A late-onset hyperammonemia syndrome caused by Ureaplasma parvum infection after kidney transplantation.

Hyperammonemia syndrome has a high mortality rate in the immunosuppressed population due to its association with mental status changes. Recently studies have shown that Ureaplasma organisms' infection can lead to hyperammonemia in post-transplant patients. Symptoms typically occur within 30 days postoperatively. However, the late-onset hyperammonemia caused by Ureaplasma parvum infection after kidney transplantation has never been reported. In this case study, a 64-year-old Chinese male presented with symptoms such as nausea, vomiting, trouble sleeping, and deteriorating mental status 81 days after kidney transplantation. His plasma ammonia level was significantly elevated, and there was no evidence of liver synthetic dysfunction. Although common methods for ammonia clearance, such as haemodialysis and oral lactulose were initiated, his serum ammonia levels remained high. Metagenomic sequencing of serum determined Ureaplasma parvum infection. Levofloxacin and minocycline were administered respectively, which resulted in a decrease in ammonia levels, but normalization was not achieved. The computed tomographic scan revealed the presence of cerebral edema. Unfortunately, the patient eventually became brain dead with multiple organ failure. This case highlights that Ureaplasma parvum can cause late-onset hyperammonemia in kidney transplant patients. Once the mental status changes are identified, immediate empiric treatments should be initiated without waiting for a confirmed diagnosis of Ureaplasma spp. infection.

A Very Rare Case of Diabetes Mellitus Occurring in a Patient With Hyperinsulinism Hyperammonemia Syndrome.

Background/Objective: To illustrate an unusual case of type 2 diabetes mellitus (T2DM) developing many years after the diagnosis of hyperinsulinism hyperammonemia (HI/HA) syndrome. Case Report: This article reports about a 36-year-old female with a history of congenital hyperinsulinism due to HI/HA syndrome, which was diagnosed in infancy. The patient presented with hypoglycemia and seizures as an infant and was treated with diazoxide and a low-protein diet for many years with reduction in her hypoglycemic events. She subsequently developed T2DM >30 years later. Genetic analysis was positive for a glutamate dehydrogenase 1 gene (GLUD1) alteration. She was treated with metformin and a glucagon-like peptide 1 agonist, with significant improvement in her blood glucose control and weight loss. Discussion: HI/HA syndrome is a rare genetic syndrome that manifests in childhood with signs and symptoms of hypoglycemia and neurologic symptoms. This is the first case reported in the literature of a patient with HI/HA syndrome due to a GLUD1 alteration who developed T2DM much later in life. Patients with this disorder usually have recurrent hypoglycemia and require long-term medical therapy or very occasionally may have a resolution. She had class 3 obesity and evidence of insulin resistance, which likely contributed to her risk of diabetes. Conclusion: This is a rare case of T2DM presenting in a patient with HI/HA syndrome. This should be considered a possible outcome in patients with this disorder, especially in the presence of obesity.

Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome has been known to be caused by dominant gain-of-function mutations in GLUD1, encoding the mitochondrial enzyme glutamate dehydrogenase. Pathogenic GLUD1 mutations enhance enzymatic activity by reducing its sensitivity to allosteric inhibition by GTP. Two recent independent studies showed that a similar HI/HA phenotype can be caused by biallelic mutations in SLC25A36, encoding pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine and guanine nucleotides across the inner mitochondrial membrane: one study reported a single case caused by a homozygous truncating mutation in SLC25A36 resulting in lack of expression of SLC25A36 in patients' fibroblasts. A second study described two siblings with a splice site mutation in SLC25A36, causing reduction of mitochondrial GTP content, putatively leading to hyperactivation of glutamate dehydrogenase. In an independent study, through combined linkage analysis and exome sequencing, we demonstrate in four individuals of two Bedouin Israeli related families the same disease-causing SLC25A36 (NM_018155.3) c.284 + 3A > T homozygous splice-site mutation found in the two siblings. We demonstrate that the mutation, while causing skipping of exon 3, does not abrogate expression of mRNA and protein of the mutant SLC25A36 in patients' blood and fibroblasts. Affected individuals had hyperinsulinism, hyperammonemia, borderline low birth weight, tonic-clonic seizures commencing around 6 months of age, yet normal intellect and no significant other morbidities. Chronic constipation, hypothyroidism, and developmental delay previously described in a single patient were not found. We thus verify that biallelic SLC25A36 mutations indeed cause HI/HA syndrome and clearly delineate the disease phenotype.

