HHH syndrome (hyperornithinaemia, hyperammonaemia, homocitrullinuria), with fulminant hepatitis‐like presentation

Fecarotta, Simona; Parenti, Giancarlo; Vajro, Pietro; Zuppaldi, A; Casa, Roberto Della; Carbone, Maria Teresa; Correra, Antonio; Torre, Giuliano; Riva, Silvia; Dionisi‐Vici, Carlo; Santorelli, Filippo M.; Andria, Generoso

doi:10.1007/s10545-006-0120-7

Cited by 40 publications

(37 citation statements)

References 11 publications

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“…Severe but reversible hepatocellular necrosis has recently been reported in HHH12 16 and our series confirms that acute hepatitis-like episodes are common in HHH. Clearly, HHH should be added to the list of metabolic causes of acute liver disease 20.…”

Section: Discussionsupporting

confidence: 90%

Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15

Lambert

Lemieux

et al. 2008

Journal of Medical Genetics

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Section: Discussionsupporting

confidence: 90%

Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15

Lambert

Lemieux

et al. 2008

Journal of Medical Genetics

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“…subdural hematoma, gingival bleeding, melena) and/or as hepatitis-like attacks [15,23,25,35,37,38,50,52,57]. Remarkably, in some cases massive elevation of transaminases, with or without signs of acute liver failure (i.e.…”

Section: Resultsmentioning

confidence: 99%

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Martinelli

Diodato

Ponzi

et al. 2015

Orphanet J Rare Dis

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BackgroundHyperornithinemia-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.MethodsA systematic review of publications reporting patients with HHH syndrome was performed.ResultsWe 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.ConclusionsThis 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 materialThe 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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“…We also functionally analyzed p.G113C and p.M273K, which we had reported previously in an atypical HHH patient [Fecarotta et al, 2006]. We chose not to test the potential missense p.A70L and the p.G216S, which were unlikely to provide new information, or mutation p.F188L.…”

Section: Resultsmentioning

confidence: 99%

“…In the acute phase, the disease is characterized by intermittent episodes of hyperammonemia accompanied by vomiting, ataxia, lethargy, confusion, and coma, as seen in other urea cycle defects [Valle and Simell, 2001]. Remarkably, some HHH patients presented with fulminant liver failure and were considered for liver transplantation [Fecarotta et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel mutations in theSLC25A15gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: A clinical, molecular, and functional study

et al. 2009

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Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle. With the exception of the French-Canadian founder effect, no common mutation has been detected in other populations. In this study, we collected 16 additional HHH cases and expanded the spectrum of SLC25A15/ORC1 mutations. Eleven novel mutations were identified including six new missense and one microrearrangement. We also measured the transport properties of the recombinant purified proteins in reconstituted liposomes for four new and two previously reported missense mutations and proved that the transport activities of these mutant forms of ORC1 were reduced as compared with the wild-type protein; residual activity ranged between 4% and 19%. Furthermore, we designed three-dimensional (3D)-modeling of mutant ORC1 proteins. While modeling the changes in silico allowed us to obtain new information on the pathomechanisms underlying HHH syndrome, we found no clear-cut genotype-phenotype correlations. Although patient metabolic alterations responded well to low-protein therapy, predictions concerning the long-term evolution of HHH syndrome remain uncertain. The preference for a hepatic rather than a neurological presentation at onset also continues, largely, to elude us. Neither modifications in oxidative metabolism-related energy, such as those expected in different mtDNA haplogroups, nor sequence variants in SLC25A2/ORC2 seem to be crucial. Other factors, including protein stability and function, and ORC1-ORC2 structural interactions should be further investigated.

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HHH syndrome (hyperornithinaemia, hyperammonaemia, homocitrullinuria), with fulminant hepatitis‐like presentation

Cited by 40 publications

References 11 publications

Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15

Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15

The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Identification of novel mutations in theSLC25A15gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: A clinical, molecular, and functional study

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