Hyperornithinemia‐Hyperammonemia‐Homocitrullinuria Syndrome (HHH) Presenting With Acute Fulminant Hepatic Failure

Mhanni, Aizeddin A.; Chan, Angela W.; Collison, Mary; Seifert, B; Lehotay, D.C; Sokoro, AH; Huynh, H; Greenberg, C. R.

doi:10.1097/mpg.0b013e318145a8e5

Cited by 22 publications

(10 citation statements)

References 9 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: 89%

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: 89%

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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“…Remarkably, in some cases massive elevation of transaminases, with or without signs of acute liver failure (i.e. coagulation abnormalities with prolonged prothombin time), occurred in the absence of overt hyperammonemia [15,38,53,55,57]. …”

Section: Resultsmentioning

confidence: 99%

“…Blood coagulation studies may be abnormal with deficiency of factor VII, X, XI, and antithrombin III [7,15,21,38,39,55-57]. …”

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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“…Coagulation factor defects have been reported in HHH (Gatfield et al 1975;Dionisi Vici et al 1987;Smith et al 1992), suggesting chronic liver failure. Histologically, mostly mild involvement has been reported: normal liver biopsy despite past ALF (Mhanni et al 2008), microvesicular steatosis (Badizadegan and Perez-Atayde 1997), mild fibrosis, slight changes such as abnormal mitochondria with cristal or rosette-like inclusions (Gatfield et al 1975;Haust and Gordon 1980;Haust et al 1981;Smith et al 1992), periportal glycogenation (Smith et al 1992; Badizadegan and Perez-Atayde 1997) or peroxisomal abnormalities (Winter et al 1980;Smith et al 1992).…”

Section: Hypoglycemia In CDmentioning

confidence: 99%

Liver involvement in urea cycle disorders: a review of the literature

Bigot¹,

Tchan²,

Thoreau³

et al. 2017

J of Inher Metab Disea

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Urea cycle disorders (UCDs) are inborn errors of metabolism of the nitrogen detoxification pathway and encompass six principal enzymatic deficiencies. The aging of UCD patients leads to a better knowledge of the long-term natural history of the condition and to the reporting of previously unnoticed manifestations. Despite historical evidence of liver involvement in UCDs, little attention has been paid to this organ until recently. Hence, we reviewed the available scientific evidence on acute and chronic liver dysfunction and liver carcinogenesis in UCDs and discuss their pathophysiology. Overall, liver involvement, such as acute liver failure or steatotic-like disease, which may evolve toward cirrhosis, has been reported in all six main UCDs. Excessive glycogen storage is also a prominent histologic feature, and hypoglycemia has been reported in citrin deficiency. Hepatocarcinomas seem frequent in some UCDs, such as in citrin deficiency, and can sometimes occur in non-cirrhotic patients. UCDs may differ in liver involvement according to the enzymatic deficiency. Ornithine transcarbamylase deficiency may be associated more with acute liver failure and argininosuccinic aciduria with chronic liver failure and cirrhosis. Direct toxicity of metabolites, downstream metabolic deficiencies, impaired tricarboxylic acid cycle, oxidative stress, mitochondrial dysfunction, energy deficit, and putative toxicity of therapies combine in various ways to cause the different liver diseases reported.

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Hyperornithinemia‐Hyperammonemia‐Homocitrullinuria Syndrome (HHH) Presenting With Acute Fulminant Hepatic Failure

Cited by 22 publications

References 9 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

Liver involvement in urea cycle disorders: a review of the literature

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