Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report

Autores
Silvera Ruiz, Silene Maite; Gemperle, Corinne; Peano, Natalia; Olivero, Valentina; Becerra, Adriana Berónica; Häberle, Johannes; Gruppi, Adriana; Laróvere, Laura Elena; Motrich, Ruben Dario
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the SLC25A15 gene. Besides the well-known metabolic complications, patients often present intercurrent infections associated with acute hyperammonemia and metabolic decompensation. However, it is currently unknown whether intercurrent infections are associated with immunological alterations besides the known metabolic imbalances. Herein, we describe the case of a 3-years-old girl affected by the HHH syndrome caused by two novel SLC25A15 gene mutations associated with immune phenotypic and functional alterations. She was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion, and lethargy. Laboratory tests revealed severe hyperammonemia, elevated serum levels of liver transaminases, hemostasis alterations, hyperglutaminemia and strikingly increased orotic aciduria. Noteworthy, serum protein electrophoresis showed a reduction in the gamma globulin fraction. Direct sequencing of the SLC25A15 gene revealed two heterozygous non-conservative substitutions in the exon 5: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly). In silico analysis indicated that both mutations significantly impair protein structure and function and are consistent with the patient clinical status confirming the diagnosis of HHH syndrome. In addition, the immune analysis revealed reduced levels of serum IgG and striking phenotypic and functional alterations in the T and B cell immune compartments. Our study has identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome. Moreover, we are reporting for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised and might be related to the high frequency of intercurrent infections observed in patients bearing urea cycle disorders. Our results point out the importance of a comprehensive analysis to gain further insights into the underlying pathophysiology of the disease that would allow better patient care and quality of life.
Fil: Silvera Ruiz, Silene Maite. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Gemperle, Corinne. University Childrens Hospital Zurich; Suiza
Fil: Peano, Natalia. Fundación Para El Progreso de la Medicina; Argentina
Fil: Olivero, Valentina. Fundación Para El Progreso de la Medicina; Argentina
Fil: Becerra, Adriana Berónica. Hospital de Niños de la Santísima Trinidad, Córdoba; Argentina
Fil: Häberle, Johannes. University Children’s Hospital Zurich; Suiza
Fil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Laróvere, Laura Elena. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Motrich, Ruben Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Materia
B CELLS
CASE REPORT
HHH SYNDROME
HYPERAMMONEMIA
IMMUNODEFICIENCY
INFECTION
T CELLS
UREA CYCLE DEFECTS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/187607
Acceder
id CONICETDig_59c23b7165277321aebae420d2871eda
oai_identifier_str oai:ri.conicet.gov.ar:11336/187607
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case ReportSilvera Ruiz, Silene MaiteGemperle, CorinnePeano, NataliaOlivero, ValentinaBecerra, Adriana BerónicaHäberle, JohannesGruppi, AdrianaLaróvere, Laura ElenaMotrich, Ruben DarioB CELLSCASE REPORTHHH SYNDROMEHYPERAMMONEMIAIMMUNODEFICIENCYINFECTIONT CELLSUREA CYCLE DEFECTShttps://purl.org/becyt/ford/3.5https://purl.org/becyt/ford/3The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the SLC25A15 gene. Besides the well-known metabolic complications, patients often present intercurrent infections associated with acute hyperammonemia and metabolic decompensation. However, it is currently unknown whether intercurrent infections are associated with immunological alterations besides the known metabolic imbalances. Herein, we describe the case of a 3-years-old girl affected by the HHH syndrome caused by two novel SLC25A15 gene mutations associated with immune phenotypic and functional alterations. She was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion, and lethargy. Laboratory tests revealed severe hyperammonemia, elevated serum levels of liver transaminases, hemostasis alterations, hyperglutaminemia and strikingly increased orotic aciduria. Noteworthy, serum protein electrophoresis showed a reduction in the gamma globulin fraction. Direct sequencing of the SLC25A15 gene revealed two heterozygous non-conservative substitutions in the exon 5: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly). In silico analysis indicated that both mutations significantly impair protein structure and function and are consistent with the patient clinical status confirming the diagnosis of HHH syndrome. In addition, the immune analysis revealed reduced levels of serum IgG and striking phenotypic and functional alterations in the T and B cell immune compartments. Our study has identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome. Moreover, we are reporting for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised and might be related to the high frequency of intercurrent infections observed in patients bearing urea cycle disorders. Our results point out the importance of a comprehensive analysis to gain further insights into the underlying pathophysiology of the disease that would allow better patient care and quality of life.Fil: Silvera Ruiz, Silene Maite. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gemperle, Corinne. University Childrens Hospital Zurich; SuizaFil: Peano, Natalia. Fundación Para El Progreso de la Medicina; ArgentinaFil: Olivero, Valentina. Fundación Para El Progreso de la Medicina; ArgentinaFil: Becerra, Adriana Berónica. Hospital de Niños de la Santísima Trinidad, Córdoba; ArgentinaFil: Häberle, Johannes. University Children’s Hospital Zurich; SuizaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Laróvere, Laura Elena. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Motrich, Ruben Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFrontiers Media2022-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/187607Silvera Ruiz, Silene Maite; Gemperle, Corinne; Peano, Natalia; Olivero, Valentina; Becerra, Adriana Berónica; et al.; Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report; Frontiers Media; Frontiers in Immunology; 13; 5-2022; 1-101664-3224CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2022.861516info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:02:37Zoai:ri.conicet.gov.ar:11336/187607instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:02:37.687CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
title Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
spellingShingle Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
Silvera Ruiz, Silene Maite
B CELLS
