Hyperammonemic Encephalopathy Research Articles

A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency

AbstractCarbonic anhydrase VA (CA‐VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in CA5A. Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA‐VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A. The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features. Two adult patients were asymptomatic, 7/18 patients had recurrent hyperammonemia, 7/18 patients developed variable degree of developmental delay, 9/11 patients had hyperCKemia, and 7/18 patients had failure to thrive. Microcephaly was seen in three patients and one patient developed a metabolic stroke. The same variant had been reported already in a single South Asian patient presenting with neonatal hyperammonemic encephalopathy and subsequent development of seizures and developmental delay. This report highlights the limitations of current understanding of the pathomechanisms involved in this disorder, and calls for further evaluation of the possible role of genetic modifiers in this condition.

Cortical Reflex Myoclonus in a Patient with Hyperammonemic Encephalopathy

Cortical Reflex Myoclonus in a Patient with Hyperammonemic Encephalopathy

Hyperammonemic Encephalopathy Caused by the c.386+5G>A Mutation in <i>OTC</i> Gene in a Young Adult Woman

Noncirrhotic hyperammonemia as a cause of acute confusion remains diagnostic challenge. Deficiency of ornithine transcarbamylase (OTC) is the urea cycle disorder, inborn errors caused by a defect of the enzymes in the urea cycle, leading to an accumulation of ammonia mainly in newborn. There were very few cases, in which OTC deficiency result in hyperammonemia in adulthood. Herein, we report a young adult woman of hyperammonemic encephalopathy with OTC deficiency, diagnosed by high blood ammonia, glutamine and low plasma levels of citrulline. Next generation sequencing showed the c.386+5G>A mutation of the <i>OTC</i> gene.

Non-cirrhotic Hyperammonemic Encephalopathy with Portosystemic Shunt

Hyperammonemic encephalopathy commonly occur in patients with liver disease, but it can also occur due to other causes. A portosystemic shunt without liver cirrhosis is one of the causes of non-cirrhotic hyperammonemic encephalopathy. Herein, we present a case of a 78-year-old male patient with hyperammonemic encephalopathy resulting from portosystemic shunts without liver cirrhosis, which was successfully treated with endovascular shunt closure.

Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example.

To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.

Valproate induced hyperammonemic encephalopathy: a rare adverse effect of a common drug

Introduction. Sodium valproate or Valproic acid (VPA) is routinely used in management of epilepsy in neurology practice. It is a well-tolerated drug with mild side effects. Valproate induced encephalopathy (VPE) is a rare but serious adverse effect of this commonly used drug. Presentation of the case. We present a case of a 42-year-old female with valproate-induced encephalopathy. She had history of development of subacute onset of Parkinsonism followed by decreased sensorium after initiation of sodium valproate. On examination, she had tremor of both upper limbs and asterixis. Her serum ammonia was raised and valproate level was mildly raised. There was improvement in her symptoms after stoppage of valproate. Conclusion. We report a case of reversible Valproate induced encephalopathy (VPE) managed by stopping the offending drug. Clinical suspicion for VPE should be considered in any patients developing new neurological symptoms while on sodium valproate.

Hyperammonemic Encephalopathy in Multiple Myeloma: Systematic Review and Case Series

Objectives: To better understand the presentation and clinical outcomes of hyperammonemic encephalopathy in multiple myeloma, we report 3 cases from our institution and present 55 published cases from the literature. Background/Intro: Hyperammonemia is a rare but life-threatening complication of multiple myeloma with poor survival despite treatment. Little is known about the clinical presentation and outcomes of patients suffering from this entity. We hereby report a systematic review and a meta-analysis of cases with hyperammonemic encephalopathy. Methods: Case reports and case series were identified using the Medline database, as well as PubMed search engine. Clinical and pathological data were collected and stratified by demographics and treatment. The data was further analyzed using SPSS. Results: A total of 58 patients were included in the study. The mean age of the affected patients was 64.4 years, male to female ratio was 1.15:1. The median ammonia level measured was 123 μmol/L. Stage III disease was most prevalent in reported cases (89%). Most common MM subtype was IgG (38%) followed by IgA (36%). Thirty-seven patients (64%) had relapsed disease, while 17 (29%) were new diagnoses. Overall, 35 out of 58 (60%) patients died while being treated as inpatients. Chemotherapy was the only variable associated with an improved survival with p-0.02. Conclusion: Hyperammonemia in the setting of multiple myeloma is an uncommon complication. It is associated with poor prognosis. Treatment should begin as soon as the diagnosis is confirmed with myeloma directed therapy in order to improve survival.

