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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Core disease...

2026-05-11
Asta MONDO:0009393 Model: Asta Scientific Corpus Retrieval 13 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Core disease...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 13
  • Snippets retrieved: 19

Relevant Papers

[1] A Novel Mutation of ORNT1 Detected in a Hyperornithinemia–Hyperammonemia–Homocitrullinuria Syndrome Child by Clinical Whole-Exome Sequencing

  • Authors: Wison Laochareonsuk, S. Osatakul, U. Intusoma, Wanwisa Maneechay, S. Sangkhathat
  • Year: 2021
  • Venue: Journal of Pediatric Genetics
  • URL: https://www.semanticscholar.org/paper/fbdfc43fe477092a1d7af79af2f3d1c9eff2de38
  • DOI: 10.1055/s-0041-1742247
  • PMID: 39086438
  • PMCID: 11288712
  • Summary: A compound heterozygous mutation in SLC25A15 from a 2-year-old girl who presented with neurological alterations and hepatic failure is reported, which identified mutations that are predicted to result in the loss of function of ORNT1.
  • Evidence snippets:
  • Snippet 1 (score: 0.577) > Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare hereditary urea cycle disorder (UCD) found in approximately 1:2,000,000 livebirths. 1 The syndrome is caused by an ornithine translocase1 (ORNT1) deficiency secondary to homozygous or compound heterozygous mutations that result in the loss of function of the SLC25A15 gene. 2 Ornithine is an intermediate metabolite in the urea cycle which transfers carbamoyl phosphate from the mitochondrial matrix to the cytosol. Defects of ORNT1 disrupt ornithine and citrulline transportation, leading to the accumulation of the precursor substrates in the plasma, as well as ornithine and ammonia, and retained carbamoyl phosphate is alternatively converted to homocitrulline and excreted through the urine. 3 s a result of episodic increases of plasma ammonia, an affected individual can present at various ages of onset with a wide spectrum of manifestations including protein-rich diet intolerance, neurological impairment, and hepatitis. 4,5 To prevent sequelae of ammonia toxicity, acute treatment is required, especially prompt reduction of plasma ammonia and correction of metabolite imbalances. For maintenance therapy, recommendations include a low-protein diet combined with essential amino acid supplements such as citrulline or arginine to archive biochemical control. In addition, some patients will need ammonia scavengers including sodium benzoate or sodium phenylbutyrate to maintain appropriate serum ammonia. 6 Long-term neurological outcomes vary from mild intellectual disturbances to severe disability. > Because of rapidly decreasing costs and increasing accuracy of high throughput technology, clinical whole-exome sequencing (WES) can potentially help clinicians to provide a timely diagnosis and appropriate treatment for rare pediatric diseases. Early diagnosis of an inborn error of metabolism leads to prompt implementation of appropriate metabolic control which improves long-term clinical outcomes. > In this case report, we described a girl with HHH syndrome who presented with neurological alterations and hepatic failure at the age of 2 years. Clinical WES comprehensively annotated the whole panel of genes involved in her UCDs.

[2] Immune Alterations in a Patient With Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: A Case Report

  • Authors: Silene M. Silvera-Ruiz, C. Gemperle, Natalia Peano, Valentina Olivero, Adriana Becerra et al.
  • Year: 2022
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/7b744a7e101c2b486c721732c26da2fb9ba712d3
  • DOI: 10.3389/fimmu.2022.861516
  • PMID: 35711415
  • PMCID: 9196877
  • Citations: 5
  • Summary: This study has identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome and reported for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised.
  • Evidence snippets:
  • Snippet 1 (score: 0.520) > The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the SLC25A15 gene. Besides the well-known metabolic complications, patients often present intercurrent infections associated with acute hyperammonemia and metabolic decompensation. However, it is currently unknown whether intercurrent infections are associated with immunological alterations besides the known metabolic imbalances. Herein, we describe the case of a 3-years-old girl affected by the HHH syndrome caused by two novel SLC25A15 gene mutations associated with immune phenotypic and functional alterations. She was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion, and lethargy. Laboratory tests revealed severe hyperammonemia, elevated serum levels of liver transaminases, hemostasis alterations, hyperglutaminemia and strikingly increased orotic aciduria. Noteworthy, serum protein electrophoresis showed a reduction in the gamma globulin fraction. Direct sequencing of the SLC25A15 gene revealed two heterozygous non-conservative substitutions in the exon 5: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly). In silico analysis indicated that both mutations significantly impair protein structure and function and are consistent with the patient clinical status confirming the diagnosis of HHH syndrome. In addition, the immune analysis revealed reduced levels of serum IgG and striking phenotypic and functional alterations in the T and B cell immune compartments. Our study has identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome. Moreover, we are reporting for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised and might be related to the high frequency of intercurrent infections observed in patients bearing urea cycle disorders. Our results point out the importance of a comprehensive analysis to gain further insights into the underlying pathophysiology of the disease that would allow better patient care and quality of life