CASE REPORT
HHH SYNDROME
HYPERAMMONEMIA
IMMUNODEFICIENCY
INFECTION
T CELLS
UREA CYCLE DEFECTS
title_short Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
title_full Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
title_fullStr Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
title_full_unstemmed Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
title_sort Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report
dc.creator.none.fl_str_mv Silvera Ruiz, Silene Maite
Gemperle, Corinne
Peano, Natalia
Olivero, Valentina
Becerra, Adriana Berónica
Häberle, Johannes
Gruppi, Adriana
Laróvere, Laura Elena
Motrich, Ruben Dario
author Silvera Ruiz, Silene Maite
author_facet Silvera Ruiz, Silene Maite
Gemperle, Corinne
Peano, Natalia
Olivero, Valentina
Becerra, Adriana Berónica
Häberle, Johannes
Gruppi, Adriana
Laróvere, Laura Elena
Motrich, Ruben Dario
author_role author
author2 Gemperle, Corinne
Peano, Natalia
Olivero, Valentina
Becerra, Adriana Berónica
Häberle, Johannes
Gruppi, Adriana
Laróvere, Laura Elena
Motrich, Ruben Dario
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv B CELLS
CASE REPORT
HHH SYNDROME
HYPERAMMONEMIA
IMMUNODEFICIENCY
INFECTION
T CELLS
UREA CYCLE DEFECTS
topic B CELLS
CASE REPORT
HHH SYNDROME
HYPERAMMONEMIA
IMMUNODEFICIENCY
INFECTION
T CELLS
UREA CYCLE DEFECTS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.5
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the SLC25A15 gene. Besides the well-known metabolic complications, patients often present intercurrent infections associated with acute hyperammonemia and metabolic decompensation. However, it is currently unknown whether intercurrent infections are associated with immunological alterations besides the known metabolic imbalances. Herein, we describe the case of a 3-years-old girl affected by the HHH syndrome caused by two novel SLC25A15 gene mutations associated with immune phenotypic and functional alterations. She was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion, and lethargy. Laboratory tests revealed severe hyperammonemia, elevated serum levels of liver transaminases, hemostasis alterations, hyperglutaminemia and strikingly increased orotic aciduria. Noteworthy, serum protein electrophoresis showed a reduction in the gamma globulin fraction. Direct sequencing of the SLC25A15 gene revealed two heterozygous non-conservative substitutions in the exon 5: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly). In silico analysis indicated that both mutations significantly impair protein structure and function and are consistent with the patient clinical status confirming the diagnosis of HHH syndrome. In addition, the immune analysis revealed reduced levels of serum IgG and striking phenotypic and functional alterations in the T and B cell immune compartments. Our study has identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome. Moreover, we are reporting for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised and might be related to the high frequency of intercurrent infections observed in patients bearing urea cycle disorders. Our results point out the importance of a comprehensive analysis to gain further insights into the underlying pathophysiology of the disease that would allow better patient care and quality of life.
Fil: Silvera Ruiz, Silene Maite. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Gemperle, Corinne. University Childrens Hospital Zurich; Suiza
Fil: Peano, Natalia. Fundación Para El Progreso de la Medicina; Argentina
Fil: Olivero, Valentina. Fundación Para El Progreso de la Medicina; Argentina
Fil: Becerra, Adriana Berónica. Hospital de Niños de la Santísima Trinidad, Córdoba; Argentina
Fil: Häberle, Johannes. University Children’s Hospital Zurich; Suiza
Fil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Laróvere, Laura Elena. Universidad Nacional de Córdoba. Facultad de Medicina. Centro de Estudios de las Metabolopatías Congénitas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
Fil: Motrich, Ruben Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
description The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the SLC25A15 gene. Besides the well-known metabolic complications, patients often present intercurrent infections associated with acute hyperammonemia and metabolic decompensation. However, it is currently unknown whether intercurrent infections are associated with immunological alterations besides the known metabolic imbalances. Herein, we describe the case of a 3-years-old girl affected by the HHH syndrome caused by two novel SLC25A15 gene mutations associated with immune phenotypic and functional alterations. She was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion, and lethargy. Laboratory tests revealed severe hyperammonemia, elevated serum levels of liver transaminases, hemostasis alterations, hyperglutaminemia and strikingly increased orotic aciduria. Noteworthy, serum protein electrophoresis showed a reduction in the gamma globulin fraction. Direct sequencing of the SLC25A15 gene revealed two heterozygous non-conservative substitutions in the exon 5: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly). In silico analysis indicated that both mutations significantly impair protein structure and function and are consistent with the patient clinical status confirming the diagnosis of HHH syndrome. In addition, the immune analysis revealed reduced levels of serum IgG and striking phenotypic and functional alterations in the T and B cell immune compartments. Our study has identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome. Moreover, we are reporting for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised and might be related to the high frequency of intercurrent infections observed in patients bearing urea cycle disorders. Our results point out the importance of a comprehensive analysis to gain further insights into the underlying pathophysiology of the disease that would allow better patient care and quality of life.
publishDate 2022
dc.date.none.fl_str_mv 2022-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/187607
Silvera Ruiz, Silene Maite; Gemperle, Corinne; Peano, Natalia; Olivero, Valentina; Becerra, Adriana Berónica; et al.; Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report; Frontiers Media; Frontiers in Immunology; 13; 5-2022; 1-10
1664-3224
CONICET Digital
CONICET
url http://hdl.handle.net/11336/187607
identifier_str_mv Silvera Ruiz, Silene Maite; Gemperle, Corinne; Peano, Natalia; Olivero, Valentina; Becerra, Adriana Berónica; et al.; Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report; Frontiers Media; Frontiers in Immunology; 13; 5-2022; 1-10
1664-3224
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2022.861516
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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