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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clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases.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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Human ORC1 homology model. Left panel shows the ORCI model, created as dcflbed in [80], viewedfroni the cytoplasnijc side ith the substrate-binding site containing L- ornithine. The central panel shows the location of the mutations causing the H H H syndrome in the ORC1 model viewed as in the left panel but displayed with residues close to the binding site colored in cyan, residues close to the substrate exit/entrance on the cytosolic side in green and residues close to the substrate exit/entrance on the matrix side in magenta. The right panel shows the ORC1 model. viewed from the membrane side with the color scheme as in the central panel.
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Fig4: Human ORC1 homology model. Left panel shows the ORCI model, created as dcflbed in [80], viewedfroni the cytoplasnijc side ith the substrate-binding site containing L- ornithine. The central panel shows the location of the mutations causing the H H H syndrome in the ORC1 model viewed as in the left panel but displayed with residues close to the binding site colored in cyan, residues close to the substrate exit/entrance on the cytosolic side in green and residues close to the substrate exit/entrance on the matrix side in magenta. The right panel shows the ORC1 model. viewed from the membrane side with the color scheme as in the central panel.

Mentions: HHH syndrome is a genetic autosomal recessive disease caused by mutations in the SLC25A15 (solute carrier family 25, member 15) gene [37]. This gene maps on chromosome 13q14.11, spans about 23 kb and contains 7 exons encoding for the isoform 1 of the ornithine carrier ORC1, a member of the mitochondrial carrier family [65]. The open reading frame is encoded by exons 2 through 7 [53]. Exon 1 encodes part of the 5’UTR. The normal product of SLC25A15 gene is a 301 amino acid protein composed, like other mitochondrial carriers, of six α-helices that traverse the inner mitochondrial membrane with the C- and N-termini exposed to the cytosolic side of the membrane. ORC1 shows a tripartite structure with three similar domains each with two transmembrane helices connected by a long hydrophilic matrix loop [65]. There is experimental evidence for the direct involvement of the ORC1 residues E77, R179 and E180 in substrate binding, whereas W224 and R275 seem to be important in triggering the substrate-induced conformational changes that leads to substrate translocation; N74 and N78 residues are part of the substrate binding pocket [81] (Figure 4).Figure 4


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)

Human ORC1 homology model. Left panel shows the ORCI model, created as dcflbed in [80], viewedfroni the cytoplasnijc side ith the substrate-binding site containing L- ornithine. The central panel shows the location of the mutations causing the H H H syndrome in the ORC1 model viewed as in the left panel but displayed with residues close to the binding site colored in cyan, residues close to the substrate exit/entrance on the cytosolic side in green and residues close to the substrate exit/entrance on the matrix side in magenta. The right panel shows the ORC1 model. viewed from the membrane side with the color scheme as in the central panel.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Human ORC1 homology model. Left panel shows the ORCI model, created as dcflbed in [80], viewedfroni the cytoplasnijc side ith the substrate-binding site containing L- ornithine. The central panel shows the location of the mutations causing the H H H syndrome in the ORC1 model viewed as in the left panel but displayed with residues close to the binding site colored in cyan, residues close to the substrate exit/entrance on the cytosolic side in green and residues close to the substrate exit/entrance on the matrix side in magenta. The right panel shows the ORC1 model. viewed from the membrane side with the color scheme as in the central panel.
Mentions: HHH syndrome is a genetic autosomal recessive disease caused by mutations in the SLC25A15 (solute carrier family 25, member 15) gene [37]. This gene maps on chromosome 13q14.11, spans about 23 kb and contains 7 exons encoding for the isoform 1 of the ornithine carrier ORC1, a member of the mitochondrial carrier family [65]. The open reading frame is encoded by exons 2 through 7 [53]. Exon 1 encodes part of the 5’UTR. The normal product of SLC25A15 gene is a 301 amino acid protein composed, like other mitochondrial carriers, of six α-helices that traverse the inner mitochondrial membrane with the C- and N-termini exposed to the cytosolic side of the membrane. ORC1 shows a tripartite structure with three similar domains each with two transmembrane helices connected by a long hydrophilic matrix loop [65]. There is experimental evidence for the direct involvement of the ORC1 residues E77, R179 and E180 in substrate binding, whereas W224 and R275 seem to be important in triggering the substrate-induced conformational changes that leads to substrate translocation; N74 and N78 residues are part of the substrate binding pocket [81] (Figure 4).Figure 4

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