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The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or c...

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Autores principales: Martinelli, Diego, Diodato, Daria, Ponzi, Emanuela, Monné, Magnus, Boenzi, Sara, Bertini, Enrico, Fiermonte, Giuseppe, Dionisi-Vici, Carlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358699/
https://www.ncbi.nlm.nih.gov/pubmed/25874378
http://dx.doi.org/10.1186/s13023-015-0242-9
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author Martinelli, Diego
Diodato, Daria
Ponzi, Emanuela
Monné, Magnus
Boenzi, Sara
Bertini, Enrico
Fiermonte, Giuseppe
Dionisi-Vici, Carlo
author_facet Martinelli, Diego
Diodato, Daria
Ponzi, Emanuela
Monné, Magnus
Boenzi, Sara
Bertini, Enrico
Fiermonte, Giuseppe
Dionisi-Vici, Carlo
author_sort Martinelli, Diego
collection PubMed
description BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia. METHODS: A systematic review of publications reporting patients with HHH syndrome was performed. RESULTS: We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life. CONCLUSIONS: This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0242-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-43586992015-03-14 The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome Martinelli, Diego Diodato, Daria Ponzi, Emanuela Monné, Magnus Boenzi, Sara Bertini, Enrico Fiermonte, Giuseppe Dionisi-Vici, Carlo Orphanet J Rare Dis Review BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia. METHODS: A systematic review of publications reporting patients with HHH syndrome was performed. RESULTS: We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life. CONCLUSIONS: This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0242-9) contains supplementary material, which is available to authorized users. BioMed Central 2015-03-11 /pmc/articles/PMC4358699/ /pubmed/25874378 http://dx.doi.org/10.1186/s13023-015-0242-9 Text en © Martinelli et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Martinelli, Diego
Diodato, Daria
Ponzi, Emanuela
Monné, Magnus
Boenzi, Sara
Bertini, Enrico
Fiermonte, Giuseppe
Dionisi-Vici, Carlo
The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
title The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
title_full The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
title_fullStr The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
title_full_unstemmed The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
title_short The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
title_sort hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358699/
https://www.ncbi.nlm.nih.gov/pubmed/25874378
http://dx.doi.org/10.1186/s13023-015-0242-9
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