Hyperammonemia syndrome post-lung transplantation: Case series and systematic review of literature.

BACKGROUND: Hyperammonemia syndrome (HS) is a rare post-transplant complication associated with high morbidity and mortality. Its incidence appears to be higher in lung transplant recipients and its pathophysiology is not well understood. In addition to underlying metabolic abnormalities, it is postulated that HS may be associated with Ureaplasma or Mycoplasma spp. lung infections. Management of this condition is not standardized and may include preemptive antimicrobials, renal replacement, nitrogen scavenging, and bowel decontamination therapies, as well as dietary modifications. METHODS: In this case series, we describe seven HS cases, five of whom had metabolic deficiencies ruled out. In addition, a literature review was performed by searching PubMed following PRISMA-P guidelines. Articles containing the terms "hyperammonemia" and "lung" were reviewed from 1 January 1997 to 31 October 2021. RESULTS: All HS cases described in our center had positive airway samples for Mycoplasmataceae, neurologic abnormalities and high ammonia levels post-transplant. Mortality in our group (57%) was similar to that published in previous cases. The literature review supported that HS is an early complication post-transplant, associated with Ureaplasma spp. and Mycoplasma hominis infections and of worse prognosis in patients presenting cerebral edema and seizures. CONCLUSION: This review highlights the need for rapid testing for Ureaplasma spp. and M. hominis after lung transplant, as well as the necessity for future studies to explore potential therapies that may improve outcomes in these patients.

Glutamate Dehydrogenase as a Promising Target for Hyperinsulinism Hyperammonemia Syndrome Therapy.

Hyperinsulinism-hyperammonemia syndrome (HHS) is a rare disease characterized by recurrent hypoglycemia and persistent elevation of plasma ammonia, and it can lead to severe epilepsy and permanent brain damage. It has been demonstrated that functional mutations of glutamate dehydrogenase (GDH), an enzyme in the mitochondrial matrix, are responsible for the HHS. Thus, GDH has become a promising target for the small molecule therapeutic intervention of HHS. Several medicinal chemistry studies are currently aimed at GDH, however, to date, none of the compounds reported has been entered clinical trials. This perspective summarizes the progress in the discovery and development of GDH inhibitors, including the pathogenesis of HHS, potential binding sites, screening methods, and research models. Future therapeutic perspectives are offered to provide a reference for discovering potent GDH modulators and encourage additional research that will provide more comprehensive guidance for drug development.

PNC2 (SLC25A36) Deficiency Associated With the Hyperinsulinism/Hyperammonemia Syndrome.

CONTEXT: The hyperinsulinism/hyperammonemia (HI/HA) syndrome, the second-most common form of congenital hyperinsulinism, has been associated with dominant mutations in GLUD1, coding for the mitochondrial enzyme glutamate dehydrogenase, that increase enzyme activity by reducing its sensitivity to allosteric inhibition by GTP. OBJECTIVE: To identify the underlying genetic etiology in 2 siblings who presented with the biochemical features of HI/HA syndrome but did not carry pathogenic variants in GLUD1, and to determine the functional impact of the newly identified mutation. METHODS: The patients were investigated by whole exome sequencing. Yeast complementation studies and biochemical assays on the recombinant mutated protein were performed. The consequences of stable slc25a36 silencing in HeLa cells were also investigated. RESULTS: A homozygous splice site variant was identified in solute carrier family 25, member 36 (SLC25A36), encoding the pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine as well as guanine nucleotides across the inner mitochondrial membrane. The mutation leads to a 26-aa in-frame deletion in the first repeat domain of the protein, which abolishes transport activity. Furthermore, knockdown of slc25a36 expression in HeLa cells caused a marked reduction in the mitochondrial GTP content, which likely leads to a hyperactivation of glutamate dehydrogenase in our patients. CONCLUSION: We report for the first time a mutation in PNC2/SLC25A36 leading to HI/HA and provide functional evidence of the molecular mechanism responsible for this phenotype. Our findings underscore the importance of mitochondrial nucleotide metabolism and expand the role of mitochondrial transporters in insulin secretion.