Ureaplasma-Induced Hyperammonemia Syndrome - an Acute Complication Post Allogeneic Stem Cell Transplant

Hyperammonemia syndrome is characterized by elevated serum ammonia levels and neurological dysfunction due to cerebral encephalopathy, andcauses lethargy, confusion, hyperventilation, seizures, death. In solid organ transplantation, hyperammonemia syndrome has been reported as a potentially fatal complication secondary to Ureaplasma infection ( Ureaplasma urealyticum or parvum). We present a patient with acute lymphoblastic leukemia (ALL) who underwent allogeneic stem cell transplant (HSCT) and developed hyperammonemia syndrome during systemic infection with Ureaplasma urealyticum. A 32-year-old female with B-ALL received a haploidentical HSCT complicated by stage II acute GvHD of the gut and skin. During her hospital course, on Day +43, cellulitis of the right arm was diagnosed and treated empirically with amoxicillin-clavulanate on discharge. She presented back to the hospital on Day +53 with bilateral elbow pain and cellulitis. She had no focal neurological deficits initially but became increasing drowsy with dilated pupils. She had no episodes of sustained fever throughout her hospitalization. Empiric antimicrobial coverage with Meropenem and Vancomycin was given, and she was intubated and admitted to the ICU all on the same day. CT head was normal, and blood cultures and lumbar puncture were negative. She developed status epilepticus and her ammonia level increased to >1500 μmol/L on Day +57. Liver function, renal function and extended electrolytes remained within normal limits. MRI was consistent with hyperammonemic encephalopathy, prompting initiation of intermittent hemodialysis, lactulose, Rifaximin, and L-carnitine. EEG revealed no discernible rhythms, and intensive life support was discontinued on Day +61. PCR testing of preserved lung tissue confirmed Ureaplasma urealyticum as the likely cause. Ureaplasma infections can be a serious complication of HSCT. The hydrolysis of urea by Ureaplasma leads to elevated serum ammonia levels when systemic infections occur in immunocompromised patients. HSCT patients often have hypogammaglobulinemia due to conditioning and immunosuppressive therapies with a reduced ability to neutralize Ureaplasma. The role of neutrophil in controlling Ureaplasma is limited, as antibody-mediated defence is the sole mechanism of protection. Other contributing factors that can exacerbate hyperammonemia include Valproic acid, severe liver disease, and TPN. Ureaplasma is challenging to diagnose due to limited growth on standard culture medium PCR testing is required for diagnosis and was the method of detection in our reported case. Numerous cases in non-HSCT immunocompromised populations have reported soft tissue infections involving Ureaplasma species, indicating a possible source for infection in the current case. Although there are no other reported cases of cellulitis and Ureaplasma infection in HSCT, a previous case with polyarthritic involvement may be mechanistically similar. A literature review was completed with results presented in Table 1 outlining details of reported cases with confirmed Ureaplasma infection post-HSCT. The cases were quite heterogenous although two of the cases were treated for Non-Hodgkin's Lymphoma where they were heavily pretreated with agents targeting B-Cells and immunoglobulin production. Empirical doxycycline should be considered first line due to the Ureaplasma resistance to other agents such as Azathioprine. Beta-lactam antibiotics and vancomycin have limited efficacy as Ureaplasma's does not have a cell wall. Adjunct therapies to reduce ammonia production and increase elimination should also be considered. Ureaplasma should be considered in immunocompromised patients in the context of fever of unknown origin and altered level of consciousness, especially if rising serum ammonia levels and soft tissue infections is present. The overall 50% mortality associated with the six cases presented demonstrates the significant risk associated with the infection.

Monocrotophos-Induced Intermediate Syndrome Complicated by Hyperammonemic Encephalopathy: A Case Report

Monocrotophos-Induced Intermediate Syndrome Complicated by Hyperammonemic Encephalopathy: A Case Report

Sunitinib-induced hyperammonemic encephalopathy in metastatic gastrointestinal stromal tumors: A case report

Type 2 diabetes mellitus (T2DM), which is distinguished by increased glucose levels in the bloodstream, is a metabolic disease with a rapidly increasing incidence worldwide. Nevertheless, the etiology and characteristics of the mechanism of T2DM remain unclear. Recently, abundant evidence has indicated that the intestinal microbiota is crucially involved in the initiation and progression of T2DM. The gut microbiome, the largest microecosystem, engages in material and energy metabolism in the human body. In this review, we concentrated on the correlation between the gut flora and T2DM. Meanwhile, we summarized the pathogenesis involving the intestinal flora in T2DM, as well as therapeutic approaches aimed at modulating the gut microbiota for the management of T2DM. Through the analysis presented here, we draw attention to further exploration of these research directions.

Histopathological examination of characteristic brain MRI findings in acute hyperammonemic encephalopathy: A case report and review of the literature.