[3] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

  • Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
  • Year: 2015
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
  • DOI: 10.1186/s13023-015-0242-9
  • PMID: 25874378
  • PMCID: 4358699
  • Citations: 93
  • Influential citations: 5
  • Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.513) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.
  • Snippet 2 (score: 0.471) > Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH, MIM #238970) syndrome is a rare genetic disorder of the urea cycle (UC) caused by mutations in the SLC25A15 or ORNT1 gene (MIM*603861), which encodes for the mitochondrial ornithine carrier ORC1 [1]. HHH syndrome represents a heterogeneous disease with high clinical variability, ranging from a mild form with learning difficulties and slight neurological involvement, to a more severe form with coma, lethargy, hepatic signs and seizures. Asides from the severe neonatal form, there is no evidence of a direct correlation between age of onset, which is variable, and disease severity [1]. As for other urea cycle disorders (UCDs), early diagnosis in infancy or childhood may improve the clinical outcome [1]. Acute treatment requires an emergency approach, whereas the long-term treatment consists of a lowprotein diet supplemented with citrulline or arginine; in some patients, sodium benzoate and/or sodium phenylbutyrate are used to maintain blood ammonia in a safe range [1]. In this paper, we aim to provide a comprehensive review of the genetic and molecular aspects of HHH syndrome, a descriptive picture of clinical features and therapeutic strategies along with a discussion on the still unsolved questions related to the disease pathomechanisms.
  • Snippet 3 (score: 0.457) > The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome
  • Snippet 4 (score: 0.435) > 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

[4] Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

  • Authors: Unknown authors
  • Year: 2020
  • Venue: Definitions
  • URL: https://www.semanticscholar.org/paper/c60059d910318f8e61dc2b4654fc9877c39fc2c6
  • DOI: 10.32388/ec0x7n
  • Summary: An autosomal recessive disorder caused by mutation(s) in the SLC25A15 gene, encoding mitochondrial ornithine transporter 1. The condition is characterized by failure to thrive, liver dysfunction, psychomotor retardation, encephalopathy and seizures.
  • Evidence snippets:
  • Snippet 1 (score: 0.505) > Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

[5] Hyperornithinemia‐hyperammonemia‐homocitrullinuria syndrome in pregnancy: Considerations for management and review of the literature