Diagnostics of Inherited Metabolic Diseases in Newborns with the Hyperammonemia Syndrome at the Onset of Disease (Pilot Study).

The aim of the study was to develop a diagnostic model that allows with a high degree of probability predicting the development of inherited metabolic disease (IMD) in newborns with the hyperammonemia syndrome at the onset of disease and determine the adequate management tactics for such patients. Materials and Methods: The study included 15 female and 5 male infants with the hyperammonemia syndrome. All the patients underwent a full range of clinical laboratory studies in accordance with the standards of treatment of the underlying disease. Blood ammonia measuring (quantitative assessment) was carried out on the basis of the biochemical laboratory of the Children's City Clinical Hospital No.1 (Nizhny Novgorod, Russia) using a portable PocketChem BA blood ammonia meter (Japan) and Ammonia Test Kit II test strips (Japan) in accordance with the manufacturer's protocol. The confirmation of the IMD diagnosis was carried out using the tandem mass spectrometry (TMS) method and molecular genetic testing (genome sequencing).To check the assumptions, all the patients during the follow-up were randomized retrospectively into two groups depending on the TMS results and molecular genetic testing. Group 1 (n=8) included the patients diagnosed with IMD and group 2 (n=12) included the patients with transient hyperammonemia in the neonatal period. Results: The clinical manifestations of the hyperammonemia syndrome in the neonatal period are most frequently realized in the form of a syndrome of CNS depression of varying degrees up to coma (75%), a convulsive syndrome (55%), vomiting (40%) without significant differences in the frequency of occurrence due to the causes of hyperammonemia. In a third of cases, the onset of the hyperammonemia syndrome occurs in the early neonatal period.The ammonia levels in patients with hyperammonemia caused by IMD are statistically significantly higher than those in patients with transient hyperammonemia (p=0.014) which may serve as the first diagnostic sign of IMD in a newborn.A tendency to a more frequent development of anemia in infants with IMD (p=0.084) has been established which might be due to the compensation of metabolic acidosis. The presence of anemia in combination with clinical features and the level of hyperammonemia increases the risk of IMD.In the course of the study, a diagnostic model was developed for predicting the risk of IMD development in a newborn at the onset of hyperammonemia. Through the discriminant analysis, a statistically significant relationship was established between the level of ammonia at the onset, blood glucose and base deficiency levels, blood lactate, hemoglobin, erythrocyte levels, the average volume of erythrocytes and the pH level (p=0.040) with the risk of IMD development. The sensitivity of the model has amounted to 87.5%, the specificity - 83.3%. The diagnostic efficiency of the model is 85.0%. Conclusion: The proposed model can be used at detecting the debut of the hyperammonemia syndrome in newborns in order to predict the probability of IMD and work out the adequate tactics of the management for these patients.

