ABSTRACT
BACKGROUND: Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5, with its prevalence and SLC22A5 gene mutation spectrum varying across races and regions. This study aimed to systematically analyze the incidence of PCD in China and delineate regional differences in the prevalence of PCD and SLC22A5 gene variants. METHODS: PubMed, Embase, Web of Science, and Chinese databases were searched up to November 2023. Following quality assessment and data extraction, a meta-analysis was performed on screening results for PCD among Chinese newborns. RESULTS: After reviewing 1,889 articles, 22 studies involving 9,958,380 newborns and 476 PCD cases were included. Of the 476 patients with PCD, 469 underwent genetic diagnosis, revealing 890 variants of 934 alleles of SLC22A5, among which 107 different variants were detected. The meta-analysis showed that the prevalence of PCD in China was 0.05 [95%CI, (0.04, 0.06)] or 1/20 000 [95%CI, (1/16 667, 1/25 000)]. Subgroup analyses revealed a higher incidence in southern China [0.07, 95%CI, (0.05, 0.08)] than in northern China [0.02, 95%CI, (0.02, 0.03)] (P < 0.001). Furthermore, the result of the meta-analysis showed that the frequency of the variant with c.1400C > G, c.51C > G, c.760C > T, c.338G > A, and c.428C > T were 45% [95%CI, (34%, 59%)], 26% [95%CI, (22%, 31%)], 14% [95%CI, (10%, 20%)], 6% [95%CI, (4%, 8%)], and 5% [95%CI, (4%, 8%)], respectively. Among the subgroup analyses, the variant frequency of c.1400C > G in southern China [39%, 95%CI, (29%, 53%)] was significantly lower than that in northern China [79, 95%CI, (47, 135)] (P < 0.05). CONCLUSIONS: This study systematically analyzed PCD prevalence and identified common SLC22A5 gene variants in the Chinese population. The findings provide valuable epidemiological insights and guidance for future PCD screening effects in newborns.
Subject(s)
Carnitine , Hyperammonemia , Solute Carrier Family 22 Member 5 , Humans , China/epidemiology , Carnitine/deficiency , Infant, Newborn , Solute Carrier Family 22 Member 5/genetics , Hyperammonemia/genetics , Hyperammonemia/epidemiology , Hyperammonemia/diagnosis , Cardiomyopathies/genetics , Cardiomyopathies/epidemiology , Muscular Diseases/genetics , Muscular Diseases/epidemiology , Mutation/genetics , Neonatal Screening/methods , East Asian PeopleABSTRACT
PURPOSE OF REVIEW: Hyperammonemia syndrome is an increasingly recognized and often fatal condition that occurs in immunosuppressed individuals, most commonly lung transplant recipients. Growing evidence suggests hyperammonemia syndrome is associated with systemic infections caused by urease-producing organisms, namely Ureaplasma spp., an organism unable to grow with routine culturing techniques. This review will summarize the epidemiology and clinical manifestations of hyperammonemia syndrome, as well as diagnostic and management strategies once hyperammonemia syndrome is suspected. RECENT FINDINGS: Hyperammonemia syndrome is being described in increasing frequency in the solid organ transplant population. Morbidity and mortality, even with treatment, is high once hyperammonemia syndrome occurs. Surveillance studies indicate the prevalence of lung donor colonization with Ureaplasma spp. is high, suggesting screening and treatment may be of benefit. Antibiotic resistance is common, and rapid diagnostics can facilitate appropriate antimicrobial therapy in the peri-transplant period. SUMMARY: Hyperammonemia syndrome is most commonly seen in lung transplant recipients and has a high mortality rate once it occurs. Screening for Ureaplasma spp. should be considered in all lung transplant donors.