Acute hyperammonemic encephalopathy is associated with distinct brain MRI findings, namely, hyperintensity in T2-weighted sequences as well as restricted diffusion in diffusion-weighted imaging with accentuation in the insular cortex and cingulate gyrus. The pathophysiology and the histopathological correlates of these characteristic MRI findings are largely unknown. We present a 57-year-old male with a history of chronic alcohol abuse, liver cirrhosis and portal hypertension, and a clinical syndrome (variceal bleeding, depression of consciousness, seizures), elevated plasma ammonia levels, and characteristic brain MRI abnormalities suggestive of acute hyperammonemic encephalopathy. A postmortem histopathological examination revealed extensive hypoxic ischemic encephalopathy without evidence for metabolic encephalopathy. No episodes of prolonged cerebral hypoxemia were documented throughout the course of the disease. We conducted a review of the literature, which exhibited no reports of hyperammonemic encephalopathy in association with characteristic brain MRI findings and a consecutive histopathological examination. This is the first report of a patient with acute hyperammonemic encephalopathy together with characteristic brain MRI findings and a histopathological correlation. Although characteristic MRI findings of acute hyperammonemic encephalopathy were present, a histopathological examination revealed only hypoxic pathology without signs of metabolic encephalopathy.

A Novel Variant of ASL Gene Mutation in a Lebanese Neonate with Severe Argininosuccinic Aciduria Phenotype

Argininosuccinic aciduria is a urea cycle defect associated with deficiency in argininosuccinate lyase enzyme, leading to a severe hyperammonemic encephalopathy, epilepsy and hepatopathy. Only very few known mutations have been linked with a severe phenotype. Here we report the case of a Lebanese newborn child with a very early manifestation of argininosuccinic aciduria, his genetic studies confirmed the presence of a mutation in the ASL gene (c.697A>C p. (Thr233Pro) at the homozygous state. To our knowledge, this is the first time this variant has been reported in literature.

“Brain on Fire”: Hyperperfusion as a Hallmark of Hyperammonemic Encephalopathy

AbstractWe describe a very rare case of acute fulminant hepatic failure as a complication of acute viral hepatitis caused by hepatitis A virus, complicated by hyperammonemic encephalopathy. The brain magnetic resonance imaging (MRI) findings were suggestive of cytotoxic edema involving bilateral cerebral hemispheres. The novel findings of hyperperfusion on arterial spin labeling perfusion MRI and hyperemic hypoxia on susceptibility weighted imaging are discussed. The patient had a rapid progression of cerebral edema and succumbed to the illness despite supportive care. Characteristic neuroimaging findings may help in the diagnosis of acute hyperammonemic encephalopathy of brain MRI, which may be useful in leading to appropriate clinical workup and diagnosis of the underlying cause of hyperammonemia. In our case, hyperammonemic encephalopathy was precipitated by fulminant hepatic failure caused by hepatitis A virus, which is a rare occurrence.

S3737 Non-Hepatic Hyperammonemic Encephalopathy: An Unmasked Urea Cycle Disorder in the Setting of Late Gastric Bypass Complication

S3737 Non-Hepatic Hyperammonemic Encephalopathy: An Unmasked Urea Cycle Disorder in the Setting of Late Gastric Bypass Complication

S3658 Hyperammonemia Encephalopathy Due to Urea Cycle Disorder Precipitated by Gastrointestinal Bleed in the Setting of Prior Bariatric Surgery

S3658 Hyperammonemia Encephalopathy Due to Urea Cycle Disorder Precipitated by Gastrointestinal Bleed in the Setting of Prior Bariatric Surgery

Use of sodium D, L-3-hydroxybutyrate as adjunct therapy in two siblings with HMG-CoA lyase deficiency

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is a rare autosomal recessive mitochondrial disease characterised by recurrent life-threatening metabolic crises generally presenting in neonates or infancy during catabolic stress triggered by prolonged fasting or intercurrent illness. Acute decompensations with lethargy, vomiting, hypoketotic hypoglycemia and metabolic acidosis may evolve into Reye-like syndrome if untreated, with acute liver failure, hyperammonemic encephalopathy, dilated cardiomyopathy, and death in 20% of cases. Long-term health complications include psychomotor retardation, white matter abnormalities, epilepsy, hepatic steatosis, pancreatitis, cardiomyopathy, and arrythmia. The mitochondrial enzyme catalyses the cleavage of HMG-CoA to acetyl-CoA and acetoacetate, the common final step of ketogenesis and leucine degradation, resulting in diagnostic urinary organic acid pattern (elevated 3-hydroxy-3-methylglutaric, 3-methylgutaconic, 3-methylglutaric, and 3-hydroxyisovaleric acids) with the absence of ketonuria, when deficient. Therapeutic interventions include dietary protein or leucine and fat restriction, carnitine supplementation, avoidance of fasting, and use of carbohydrate-based high caloric intake when unwell. We describe the clinical course and diagnostic work-up in two affected siblings, with the proband presenting with severe neonatal onset disease with metabolic acidosis, non-ketotic hypoglycaemia, hyperammonemia and white matter changes on brain MRI. High-risk screening for a younger sibling led to pre-emptive management with good outcomes. Sodium D, L-3-hydroxybutyrate (S-DL-3OHB) was used in both siblings as an adjunct therapy to prevent cerebral dysfunction and cardiomyopathy, with the rationale that decreased ketogenesis in this disorder may impact the major energy source for the brain and heart during starvation. S-DL-3OHB therapy is a well-tolerated and effective therapeutic option for this disorder.

