“…Coma and lethargy at onset are quite common in the earlier onset group (about 70%), becoming progressively less frequent in patients with later onset. Variable neurological symptoms may characterize the acute presentation and include seizures, dysphasia, movement and gait disturbances, drop-attacks and behavioural changes [ 38 , 57 , 58 ]. Figure 2 The graph shows the frequency of clinical features in HHH syndrome.…”
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clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases.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.
“…Coma and lethargy at onset are quite common in the earlier onset group (about 70%), becoming progressively less frequent in patients with later onset. Variable neurological symptoms may characterize the acute presentation and include seizures, dysphasia, movement and gait disturbances, drop-attacks and behavioural changes [ 38 , 57 , 58 ]. Figure 2 The graph shows the frequency of clinical features in HHH syndrome.…”
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.
“…Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive inborn error of the urea cycle (1-5), (OMIM#238970) (6)(7)(8), it is located on chromosome 13q14 (7,9). This syndrome occurs in the early infancy or childhood period, although, few cases of adult onset have also been reported (7,(10)(11)(12)(13)(14). HHH syndrome is caused by mutations in the SLC25A15 gene that codes the mitochondrial ornithine transporter, which transports ornithine across the inner mitochondrial membrane from the cytosol to the mitochondrial matrix (15).…”
Section: Introductionmentioning
confidence: 99%
“…20 pathogenic SNPs effect on the SLC25A15 protein function and structure were reveled in this study. 12 of these 20 missense SNPs are proposedly to be considered as novel mutations, while; L71Q, G113C, F188S, G216S, G220R, Q238R, R275Q, and R275L are not originals, due to their previous mentions in studies (1,11,12,26,52,53).…”
Background: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive inborn error of the urea cycle. It is caused by mutations in the SLC25A15 gene that codes the mitochondrial ornithine transporter. The aim of this study is to detect and identify the pathogenic SNPs in SLC25A15 gene through a combination set of bioinformatics tools and their effect on the structure and function of the protein.
Methods:The deleterious SNPs in SLC25A15 are detected by various bioinformatics tools, with addition to identifying their effects on the structure and function of this gene.Results: 20 deleterious SNPs out 287of were found to have their own damaging effects on the structure and function of the SLC25A15 gene.
Conclusion:This study is the first in silico analysis of SLC25A15 using a selection of bioinformatics tools to detect functional and structural effects of deleterious SNPs. Finding the pathogenic SNPs is a promising start to innovate new, useful SNP diagnostic markers for medical testing and for safer novel therapies specifically targeting mutant SLC25A15.
“…6 HHH syndrome has not been reported locally and only been reported once previously in an individual of Indian descent. 7 We describe an additional case of a girl of Indian descent, who presented with recurrent episodes of altered mental state in association with febrile illnesses and was subsequently diagnosed with HHH syndrome.…”
Section: Milder Form Of Urea Cycle Defect Revisited: Report and Revie...mentioning
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