Subject(s)
Hyperammonemia , Ureaplasma Infections , Humans , Hyperammonemia/diagnosis , Hyperammonemia/epidemiology , Hyperammonemia/etiology , Immunocompromised Host , Syndrome , Transplant Recipients , Ureaplasma , Ureaplasma Infections/complications , Ureaplasma Infections/diagnosis , Ureaplasma Infections/drug therapyABSTRACT
In certain pediatric patients on valproic acid, therapeutic range (50-100 µg/mL) is maximized or exceeded to achieve better seizure control. This study compared incidence of common valproic acid adverse effects (thrombocytopenia, hepatotoxicity, and hyperammonemia) across maintenance concentration and age group. One hundred twenty-four children on maintenance valproic acid between January 2013 and January 2021 were eligible for inclusion. Fifty-six patients were maintained in concentration range 50 to 80â µg/mL, an additional 44 between 80 and 100â µg/mL and 24 between 100 and 120â µg/mL. Forty-one patients were prepubescent, 57 pubescent, and 26 postpubescent. There were no statistically significant differences observed in the primary endpoint of thrombocytopenia across serum concentration range (P = .093) or age group (P = .628). No significant differences in hepatic dysfunction (P = .099) or hyperammonemia (P = .548) were observed in serum concentration groups. Similarly, age group analysis observed no difference in hepatic dysfunction (P = .615) or hyperammonemia (P = .369). Serum valproic acid levels >100 µg/mL can be considered in select pediatric patients based on this study.
Subject(s)
Hyperammonemia , Thrombocytopenia , Anticonvulsants/adverse effects , Child , Humans , Hyperammonemia/chemically induced , Hyperammonemia/epidemiology , Incidence , Valproic Acid/adverse effectsABSTRACT
OBJECTIVES: To review ICU patients with elevated ammonia without a clear hepatic etiology, to compare outcomes between those who received lactulose and those who did not. DESIGN: Retrospective observational study. SETTING: Medical, surgical, and subspecialty intensive care units at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina between December 2012 and August 2016. PATIENTS: Adults with ammonia levels above 50 µmol/L, excluding those with known chronic liver disease, inborn error of metabolism, active use of valproic acid, total bilirubin ≥ 2 µmol/L, or alanine aminotransferase ≥ 100 units/L. INTERVENTIONS: Comparison in ICU length of stay (LOS), hospital LOS, in-hospital mortality, and mortality at 30 and 90 days. MEASUREMENTS AND MAIN RESULTS: Criteria for inclusion were met in 103 cases. Mean ammonia level was 75 µmol/L, with undetermined etiology in the majority of subjects. Lactulose was given in 48 cases (46.6%), with a median of 9.5 doses given. There were no significant differences in outcomes between the lactulose and non-lactulose groups. Among subjects with multiple data points, lactulose did not have a dose-dependent effect on ammonia level, and was not associated with faster ammonia normalization compared to non-lactulose. When analyzed separately, patients with moderate hyperammonemia (60-99 µmol/L) who received lactulose had longer hospital and ICU length of stay compared to non-lactulose (417.8 hours vs. 208.4 hours, P = 0.003, and 229.2 hours vs. 104.7 hours, P = 0.025; respectively), though confounders were present. CONCLUSIONS: Routine use of lactulose to treat mild to moderate hyperammonemia in this patient population was not associated with improved outcomes.
Subject(s)
Carcinoma, Hepatocellular , Hyperammonemia , Liver Neoplasms , Adult , Ammonia/metabolism , Ammonia/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Humans , Hyperammonemia/drug therapy , Hyperammonemia/epidemiology , Intensive Care Units , Lactulose/therapeutic use , Liver Neoplasms/drug therapyABSTRACT
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% (nâ =â 48) of patients had negative screening tests in donor and candidate pre-lung transplant, 8.3% (nâ =â 5) of recipients had positive Ureaplasma spp testing in urine pre-transplant, and 13.3% (nâ =â 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.