Hyperammonemia syndrome associated with Ureaplasma spp. Infections in immunocompromised patients and transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Hyperammonemia syndrome (HS) is reported to occur in patients with Ureaplasma spp. infections. We performed a systematic review and meta-analysis of studies reporting HS in patients with Ureaplasma spp. infection. METHODS: We searched several databases (CINAHL, OVID, ProQuest, and Scopus) from inception to January 2021. We described case reports and series, and performed a meta-analysis for all cohort studies. The pooled risk ratio (RR) for the association between HS and Ureaplasma spp. infections was derived using a random-effects model. RESULTS: The systematic review yielded 18 studies. HS was reported in 53 patients with Ureaplasma spp. infections. The most common clinical manifestations were neurologic. Meta-analysis showed a higher incidence of HS (41.67%) and peak ammonia concentration among Ureaplasma spp.-infected lung transplant recipients compared with Ureaplasma spp.-negative recipients (2.84%). The risk of HS was significantly increased in Ureaplasma spp.-infected recipients compared with Ureaplasma spp.-negative recipients (RR: 14.64; CI: 2.85-75.24). Mortality from Ureaplasma-associated HS was 27.27% compared with 5.24% in those with HS from other causes. CONCLUSIONS: The risk of developing HS is higher among Ureaplasma-infected patients compared with uninfected patients. Lung transplant recipients appear to be disproportionally affected, and HS should be suspected in those who present with neurologic symptoms.

Impact of Screening and Treatment of Ureaplasma species on Hyperammonemia Syndrome in Lung Transplant Recipients: A Single Center Experience.

BACKGROUND: Infection with Ureaplasma species (spp) has been linked to fatal hyperammonemia syndrome (HS) in lung transplant recipients. We sought to characterize the epidemiology of Ureaplasma spp in candidates and donors and describe outcomes of antimicrobial therapy in preventing and treating HS. METHODS: Candidate testing for Ureaplasma spp was performed with urine culture and polymerase chain reaction (PCR) pretransplant. Positive candidates were treated with levofloxacin. Donor testing was performed with bronchoalveolar lavage (BAL) culture and PCR intraoperatively. From 7/2014 to 2/2017 patients were treated according to results; from 2/2017 to 10/2018 recipients received empiric levofloxacin and azithromycin at transplant until testing returned negative. HS was defined as new onset altered mental status after transplant with ammonia > 200 µmol/L. RESULTS: In total, 60 patients who underwent lung transplant were included. And 80% (n = 48) of patients had negative screening tests in donor and candidate pre-lung transplant, 8.3% (n = 5) of recipients had positive Ureaplasma spp testing in urine pre-transplant, and 13.3% (n = 8) had positive donor BAL testing at the time of lung transplant. Three patients developed HS a median of 7 days posttransplant; 2 died of HS. Recipients of organs with Ureaplasma spp who received empiric therapy did not develop HS. Donors with Ureaplasma spp were younger and more sexually active. CONCLUSIONS: Donor-derived Ureaplasma spp in lung transplant was associated with HS. Screening lung donors for Ureaplasma spp might allow for targeted therapy to reduce risk for development of HS, but future confirmatory studies are needed.

Diazoxide-Induced Neutropenia and Long-Term Follow-up in a Patient with Hyperinsulinemia-Hyperammonemia due to GLUD1 Mutation.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic hypoglycemia, in addition to persistently elevated plasma ammonia levels. First-line treatment is diazoxide, and most patients respond well to this agent, however side effects may be observed. The most frequent side effect of diazoxide is fluid retention and hypertrichosis, while hyperuricemia and hematologic side effects are observed less often. Herein, we report a case who had a heterozygous mutation of GLUD1 gene and who developed diazoxide related neutropenia 8 years after the start of treatment. On follow-up, leucopenia and mild neutropenia persisted and the treatment was changed to somatostatin analogues. However, she developed persistent severe symptomatic hypoglycemia and required diazoxide retreatment. A lower dose of diazoxide (6 mg/kg/day) successfully controlled hypoglycemia and cell counts increased even though they were not normalized. Neutropenia in current case presented after a long period of time of diazoxide use and this period is the longest defined in the literature. Long-term endocrine and hematologic follow-up of this patient up to 18 years old will also be presented.