  • Authors: Bernice Ho, J. MacKenzie, J. Walia, M. Geraghty, Graeme N. Smith et al.
  • Year: 2019
  • Venue: JIMD Reports
  • URL: https://www.semanticscholar.org/paper/8e5ac7ecb394e92fd984385c83e1002e663c9810
  • DOI: 10.1002/jmd2.12025
  • PMID: 31240152
  • PMCID: 6498866
  • Citations: 5
  • Summary: Recommendations for pregnancy management are made, including a detailed protocol for clinicians to use for disease management at delivery and in the post‐partum period, and a new concern of fetal intrauterine growth restriction is identified.
  • Evidence snippets:
  • Snippet 1 (score: 0.495) > Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (MIM 238970) is a rare autosomal recessive, urea cycle disorder. 1 First described in 1969, 2 HHH syndrome is caused by mutations of the SLC5A15 gene, which codes for the mitochondrial ornithine carrier ORC1. 1 Classical presentation of the condition consists of a combination of clinical and biochemical signs of hyperammonemia, hyperornithinemia, and urine excretion of homocitrulline. 1 Clinical presentation includes irregular episodes of vomiting, confusion, and hepatitis-like attacks. 1 Patients can also demonstrate chronic clinical signs, including avoidance of protein-rich foods, psychological disorders, ataxia, seizures, and pyramidal dysfunction. 1 The treatment for HHH syndrome is similar to other urea cycle conditions and early diagnosis may improve clinical progression. Long-term management entails a low-protein diet based on ammonia levels and amino acid profiles, supplementation with citrulline or arginine, essential amino acids as required, and possibly ammonia lowering agents, such as sodium benzoate or sodium phenylbuterate. 3 In addition, additional calories to spare protein are often required. > HHH syndrome is a rare metabolic disorder with approximately 100 patients reported in the literature. 1 To our knowledge, there are less than three patients with successful pregnancies and deliveries found in the literature. [4][5][6] We summarize the current state of knowledge regarding HHH and pregnancy, and suggest a protocol for management during metabolic decompensation (Table 1).

[6] Clinical heterogeneity of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in thirteen palestinian patients and report of a novel variant in the SLC25A15 gene

  • Authors: Imad Dweikat, R. Khalaf-Nazzal
  • Year: 2022
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/d74932b6a6a1553d383e10dc57f14fae430cd782
  • DOI: 10.3389/fgene.2022.1004598
  • PMID: 36506307
  • PMCID: 9730883
  • Citations: 5
  • Influential citations: 1
  • Summary: The results confirm the marked clinical heterogeneity of HHH including severe neonatal presentation, hepatic failure, and progressive pyramidal tract dysfunction in all age groups and report a novel pathogenic variant in the SLC25A15 gene, further expanding the molecular spectrum of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.485) > Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome (Phenotype MIM number 238970) is a rare genetic disease of the urea cycle caused by disease-causing variants in the Solute Carrier Family 25, Member 15 gene; SLC25A15 (alias Ornithine Transporter, Mitochondrial, one; ORNT1, gene MIM number 603861) (Camacho et al., 1999;Tsujino et al., 2000;Salvi et al., 2001;Martinelli et al., 2015). Disease-causing variants in this gene result in impaired ornithine transport across the mitochondrial membrane; this interrupts the urea cycle and causes hyperammonemia. Impaired transport of ornithine causes its accumulation in the cytosol leading to hyperornithinemia (Oyanagi et al., 1983;Camacho et al., 1999). Inside the mitochondria, ornithine deficiency leads to the accumulation of carbamoylphosphate (Hommes et al., 1986;Inoue et al., 1988). The increased mitochondrial level of carbamoylphosphate results in either an excess production of orotic acid through the cytosolic pyrimidine biosynthetic pathway or the formation of homocitrulline from lysine by ornithine transcarbamylase (Panza et al., 2019). The combination of Hyperornithinemia, Hyperammonemia, and Homocitrullinuria is pathognomonic for HHH syndrome and is usually accompanied by the detection of increased levels of orotic acid in plasma or urine. However, initially, some patients may present with incomplete biochemical profiles such as normal plasma ornithine levels or minimal excretion of homocitrulline in urine (Shimizu et al., 1990;Martinelli et al., 2015). > HHH is characterized by marked phenotypic variability including age at onset, clinical presentation, and severity of symptoms.
  • Snippet 2 (score: 0.462) > Background: Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, is a rare autosomal recessive disorder characterized by impaired ornithine transport across the inner mitochondrial membrane. HHH is caused by biallelic disease-causing variants in the SLC25A15 gene. The clinical presentation of HHH is highly variable ranging from severe neonatal encephalopathy and hepatic failure to a milder form with corresponding learning difficulties. Methods: In this study, data from thirteen patients with HHH syndrome, diagnosed between the age of 1 week–29 years at two tertiary care centers in Palestine, is presented. The clinical, biochemical, and molecular data are reviewed. Results: Analysis of the SLC25A15 gene sequence revealed a novel homozygous frameshift deletion in exon 5, NM_014252.4:c.552-555delTTTC; p (Phe185SerfsTer8) in nine patients. The remaining four patients had a recurrent homozygous frameshift variant; NM_014252.4:c.446delG, (p.Ser149ThrfsTer45). The major acute clinical presentation found was encephalopathy and liver dysfunction. Nervous system involvement was common, progressive, and presented with signs of upper motor neuron disease as well as variable degrees of cognitive impairment. One patient had an initial presentation in adulthood with acute encephalopathy that responded well to treatment. There was no clear genotype-phenotype correlation. Conclusion: Our results confirm the marked clinical heterogeneity of HHH including severe neonatal presentation, hepatic failure, and progressive pyramidal tract dysfunction in all age groups. The disease progression was variable, even in patients with the same genetic variant, and in patients with severe neonatal-onset hepatic encephalopathy. We report a novel pathogenic variant in the SLC25A15 gene, further expanding the molecular spectrum of the disease.