Subject(s)
Hyperammonemia , Ureaplasma Infections , Humans , Hyperammonemia/diagnosis , Hyperammonemia/epidemiology , Hyperammonemia/etiology , Lung , Transplant Recipients , Ureaplasma , Ureaplasma Infections/diagnosis , Ureaplasma Infections/drug therapy , Ureaplasma Infections/epidemiologyABSTRACT
BACKGROUND: Ammonia is a normal constituent of body fluids and is found mainly through the formation of urea in the liver. Blood levels of ammonia must remain low as even slightly elevated concentrations (hyperammonemia) are toxic to the central nervous system. AIM: To examine the relationship between the incidence of non-hepatic hype-rammonemia (NHH) and the prognosis of patients who were admitted to the intensive care unit (ICU). METHODS: This is a prospective, observational and single-center study. A total of 364 patients who were admitted to the ICU from November 2019 to February 2020 were initially enrolled. Changes in the levels of blood ammonia at the time of ICU admission and after ICU admission were continuously monitored. In addition, factors influencing the prognosis of NHH patients were analyzed. RESULTS: A total of 204 patients who met the inclusion criteria were enrolled in this study, including 155 NHH patients and 44 severe-NHH patients. The incidence of NHH and severe-NHH was 75.98% and 21.57%, respectively. Patients with severe-NHH exhibited longer length of ICU stay and higher Acute Physiologic Assessment and Chronic Health Evaluation and Sequential Organ Failure Assessment scores compared to those with mild-NHH and non-NHH. Glasgow Coma Scale scores of patients with severe-NHH were than those of non-NHH patients. In addition, the mean and initial levels of ammonia in the blood might be helpful in predicting the prognosis of NHH. CONCLUSION: High blood ammonia level is frequent among NHH patients admitted to the ICU, which is related to the clinical characteristics of patients. Furthermore, the level of blood ammonia may be helpful for prognosis prediction.
Subject(s)
Hyperammonemia , Humans , Hyperammonemia/diagnosis , Hyperammonemia/epidemiology , Incidence , Intensive Care Units , Prognosis , Prospective StudiesABSTRACT
OBJECTIVE: Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH. METHODS: This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction. RESULTS: In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 µmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 µmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed. CONCLUSIONS: Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients.
Subject(s)
Anticonvulsants/adverse effects , Hyperammonemia/chemically induced , Hyperammonemia/epidemiology , Neurosurgical Procedures/adverse effects , Valproic Acid/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Incidence , Male , Middle Aged , Prospective Studies , Risk Factors , Young AdultABSTRACT
Background Fatty acid ß-oxidation disorders (FAODs) include more than 15 distinct disorders and have a wide variety of symptoms, usually not evident between episodes of acute decompensation. After the introduction of newborn screening (NBS) using tandem mass spectrometry (MS/MS), early identification of FAODs has become feasible. We analyzed the MS/MS results in Tianjin, China during a six-year period to evaluate the incidence, disease spectrum, and genetic characteristics of FAODs. Methods We analyzed the MS/MS results for screening FAODs from May 2013 to December 2018 in Tianjin, China. Infants with positive screening results were confirmed through next-generation sequencing and validated by Sanger sequencing. Results A total of 220,443 infants were screened and 25 FAODs patients were identified (1:8,817). Primary carnitine deficiency (PCD) with an incidence rate up to 1:20,040 was the most common disorder among all FAODs. Recurrent mutations of relatively common diseases, like PCD and short-chain acyl-CoA dehydrogenase deficiency (SCADD), were identified. During the follow-up, two patients suffered from sudden death due to carnitine palmitoyl transferase-â ¡ deficiency (CPT â ¡) and very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD). Conclusion Our data indicated that FAODs are relatively common in Tianjin and may even cause infant death in certain cases. The elucidated disease spectrum and genetic backgrounds elucidated in this study may contribute to the treatment and prenatal genetic counseling of FAODs.