Understanding rare infections post-lung transplantation.

Introduction: Lung transplant recipients are at the highest risk of infectious complications among all solid-organ transplant (SOT) recipients. In the current era, many standardized protocols in terms of diagnostic algorithms, prophylaxis, and therapeutic strategies have improved the management of the most common infectious complications. Conversely, diagnosis of rare infections can be particularly challenging and this can delay appropriate treatment.Areas covered: This article will review the epidemiology, clinical presentation, diagnostic and therapeutic management of certain rarely reported viral, fungal, bacterial and parasitic infections in lung transplant recipients.Expert opinion: Once the most frequent infections are excluded, clinical suspicion combined with molecular diagnostic methods such as targeted and broad-spectrum PCRs can allow diagnosis of a rare infection. A multidisciplinary team, including transplant pulmonologists, transplant infectious diseases specialists, microbiologists and pathologists is essential for prompt diagnosis and optimal therapeutic management.

Successful management of noncirrhotic hyperammonemia syndrome after kidney transplantation from putative Ureaplasma infection.

Noncirrhotic hyperammonemia (NCH) is a rare but often fatal complication of solid organ transplantation. We present a case wherein an infectious cause of NCH was suspected following kidney transplantation (KT) and the patient was promptly started on empirical antibiotic treatment which proved to be lifesaving. A 56-year-old Chinese woman with a past medical history of end-stage renal disease secondary to ischemic nephropathy and cerebrovascular accident received a kidney from a 52-year-old brain-dead donor with a Kidney Donor Profile Index score of 70%. She experienced immediate graft function and was discharged on post-operative day (POD) 4. On POD 10, she presented with a fever, acute onset of confusion, and abdominal pain. Her mental status deteriorated and required emergent intubation. Empiric broad-spectrum antibiotics were initiated. On hospital day 3, a serum ammonia was 889 µmol/L (normal <53 µmol/L). A urine sample was sent for Ureaplasma polymerase chain reaction (PCR) testing, and moxifloxacin and doxycycline were empirically started. Her ammonia rapidly normalized, and her mental status improved 48 hours after antibiotic initiation. She was extubated 5 days into treatment and was discharged after an 11-day hospitalization. Following discharge, her urine test resulted positive for Ureaplasma parvum or Ureaplasma urealyticum DNA detection with the 16S rRNA gene amplification probe. Mental status changes and hyperammonemia in the first 30 days post-KT should raise suspicion for NCH, and prompt empiric treatment with antimicrobials covering Ureaplasma and Mycoplasma should be considered.

Hyperinsulinism associated with GLUD1 mutation: allosteric regulation and functional characterization of p.G446V glutamate dehydrogenase.

BACKGROUND: Gain-of-function mutations in the GLUD1 gene, encoding for glutamate dehydrogenase (GDH), result in the hyperinsulinism/hyperammonemia HI/HA syndrome. HI/HA patients present with harmful hypoglycemia secondary to protein-induced HI and elevated plasma ammonia levels. These symptoms may be accompanied by seizures and mental retardation. GDH is a mitochondrial enzyme that catalyzes the oxidative deamination of glutamate to α-ketoglutarate, under allosteric regulations mediated by its inhibitor GTP and its activator ADP. The present study investigated the functional properties of the GDH-G446V variant (alias c.1496G > T, p.(Gly499Val) (NM_005271.4)) in patient-derived lymphoblastoid cells. RESULTS: The calculated energy barrier between the opened and closed state of the enzyme was 41% lower in GDH-G446V compared to wild-type GDH, pointing to altered allosteric regulation. Computational analysis indicated conformational changes of GDH-G446V in the antenna region that is crucial for allosteric regulators. Enzymatic activity measured in patient-derived lymphoblastoid cells showed impaired allosteric responses of GDH-G446V to both regulators GTP and ADP. In particular, as opposed to control lymphoblastoid cells, GDH-G446V cells were not responsive to GTP in the lower range of ADP concentrations. Assessment of the metabolic rate revealed higher mitochondrial respiration in response to GDH-dependent substrates in the GDH-G446V lymphoblastoid cells compared to control cells. This indicates a shift toward glutaminolysis for energy provision in cells carrying the GDH-G446V variant. CONCLUSIONS: Substitution of the small amino acid glycine for the hydrophobic branched-chain valine altered the allosteric sensitivity to both inhibitory action of GTP and activation by ADP, rendering cells metabolically responsive to glutamine.