[7] Hyperornithinemia–Hyperammonemia–Homocitrullinuria Syndrome in Vietnamese Patients

  • Authors: Khanh Ngoc Nguyen, V. Tran, N. Nguyen, Thi Bich Ngoc Can, Thi Kim Giang Dang et al.
  • Year: 2024
  • Venue: Medicina
  • URL: https://www.semanticscholar.org/paper/f82156789e5dd35cf5b0ac96c15b838cccaced3f
  • DOI: 10.3390/medicina60111877
  • PMID: 39597062
  • PMCID: 11596723
  • Citations: 1
  • Summary: The results highlighted the clinical and biochemical heterogeneity of HHH syndrome and posed that HHH syndrome should be considered when individuals have hyperammonemia, elevated transaminase, and decreased prothrombin time.
  • Evidence snippets:
  • Snippet 1 (score: 0.481) > Those with later onset may display chronic neurocognitive deficits and/or unexplained seizures, spasticity, acute encephalopathy secondary to hyperammonemic crisis, or chronic liver dysfunction. > Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome can be diagnosed by mutations in the SLC25A15 gene and marked by elevated ammonia, homocitrulline, and ornithine levels [6]. HHH syndrome differs from other defects due to high urinary homocitrulline and ornithine [7]. Hyperornithinemia is present in almost all patients; however, a small proportion does not exhibit hyperammonemia and homocitrullinuria. Therefore, genetic testing for SLC25A15 variants accompanied by at least one of three metabolic traits, hyperornithinemia, hyperammonemia, and homocitrullinuria, is pivotal for a definite diagnosis of HHH syndrome [8]. Early diagnosis improves clinical outcomes [8]. Acute treatment of HHH syndrome is similar to other urea cycle disorders, whereas long-term treatment of HHH syndrome is similar to carbamoyl phosphate synthetase I and ornithine transcarbamylase deficiency [7]. Protein restriction, citrulline, arginine, supplementation of essential amino acids, and sodium benzoate/sodium phenylbutyrate are required. > The pathogenic variants in the SLC25A15 gene, an autosomal recessive inheritance pattern, cause hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome [2]. The SLC25A15 gene is located on chromosome 13q14.11 and comprises seven exons encoding for isoform 1 of the ornithine carrier ORC1 with a length of 301 amino acids [9]. The substrate binding of the ORC1 includes Glu77, Arg179, and Glu180 residues, and the Asn74 and Asn78 are situated in the substrate binding pocket [10].

[8] Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis.

  • Authors: Hencher Han-Chih Lee, K. Poon, C. Lai, K. Au, T. Siu et al.
  • Year: 2014
  • Venue: Hong Kong medical journal = Xianggang yi xue za zhi
  • URL: https://www.semanticscholar.org/paper/66906e104ea0ceee49e6bad83c0ccda03c30bdeb
  • DOI: 10.12809/hkmj133826
  • PMID: 24473688
  • Citations: 15
  • Summary: Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.471) > Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis.