Subject(s)
Fatty Acids/metabolism , Lipid Metabolism Disorders/diagnosis , Lipid Metabolism Disorders/epidemiology , Lipid Metabolism Disorders/genetics , Cardiomyopathies/diagnosis , Cardiomyopathies/epidemiology , Cardiomyopathies/genetics , Carnitine/deficiency , Carnitine/genetics , Carnitine O-Palmitoyltransferase/deficiency , Carnitine O-Palmitoyltransferase/genetics , China/epidemiology , Congenital Bone Marrow Failure Syndromes/diagnosis , Congenital Bone Marrow Failure Syndromes/epidemiology , Congenital Bone Marrow Failure Syndromes/genetics , Female , Follow-Up Studies , Humans , Hyperammonemia/diagnosis , Hyperammonemia/epidemiology , Hyperammonemia/genetics , Infant, Newborn , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/epidemiology , Lipid Metabolism, Inborn Errors/genetics , Male , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/epidemiology , Metabolism, Inborn Errors/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/epidemiology , Mitochondrial Diseases/genetics , Muscular Diseases/diagnosis , Muscular Diseases/epidemiology , Muscular Diseases/genetics , Neonatal Screening/methods , Oxidation-Reduction , Tandem Mass SpectrometrySubject(s)
Genetic Testing/methods , Hyperammonemia/genetics , Ornithine/deficiency , Urea Cycle Disorders, Inborn/genetics , Genetic Testing/standards , Humans , Hyperammonemia/epidemiology , Hyperammonemia/pathology , Mitochondrial Membrane Transport Proteins/genetics , Mutation , Ornithine/genetics , Phenotype , Sensitivity and Specificity , Urea Cycle Disorders, Inborn/epidemiology , Urea Cycle Disorders, Inborn/pathologyABSTRACT
BACKGROUND: 5-Fluorouracil (5-FU)-induced hyperammonaemic encephalopathy is a rare but serious 5-FU adverse drug reaction (ADR). Given the growing number of cancers treated with 5-FU and the paucity of data regarding this ADR, we performed a retrospective national survey to better characterise 5-FU-induced hyperammonaemic encephalopathy. PATIENTS AND METHODS: Since inception of the French pharmacovigilance database, we identified all patients who experienced 5-FU-induced hyperammonaemic encephalopathy. Variables regarding demographics, characteristics, management and outcome of patients were collected. RESULTS: From 1986 to 2018, 30 patients were included. 5-FU-induced hyperammonaemic encephalopathy started 2 [1-4] days after 5-FU infusion onset. Most common neurological disorders were consciousness impairment, seizures and confusion. hyperammonaemia tended to be higher in patients with the lowest Glasgow score and admitted in intensive care unit (ICU) compared to non-ICU patients (250 [133-522] versus 139 [68-220] µmol/L respectively, p = NS). Dihydropyrimidine dehydrogenase deficiency was found in 27% of tested patients (n = 3/11). Encephalopathy-induced mortality was 17%, 57% of patients were admitted in ICU and 70% had a complete neurological recovery within 5 [2-10] days. A 5-FU rechallenge was considered in 14 (67%) patients with neurological recovery and a relapse was observed in 57% of them. No 5-FU-induced hyperammonaemic encephalopathy relapse was observed as long as 5-FU rechallenge was performed with decreased 5-FU dosage. CONCLUSION: We report the largest cohort of 5-FU-induced hyperammonaemic encephalopathy cases so far. This ADR should be suspected and ammonaemia measured in all patients experiencing neurological disorders after 5-FU administration. In patients with complete neurological recovery, a 5-FU rechallenge could be cautiously considered.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Brain Diseases/epidemiology , Fluorouracil/adverse effects , Hyperammonemia/epidemiology , Neoplasms/drug therapy , Aged , Ammonia/blood , Antimetabolites, Antineoplastic/administration & dosage , Brain Diseases/blood , Brain Diseases/chemically induced , Brain Diseases/therapy , Citric Acid Cycle/drug effects , Dose-Response Relationship, Drug , Female , Fluorouracil/administration & dosage , France/epidemiology , Humans , Hyperammonemia/blood , Hyperammonemia/chemically induced , Hyperammonemia/therapy , Incidence , Male , Middle Aged , Pharmacovigilance , Retrospective Studies , Treatment Outcome , Urea/metabolismABSTRACT
OBJECTIVE: To study the prevalence, clinical and genetic characteristics of primary carnitine deficiency (PCD). METHODS: From January 2013 to December 2017, 720 667 newborns and their mothers were tested for PCD by tandem mass spectrometry. Potential mutations of carnitine transporter gene SLC22A5 among suspected PCD patients were analyzed. Dietary guidance and L-carnitine supplementation were provided to the parents. Growth and intelligence development were surveyed during follow-up. RESULTS: In total 21 neonates and 6 mothers were diagnosed with PCD, which yielded an incidence of 1 in 34 317. Eighteen SLC22A5 mutations were detected, which included 4 novel mutations, namely c.1484T>C, c.394-1G>T, c.431T>C and c.265-266insGGCTCGCCACC. Eighteen patients were found to carry compound heterozygous mutations and 3 have carried homozygous SLC22A5 mutations. Three mothers carried compound heterozygous mutations and 2 carried homozygous mutations. Common mutations included c.1400C>G (42.3%), c.760C>T (11.5%) and c.51C>G (7.7%). During the 8-42 month follow-up, neonates with PCD showed no clinical symptoms but normal growth. Blood level of free carnitine was raised in all mothers after the treatment. CONCLUSION: The incidence of neonatal PCD in Henan is 1 in 34 317, with the most common mutation being c.1400C>G. Above finding has enriched the spectrum of SLC22A5 gene mutations.
Subject(s)
Cardiomyopathies/genetics , Carnitine/deficiency , Hyperammonemia/genetics , Muscular Diseases/genetics , Solute Carrier Family 22 Member 5/genetics , Cardiomyopathies/epidemiology , Carnitine/administration & dosage , Carnitine/genetics , China , Female , Humans , Hyperammonemia/epidemiology , Infant, Newborn , Muscular Diseases/epidemiology , Mutation , Neonatal ScreeningABSTRACT
BACKGROUND: The incidence, prevalence, and molecular epidemiology of urea cycle disorders (UCDs) in Argentina remain underexplored. The present study is the first to thoroughly assess the clinical and molecular profiles of UCD patients examined at a single reference center in Argentina. RESULTS: Forty-nine UCD cases were collected. About half (26/49, 53%) manifested neonatally with classical presentation and had a high mortality (25/26, 96%). Ornithine transcarbamylase deficiency (OTCD) was the most common UCD (26 patients). Argininosuccinate synthetase deficiency (ASSD) was detected in 19 cases, while argininosuccinate lyase deficiency (ASLD) was diagnosed in 4 cases. Molecular genetic analysis revealed 8 private OTC mutations and two large deletion/duplication events in the OTC gene. Most mutations in the ASS1 and ASL genes were recurrent missense changes, and four alterations were novel. The clinical outcome of our UCD cohort was poor, with an overall mortality of 57% (28/49 cases), and a 28% (6/21) disability rate among the survivors. CONCLUSIONS: Most patients in our case series showed severe neonatal onset, with high morbidity/mortality. We detected in total 19 mutations, most of them recurrent and of high frequency worldwide. Noteworthy, we highlight the presence of a geographic cluster with high prevalence of a point mutation in the ASS1 gene. This study suggests that these disorders may be more frequent than commonly assumed, and stresses the need for increased awareness amongst health professionals and greater availability of diagnostic tools for accurate identification, early diagnosis, and timely treatment.
Subject(s)
Urea Cycle Disorders, Inborn/epidemiology , Urea Cycle Disorders, Inborn/genetics , Urea Cycle Disorders, Inborn/pathology , Argentina/epidemiology , Argininosuccinic Aciduria/epidemiology , Argininosuccinic Aciduria/genetics , Argininosuccinic Aciduria/pathology , Child , Child, Preschool , Citrullinemia/epidemiology , Citrullinemia/genetics , Citrullinemia/pathology , Female , Humans , Hyperammonemia/epidemiology , Hyperammonemia/genetics , Hyperammonemia/pathology , Infant , Infant, Newborn , Male , Mutation/genetics , Ornithine Carbamoyltransferase Deficiency Disease/epidemiology , Ornithine Carbamoyltransferase Deficiency Disease/genetics , Ornithine Carbamoyltransferase Deficiency Disease/pathologyABSTRACT
OBJECTIVE: Valproic acid (VPA)-induced hyperammonemia (VIH), is an increase in blood ammonia levels without any alteration of hepatic enzymes, which can occur during VPA treatment. We aimed to determine the prevalence rate and the risk factors for VIH and its association with cognitive functions. METHOD: A prospective, cross-sectional study was conducted. Patients aged between 18 and 64 who were on VPA treatment and who diagnosed with mood disorders or epilepsy were enrolled in this study (nâ¯=â¯107). For cognitive assessment, Serial 7's and Subjective Memory Complaints Questionnaire (SMCQ) were used. Blood samples were collected for blood VPA and ammonia levels along with other laboratory tests. RESULTS: 55,3% of the sample were considered as VIH. Blood ammonia level significantly correlates with VPA blood levels, total daily dose of VPA and total number of medications concurrently used, but no significant correlation was found between blood ammonia level and cognitive test scores. Gender, body weight, blood VPA levels and the total number of medications concurrently used significantly predicted blood ammonia levels (F(4,81)â¯=â¯2670, pâ¯=â¯0,038, R2â¯=â¯0,116). CONCLUSION: VIH is relatively high in our sample. There is a dose-dependent association between VPA and blood ammonia level. No association was found between cognitive functions and hyperammonemia however with some limitations. Future, prospective cohort studies are needed.