Successful management of hyperammonemia syndrome in a patient after skin transplantation: a case report and a literature review on 41 patients / 中华危重病急救医学

Hyperammonemia syndrome (HS) is a comparatively rare but often fatal clinical syndrome characterized by progressive respiratory alkalosis and abrupt mental status alteration associated with markedly elevated plasma ammonium levels. Although the exact mechanism of HS remains unclear, infection with urease producing microbes is proposed as the main etiology of HS recently. A patient with HS after repeated autologous skin transplantation was admitted to Tianjin First Center Hospital in March 2018, presented with fever, coma and epilepsy. The infection of Mycoplasma hominis was confirmed in blood sample by high throughput gene detection. The patient was survived after multimodal management including antimicrobial treatment, aggressive ammonia removal by continuous renal replacement therapy in combination with lactulose, and mechanical ventilation. She was successfully discharged from intensive care unit (ICU) with clear consciousness, normal temperature and smooth breath. In view of the experience of the case treatment, a review of literature was conducted to discuss the epidemiology and clinical characteristics, possible etiologies and mechanisms, and outcomes with emphasis on treatment strategies of HS and to promote more clinicians to recognize this rare disease.

Recent advances in understanding and managing infectious diseases in solid organ transplant recipients.

Background: Undergoing solid organ transplantation (SOT) exposes the recipient to various infectious risks, including possible transmission of pathogen by the transplanted organ, post-surgical infections, reactivation of latent pathogens, or novel infections. Recent advances: In the last few years, the emergence of Zika virus has raised concerns in the transplant community. Few cases have been described in SOT patients, and these were associated mainly with moderate disease and favorable outcome; the notable exception is a recent case of fatal meningo-encephalopathy in a heart transplant recipient. Because of the advances in treating hepatitis C, several teams recently started to use organs from hepatitis C-positive donors. The worldwide increasing incidence of multidrug-resistant pathogens, as well as the increasing incidence of Clostridioidesdifficile infection, is of particular concern in SOT patients. In the field of mycology, the main recent therapeutic advance is the availability of isavuconazole for the treatment of invasive aspergillosis and mucormycosis. This drug has the advantage of minimal interaction with calcineurin inhibitors. Regarding the viral reactivations occurring after transplant, cytomegalovirus (CMV) infection is still a significant issue in SOT patients. The management of resistant CMV remains particularly difficult. The approval of letermovir, albeit in bone marrow transplantation, and the therapeutic trial of maribavir bring a ray of hope. Another advancement in management of post-transplant infections is the development of in vitro tests evaluating pathogen-specific immune response, such as immunodiagnostics for CMV and, more recently, tests for monitoring immunity against BK virus. Conclusion: The increasing number of organ transplantations, the use of newer immunosuppressive drugs, and high-risk donors continue to define the landscape of transplant infectious diseases in the current era.

Neonatal hyperinsulinism/hyperammonemia syndrome / 中国小儿急救医学

Neonatal hyperinsulinism/hyperammonemia syndrome is a genetic disease result from glutamate dehydrogenase gene mutations.The clinical manifestations are hypoglycemia,hyperinsulinemia and mild hyperammonemia.Hypoglycemia may occur quickly due to eating protein.It is a rare neonatal disease that was easily ignored or delayed diagnosis and treatment causing serious sequelae of nervous system.This review summarized pathogenesis,clinical manifestation and diagnosis of the disease.