[9] Hereditary Spastic Paraplegia Is a Common Phenotypic Finding in ARG1 Deficiency, P5CS Deficiency and HHH Syndrome: Three Inborn Errors of Metabolism Caused by Alteration of an Interconnected Pathway of Glutamate and Urea Cycle Metabolism

  • Authors: Emanuele Panza, D. Martinelli, P. Magini, C. Dionisi Vici, M. Seri
  • Year: 2019
  • Venue: Frontiers in Neurology
  • URL: https://www.semanticscholar.org/paper/2743986e24a75ea2b24c004e412709715c1d6e2a
  • DOI: 10.3389/fneur.2019.00131
  • PMID: 30853934
  • PMCID: 6395431
  • Citations: 24
  • Influential citations: 2
  • Summary: Comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype are commented on.
  • Evidence snippets:
  • Snippet 1 (score: 0.457) > The association of hyperornithinaemia, hyperammonaemia, and homocitrullinuria is pathognomonic for HHH syndrome (MIM#238970), an autosomal recessive disease caused by biallelic mutations in SLC25A15 gene (alias ORNT1, MIM#603861). This gene maps on 13q14.11, and it encodes for the mitochondrial ornithine/citrulline antiporter ORC1. Mutations in this gene result in a defect of ornithine transport through the mitochondrial membrane (Figure 1), causing a functional deficiency of the urea cycle. This mechanism results in the increase of ornithine levels in cytosol (and in plasma), while causing ornithine deficiency inside mitochondria, affecting the urea cycle. The latter situation leads to the accumulation of carbamoylphosphate, which is shifted to the formation of orotic acid by an alternative pathway, and induces the formation of homocitrulline from lysine by ornithine transcarbamylase. > HHH can occur at any age (15)(16)(17). The clinical presentation of HHH syndrome covers a broad spectrum of symptoms, including protein intolerance, vomiting, seizures, confusion, and developmental delay. The most severe forms have been reported with neonatal onset of lethargy, hypotonia, and seizures developing into coma and even death (18). There are also slowly/chronic progressive forms, characterized by the patients aversion to food rich in proteins, variable intellectual disabilities and/or cognitive regression, and signs of motor deficit (18). > Most patients develop neurological dysfunction mainly characterized by pyramidal tract signs with spastic gait, associated with cerebellar symptoms (Table 1).
  • Snippet 2 (score: 0.448) > Hereditary Spastic Paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by a progressive rigidity and weakness of the lower limbs, caused by pyramidal tract lesions. As of today, 80 different forms of HSP have been mapped, 64 genes have been cloned, and new forms are constantly being described. HSPs represent an intensively studied field, and the functional understanding of the biochemical and molecular pathogenetic pathways are starting to be elucidated. Recently, dominant and recessive mutations in the ALDH18A1 gene resulting in the deficiency of the encoded enzyme (delta-1-pyrroline-5-carboxylate synthase, P5CS) have been pathogenetically linked to HSP. P5CS is a critical enzyme in the conversion of glutamate to pyrroline-5-carboxylate, an intermediate that enters in the proline biosynthesis and that is connected with the urea cycle. Interestingly, two urea cycle disorders, Argininemia and Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, are clinically characterized by highly penetrant spastic paraplegia. These three diseases represent a peculiar group of HSPs caused by Inborn Errors of Metabolism. Here we comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype.
  • Snippet 3 (score: 0.448) > Hereditary Spastic Paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by a progressive rigidity and weakness of the lower limbs, caused by pyramidal tract lesions. As of today, 80 different forms of HSP have been mapped, 64 genes have been cloned, and new forms are constantly being described. HSPs represent an intensively studied field, and the functional understanding of the biochemical and molecular pathogenetic pathways are starting to be elucidated. Recently, dominant and recessive mutations in the ALDH18A1 gene resulting in the deficiency of the encoded enzyme (delta-1-pyrroline-5-carboxylate synthase, P5CS) have been pathogenetically linked to HSP. P5CS is a critical enzyme in the conversion of glutamate to pyrroline-5-carboxylate, an intermediate that enters in the proline biosynthesis and that is connected with the urea cycle. Interestingly, two urea cycle disorders, Argininemia and Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, are clinically characterized by highly penetrant spastic paraplegia. These three diseases represent a peculiar group of HSPs caused by Inborn Errors of Metabolism. Here we comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype.