Subject(s)
Central Nervous System Agents/adverse effects , Cognitive Dysfunction , Epilepsy , Hyperammonemia , Mood Disorders , Valproic Acid/adverse effects , Adolescent , Adult , Central Nervous System Agents/blood , Cognitive Dysfunction/blood , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/epidemiology , Cross-Sectional Studies , Epilepsy/drug therapy , Epilepsy/epidemiology , Female , Humans , Hyperammonemia/blood , Hyperammonemia/chemically induced , Hyperammonemia/epidemiology , Male , Middle Aged , Mood Disorders/drug therapy , Mood Disorders/epidemiology , Prevalence , Risk Factors , Valproic Acid/blood , Young AdultABSTRACT
Urea cycle disorders (UCD) are a group of rare inherited metabolic conditions of amino acid catabolism caused by an enzyme deficiency within the hepatic ammonia detoxification pathway. The presentation of these disorders ranges from life-threatening intoxication in the neonate to asymptomatic status in adults. Late-onset UCDs can present for the first time in adulthood and may mimic other causes of acute confusion or psychiatric diseases, and are often associated with neurological symptoms. Late-onset UCDs may become apparent during periods of metabolic stress such as rapid weight loss, gastric bypass surgery, chronic starvation or the postpartum period. Early diagnosis is critical for effective treatment and to prevent long-term complications of hyperammonemia. The challenges of management of adults include for example: (a) poor compliance to dietary and medical treatment which can result in recurrent hospital admissions; (b) severe neurological dysfunction; (c) the management of pregnancy and the postpartum period; and (d) access to multidisciplinary care peri-operatively. In this review, we highlight a number of challenges in the diagnosis and management of adult patient with late-onset UCDs and suggest a systematic management approach.
Subject(s)
Urea Cycle Disorders, Inborn/diagnosis , Urea Cycle Disorders, Inborn/therapy , Adult , Age Factors , Age of Onset , Diagnosis, Differential , Female , Humans , Hyperammonemia/diagnosis , Hyperammonemia/epidemiology , Hyperammonemia/etiology , Hyperammonemia/therapy , Infant, Newborn , Male , Neurocognitive Disorders/diagnosis , Neurocognitive Disorders/epidemiology , Neurocognitive Disorders/etiology , Neurocognitive Disorders/therapy , Ornithine Carbamoyltransferase Deficiency Disease/complications , Ornithine Carbamoyltransferase Deficiency Disease/diagnosis , Ornithine Carbamoyltransferase Deficiency Disease/epidemiology , Ornithine Carbamoyltransferase Deficiency Disease/therapy , Pregnancy , Puerperal Disorders/diagnosis , Puerperal Disorders/epidemiology , Puerperal Disorders/etiology , Puerperal Disorders/therapy , Treatment Outcome , Urea Cycle Disorders, Inborn/complications , Urea Cycle Disorders, Inborn/epidemiologyABSTRACT
In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.
