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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clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases.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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The urea cycle and related patwhays. The acronyms correspond to: NAGS, N-acetylglutamate synthase; CPS, carbamyl-phosphate synthetase; OTC omithine transcarbamylase; ORC1, ornithine carrier 1; ASS argininosuccinate synthetase; ASL argininosuccinate lyase; NOS, nitric oxide synthase: ODC ortnithine decarboxylase; AGAT, argine: glycine amidinotransferase; GAMT, guanidinoacetate N-methyltransferase; OAT, ornithine delta-aminotransferase; P5CD 1- pyrrolin-e5-carboxylate dehydrogenase; P5CS, 1-pyrroline-5 carboxylate synthetase; P5CR,1-pyrroline-5-carboxylate reductase; PO, proline oxidase. The dashed circle indicates the multiprotien complex, which also includes cationic aminoacid transporter 1 (CAT1) and heat shock protein 90 (HSP 90).
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Fig3: The urea cycle and related patwhays. The acronyms correspond to: NAGS, N-acetylglutamate synthase; CPS, carbamyl-phosphate synthetase; OTC omithine transcarbamylase; ORC1, ornithine carrier 1; ASS argininosuccinate synthetase; ASL argininosuccinate lyase; NOS, nitric oxide synthase: ODC ortnithine decarboxylase; AGAT, argine: glycine amidinotransferase; GAMT, guanidinoacetate N-methyltransferase; OAT, ornithine delta-aminotransferase; P5CD 1- pyrrolin-e5-carboxylate dehydrogenase; P5CS, 1-pyrroline-5 carboxylate synthetase; P5CR,1-pyrroline-5-carboxylate reductase; PO, proline oxidase. The dashed circle indicates the multiprotien complex, which also includes cationic aminoacid transporter 1 (CAT1) and heat shock protein 90 (HSP 90).

Mentions: The biochemical role of ORC1 is complex and highly relevant for the different tissues where it is expressed. ORC1 transports ornithine, lysine and arginine into the mitochondrial matrix of peripheral tissues and pericentral hepatocytes; in periportal hepatocytes, in which UC enzymes are expressed, it catalyzes a very efficient ornithine/citrulline exchange reaction [65], connecting the enzyme activities of urea synthesis in the cytosol to those in the mitochondria. ORC1 plays therefore a key role in the UC (Figure 3). ORC1 catalyzes the transport of the L-isomers of ornithine, citrulline, lysine and arginine by a 1:1 substrate exchange reaction and less efficiently exchanges a basic amino acid for an H+ [65-67]. Two human isoforms of the mitochondrial ornithine carrier, ORC1 and ORC2, have been identified so far. Despite having a high sequence identity (87%) with ORC1, ORC2 is less active, presents a lower affinity for ornithine and citrulline, and shows a broader substrate specificity because of its capability to transport histidine and homocitrulline as well as the D-isomers of ornithine, lysine and arginine [68]. Both isoforms are mainly expressed in liver, pancreas, lungs, and testis, although ORC2 to a much lesser extent than ORC1 in all tissues investigated [68]. The total mitochondrial ornithine/citrulline exchange activity per whole organ in vivo is unknown; it has been suggested that the late onset and the variable clinical phenotype of HHH syndrome may be due to the redundancy of this exchange activity [8,37]. This is catalyzed either by ORC2 [68] or by the SLC25A29 gene product (previously reported to be a mitochondrial carnitine/acylcarnitine- or ornithine-like carrier called ORNT3 [69]), which is able to rescue the ornithine metabolism deficiency in fibroblasts of HHH patients [69,70] and to transport basic amino acids as well as ornithine into proteoliposomes [71]. The residual ornithine transport in cultured fibroblasts and liver of affected individuals supports this hypothesis of gene redundancy in HHH syndrome [8,37].Figure 3


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 urea cycle and related patwhays. The acronyms correspond to: NAGS, N-acetylglutamate synthase; CPS, carbamyl-phosphate synthetase; OTC omithine transcarbamylase; ORC1, ornithine carrier 1; ASS argininosuccinate synthetase; ASL argininosuccinate lyase; NOS, nitric oxide synthase: ODC ortnithine decarboxylase; AGAT, argine: glycine amidinotransferase; GAMT, guanidinoacetate N-methyltransferase; OAT, ornithine delta-aminotransferase; P5CD 1- pyrrolin-e5-carboxylate dehydrogenase; P5CS, 1-pyrroline-5 carboxylate synthetase; P5CR,1-pyrroline-5-carboxylate reductase; PO, proline oxidase. The dashed circle indicates the multiprotien complex, which also includes cationic aminoacid transporter 1 (CAT1) and heat shock protein 90 (HSP 90).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: The urea cycle and related patwhays. The acronyms correspond to: NAGS, N-acetylglutamate synthase; CPS, carbamyl-phosphate synthetase; OTC omithine transcarbamylase; ORC1, ornithine carrier 1; ASS argininosuccinate synthetase; ASL argininosuccinate lyase; NOS, nitric oxide synthase: ODC ortnithine decarboxylase; AGAT, argine: glycine amidinotransferase; GAMT, guanidinoacetate N-methyltransferase; OAT, ornithine delta-aminotransferase; P5CD 1- pyrrolin-e5-carboxylate dehydrogenase; P5CS, 1-pyrroline-5 carboxylate synthetase; P5CR,1-pyrroline-5-carboxylate reductase; PO, proline oxidase. The dashed circle indicates the multiprotien complex, which also includes cationic aminoacid transporter 1 (CAT1) and heat shock protein 90 (HSP 90).
Mentions: The biochemical role of ORC1 is complex and highly relevant for the different tissues where it is expressed. ORC1 transports ornithine, lysine and arginine into the mitochondrial matrix of peripheral tissues and pericentral hepatocytes; in periportal hepatocytes, in which UC enzymes are expressed, it catalyzes a very efficient ornithine/citrulline exchange reaction [65], connecting the enzyme activities of urea synthesis in the cytosol to those in the mitochondria. ORC1 plays therefore a key role in the UC (Figure 3). ORC1 catalyzes the transport of the L-isomers of ornithine, citrulline, lysine and arginine by a 1:1 substrate exchange reaction and less efficiently exchanges a basic amino acid for an H+ [65-67]. Two human isoforms of the mitochondrial ornithine carrier, ORC1 and ORC2, have been identified so far. Despite having a high sequence identity (87%) with ORC1, ORC2 is less active, presents a lower affinity for ornithine and citrulline, and shows a broader substrate specificity because of its capability to transport histidine and homocitrulline as well as the D-isomers of ornithine, lysine and arginine [68]. Both isoforms are mainly expressed in liver, pancreas, lungs, and testis, although ORC2 to a much lesser extent than ORC1 in all tissues investigated [68]. The total mitochondrial ornithine/citrulline exchange activity per whole organ in vivo is unknown; it has been suggested that the late onset and the variable clinical phenotype of HHH syndrome may be due to the redundancy of this exchange activity [8,37]. This is catalyzed either by ORC2 [68] or by the SLC25A29 gene product (previously reported to be a mitochondrial carnitine/acylcarnitine- or ornithine-like carrier called ORNT3 [69]), which is able to rescue the ornithine metabolism deficiency in fibroblasts of HHH patients [69,70] and to transport basic amino acids as well as ornithine into proteoliposomes [71]. The residual ornithine transport in cultured fibroblasts and liver of affected individuals supports this hypothesis of gene redundancy in HHH syndrome [8,37].Figure 3

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