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The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C - Orphanet J Rare Dis (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

ABSTRACT

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clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases.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.

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Related in: MedlinePlus

The graph shows the age at onset(white bars)and the age at diagnosis(gray bars)of HHH syndrome patients. Patients are divided into four age categories: neonatal (birth —1 month) infantile (> 1 month—1 year), childhood (> 1 years— 12 yrs), and adolescence/adulthood (> 12 years). Values are expressed as percentage of the total.
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Fig1: The graph shows the age at onset(white bars)and the age at diagnosis(gray bars)of HHH syndrome patients. Patients are divided into four age categories: neonatal (birth —1 month) infantile (> 1 month—1 year), childhood (> 1 years— 12 yrs), and adolescence/adulthood (> 12 years). Values are expressed as percentage of the total.

Mentions: The retrospective review of the literature provided information on the age at onset in 54 HHH syndrome patients and on the age at diagnosis in 105 subjects (Table 1), whom we arbitrarily divided into four categories: neonatal (birth – 1 month), infantile (>1 month – 1 year), childhood (>1 years – 12 years), and adolescence/adulthood (>12 years). In 14 patients there was a prospective diagnosis, because of an affected sibling or previous familial HHH syndrome cases; only one patient was identified by newborn screening. Figure 1 shows the percentage of patients grouped into the four categories at onset and at diagnosis, respectively. As shown in the figure, 22% had a neonatal presentation, 24% infantile, 44% manifested the disorder in childhood, and 9% in adolescence/adulthood. Although symptoms began most frequently in neonatal age/infancy (46% of patients), the diagnosis was often delayed with at least one fourth of cases identified in adulthood. Remarkably, in one third of patients with neonatal onset of symptoms, the diagnosis was delayed into subsequent diagnostic age categories. By comparing the age at onset of the clinical symptoms with the age of diagnosis for those cases in which both these data were available, there was a mean diagnostic delay of 6.3 ± 10.1 years (range 0 – 37 years).Figure 1


The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C - Orphanet J Rare Dis (2015)

The graph shows the age at onset(white bars)and the age at diagnosis(gray bars)of HHH syndrome patients. Patients are divided into four age categories: neonatal (birth —1 month) infantile (> 1 month—1 year), childhood (> 1 years— 12 yrs), and adolescence/adulthood (> 12 years). Values are expressed as percentage of the total.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4358699&req=5

Fig1: The graph shows the age at onset(white bars)and the age at diagnosis(gray bars)of HHH syndrome patients. Patients are divided into four age categories: neonatal (birth —1 month) infantile (> 1 month—1 year), childhood (> 1 years— 12 yrs), and adolescence/adulthood (> 12 years). Values are expressed as percentage of the total.
Mentions: The retrospective review of the literature provided information on the age at onset in 54 HHH syndrome patients and on the age at diagnosis in 105 subjects (Table 1), whom we arbitrarily divided into four categories: neonatal (birth – 1 month), infantile (>1 month – 1 year), childhood (>1 years – 12 years), and adolescence/adulthood (>12 years). In 14 patients there was a prospective diagnosis, because of an affected sibling or previous familial HHH syndrome cases; only one patient was identified by newborn screening. Figure 1 shows the percentage of patients grouped into the four categories at onset and at diagnosis, respectively. As shown in the figure, 22% had a neonatal presentation, 24% infantile, 44% manifested the disorder in childhood, and 9% in adolescence/adulthood. Although symptoms began most frequently in neonatal age/infancy (46% of patients), the diagnosis was often delayed with at least one fourth of cases identified in adulthood. Remarkably, in one third of patients with neonatal onset of symptoms, the diagnosis was delayed into subsequent diagnostic age categories. By comparing the age at onset of the clinical symptoms with the age of diagnosis for those cases in which both these data were available, there was a mean diagnostic delay of 6.3 ± 10.1 years (range 0 – 37 years).Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus