, Elon

AU - Reznik-Wolf, Haike

AU - Saada, Ann

AU - Segel, Reeval

AU - Shaag, Avraham

AU - Shaul Lotan, Nava

AU - Spiegel, Ronen

AU - Tal, Galit

AU - Vaisid, Taly

AU - Zeharia, Avi

AU - Almashanu, Shlomo

PY - 2021/5/1

Y1 - 2021/5/1

N2 - 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.

AB - 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.

KW - citrulline

KW - newborn screening

KW - ornithine transcarbamylase deficiency

KW - orotic acid

KW - urea cycle disorders

UR - http://www.scopus.com/inward/record.url?scp=85096927181&partnerID=8YFLogxK

U2 - 10.1002/jimd.12331

DO - 10.1002/jimd.12331

M3 - Article

C2 - 33190319

AN - SCOPUS:85096927181

SN - 0141-8955

VL - 44

SP - 606

EP - 617

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

IS - 3

ER -

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

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Keywords

ASJC Scopus subject areas

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