[10] Late onset hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome, presenting as recurrent metabolic encephalopathy, A case report

  • Authors: Fajr M A Sarhan, Afnan W. M. Jobran, Ali Fayyad, Zaid Ghanim, Imad Dweikat et al.
  • Year: 2022
  • Venue: Annals of Medicine and Surgery
  • URL: https://www.semanticscholar.org/paper/2f02f0c9134c07db7e3199404d2988c7f42ea035
  • DOI: 10.1016/j.amsu.2022.104842
  • PMID: 36582900
  • PMCID: 9793129
  • Summary: High suspicion for genetic causes of metabolic encephalopathy should be maintained even for older patients without prior diagnosis in childhood/adolescence, and treatment focuses on reduction of the ammonia levels using sodium benzoat, citrulline or arginine, and low protein diet.
  • Evidence snippets:
  • Snippet 1 (score: 0.444) > Late onset hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome, presenting as recurrent metabolic encephalopathy, A case report

[11] Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease

  • Authors: Ranya Erdal, Kıvanç Birsoy, G. Unlu
  • Year: 2025
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/2c1c09359e82a1bec3601ec57b7b48eaca82c5c0
  • DOI: 10.3390/metabo15070446
  • PMID: 40710547
  • PMCID: 12300550
  • Citations: 4
  • Summary: It is discussed how emerging genetic and metabolic interventions—including dietary modulation, cofactor replacement, and gene therapy—are reshaping treatment of liver-based metabolic disorders and reveals actionable vulnerabilities in metabolic disease and cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > 4.1. Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (SLC25A15 Deficiency) > Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder resulting from a deficiency in the SLC25A15 gene, which encodes ornithine carrier 1 (ORC1). ORC1 plays a critical role in facilitating the transport of ornithine into the mitochondria and citrulline out of the mitochondria, thus enabling proper urea cycle function (Figure 1). Dysfunction in ORC1 results in the accumulation of ornithine in the cytosol, leading to hyperornithinemia. The consequent reduction of mitochondrial ornithine levels diminishes the activity of OTC, resulting in elevated carbamoyl phosphate levels and subsequent hyperammonemia. Increased carbamoyl phosphate levels, due to decreased OTC activity, further account for the increased urinary excretion of orotic acid as carbamoyl phosphate enters the pyrimidine synthesis pathway. Clinical manifestations of HHH syndrome are akin to those observed in other proximal urea cycle disorders (Table 1). Affected individuals experience symptoms of hyperammonemia, including lethargy, vomiting, failure to thrive, seizures, and, in severe cases, coma [36].

[12] Severe Neurological Sequelae and Radiological Findings in a Lost-to-Follow-Up Case of Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

  • Authors: A. Mohamed, Ahaan Gupta, Reem Zakzouk
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/c3c1d501580ab638319ec42bf3b1ee932b897edb
  • DOI: 10.7759/cureus.93690
  • PMID: 41189871
  • PMCID: 12580580
  • Summary: Investigations demonstrated radiological evidence of neurological damage, including corpus callosal atrophy, alongside biochemical and ultrasonographic features of hepatic dysfunction, alongside biochemical and ultrasonographic features of hepatic dysfunction in a patient who was treated for hyperammonemic crisis at birth and subsequently diagnosed with HHH syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.435) > Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder caused by defective hepatic ornithine transport, leading to hyperammonemia and progressive neurological complications. We report the case of a patient who was treated for hyperammonemic crisis at birth and subsequently diagnosed with HHH syndrome. Management, including ammonia-lowering therapy and a low-protein diet, was initiated; however, due to significant socioeconomic barriers, he was lost to follow-up from the age of two. He re-presented at the age of 12 in a severely debilitated state with global developmental delay and refractory epilepsy. Investigations demonstrated radiological evidence of neurological damage, including corpus callosal atrophy, alongside biochemical and ultrasonographic features of hepatic dysfunction. This case highlights the critical importance of sustained treatment, multidisciplinary follow-up, and adequate social support in preventing irreversible complications of HHH syndrome.

[13] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 30
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

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