Risk factors of hyperammonemia in epilepsy patients with valproic acid therapy

BackgroundHyperammonemia can occur after acute overdose or chronic use of valproic acid (VPA). Although VPA-related hyperammonemic encephalopathy (VHE) is a rare complication of VPA therapy, early recognition of VHE and identifying its risk factors are important because VHE can lead to loss of consciousness and increased seizure frequency. PurposeThe purpose of our study is to evaluate the risk factors of hyperammonemia in epilepsy patients during treatment with VPA therapy. MethodsWe reviewed the medical records of 1084 adult patients with epilepsy and enrolled 116 patients with VPA therapy who had results of blood levels of ammonia over a 3-year period. Hyperammonemia was defined as a blood ammonia level exceeding 80 µg/dL. Correlations of blood levels of ammonia with dosages and blood levels of VPA were evaluated. We further performed univariate and multivariate linear regression analyses to identify risk factors for hyperammonemia in epilepsy patients treated with VPA therapy. ResultsBlood levels of ammonia were well correlated with dosages of VPA (p = 0.036), but not with blood levels of VPA (p = 0.463). Hyperammonemia was more common in patients with higher VPA dosage and higher total drug loads of concurrent antiseizure medications (ASMs). Hyperammonemia was also associated with the use of topiramate and phenobarbital. In multivariate analysis, we identified total drug load of ASMs (p = 0.003) and use of topiramate (p = 0.007) as independent predictors of hyperammonemia. Four patients (4/116, 3.4 %) had clinical symptoms of VHE. Three of them had hyperammonemia while the other patient had normal blood level of ammonia with a high blood level of VPA. ConclusionOur study shows that higher total drug loads of concurrent ASMs and use of topiramate were independent risk factors of hyperammonemia in epilepsy patients with VPA therapy. Although the incidence of VHE was not high in our study, clinicians should be aware of this potential adverse effect of VPA therapy, especially in patients with polytherapy of ASMs including topiramate.

Valproate‐associated hyperammonemic encephalopathy

Valproate is frequently used to manage neuropsychiatric disorders, including epilepsy, mania, and migraine. One of the side effects associated with its use is idiosyncratic hyperammonemia in the setting of normal levels of liver enzymes, including aspartate aminotransferase, alanine aminotransferase, and bilirubin (Adler et al., 2015). The literature on valproate‐associated hyperammonemia, including the development of encephalopathy, has been primarily based on case reports, and the precise incidence is not known.

A case with hyperammonemic encephalopathy triggered by urinary tract infection with urease-producing bacteria

A case with hyperammonemic encephalopathy triggered by urinary tract infection with urease-producing bacteria

Hyperammonemia Secondary to 5-Fluorouracil.

5-fluorouracil (5-FU) is one of the most common adjuvant antineoplastic agents used in the treatment of localized and metastatic colon cancer. Frequent side effects of 5-FU include myelosuppression, mucositis, nausea, vomiting, and diarrhea. However, hyperammonemic encephalopathy is a rare neurologic toxicity that can occur after 5-FU chemotherapy administration. Patients with 5-FU-induced hyperammonemic encephalopathy often exhibit symptoms of altered mental status with no radiologic abnormalities or laboratory abnormalities except for significantly elevated ammonia levels with occasional lactic acidosis and respiratory alkalosis. We report a case of a patient with stage IV colon adenocarcinoma who experienced altered state of consciousness due to hyperammonemia during the administration of palliative chemotherapy with 5-FU, bevacizumab, and leucovorin. On cycle 1 day 2 of chemotherapy, the patient became drowsy and confused at home, prompting a visit to the emergency department and ultimately hospital admission. Laboratory tests revealed an elevated blood ammonia level (838 μg/dL). After an extensive negative workup, his altered state of consciousness was thought to be secondary to 5-FU-induced hyperammonemia. Upon admission, 5-FU was immediately discontinued and the patient was treated with lactulose enemas, intravenous fluids, rifaximin, and continuous renal replacement therapy with gradual recovery to baseline mental status. It is crucial for advanced practitioners to be aware of this rare side effect to ensure prompt diagnosis and maximize treatment effectiveness.