Subject(s)
Practice Guidelines as Topic , Urea Cycle Disorders, Inborn/diagnosis , Urea Cycle Disorders, Inborn/therapy , Adult , Age of Onset , Child , Consensus , Endocrinology/organization & administration , Endocrinology/standards , Europe/epidemiology , Humans , Hyperammonemia/diagnosis , Hyperammonemia/epidemiology , Hyperammonemia/therapy , Infant, Newborn , Neonatal Screening/methods , Neonatal Screening/standards , Pediatrics/organization & administration , Pediatrics/standards , Practice Guidelines as Topic/standards , Urea Cycle Disorders, Inborn/epidemiologyABSTRACT
Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diet therapy , Amino Acids/administration & dosage , Dietary Supplements , Propionic Acidemia/diet therapy , Urea Cycle Disorders, Inborn/diet therapy , Adolescent , Adult , Amino Acid Metabolism, Inborn Errors/epidemiology , Child , Child, Preschool , Cross-Sectional Studies , Europe/epidemiology , Feasibility Studies , Female , Humans , Hyperammonemia/diet therapy , Hyperammonemia/epidemiology , Infant , Male , Ornithine/deficiency , Propionic Acidemia/epidemiology , Registries , Retrospective Studies , Treatment Outcome , Urea Cycle Disorders, Inborn/epidemiology , Young AdultABSTRACT
OBJECTIVES: To evaluate the epidemiology of hyperammonemia unrelated to liver failure in the critical care setting. DESIGN: Retrospective case series. SETTING: Critically ill patients admitted to ICUs at Mayo Clinic, Rochester, MN (medical ICU, two mixed medical-surgical ICUs, coronary care unit, or the cardiosurgical ICU) between July 1, 2004, and October 31, 2015. PATIENTS: Adult critically ill patients with hyperammonemia not related to acute or chronic liver failure. We excluded patients with diagnosis of moderate or severe liver disease, hyperbilirubinemia, and patients who denied the use of their medical records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 3,908 ICU patients with hyperammonemia, 167 (4.5%) had no evidence of acute or chronic liver failure. One-hundred one patients (60.5%) were male with median age of 65.7 years (interquartile range, 50-74.5 yr) and median serum ammonia level of 68 µg/dL (interquartile range, 58-87 µg/dL). Acute encephalopathy was present in 119 patients (71%). Predisposing conditions included malnutrition 27 (16%), gastric bypass six (3.6%), total parenteral nutrition four (2.4%); exposure to valproic acid 17 (10%); status epilepticus 11 (6.6%), high tumour burden 19 (11.3%), and renal failure 82 (49.1%). Urea cycle defects were diagnosed in seven patients (4.1%). Hospital mortality was high (30%), and median ammonia level was higher among the nonsurvivors (74 vs 67 µg/dL; p = 0.05). Deaths were more likely in hyperammonemic patients who were older (p = 0.016), had greater illness severity (higher Acute Physiology and Chronic Health Evaluation III score, p < 0.01), malignancy (p < 0.01), and solid organ transplantation (p = 0.04), whereas seizure disorder was more common in survivors (p = 0.02). After adjustment, serum ammonia level was not associated with increased mortality. CONCLUSIONS: Hyperammonemia occurs in a substantial minority of critically ill patients without liver failure. These patients have a poor prognosis, although ammonia level per se is not independently associated with mortality. Serum ammonia should be measured when risk factors are present, such as nutritional deficiencies and protein refeeding, treatment with valproic acid, high tumour burden, and known or suspected urea cycle abnormalities.
Subject(s)
Hyperammonemia/epidemiology , Adult , Aged , Cohort Studies , Female , Humans , Intensive Care Units , Liver Failure , Male , Middle Aged , Retrospective StudiesABSTRACT
Erwinia chrysanthemi-derived asparaginase is increasingly integral to acute lymphoblastic leukemia therapy. In our series, 16% of patients developed symptomatic hyperammonemia following Erwinia administration with symptoms including refractory nausea, vomiting, profound fatigue, malaise, and coma. This series of patients receiving Erwinia indicates higher than expected incidence of hyperammonemia, correlation between ammonia and asparaginase levels and therapeutic asparaginase activity levels despite dose reduction. The series provides evidence for investigation into which patients require intervention to prevent toxicity, which patients may have ammonia levels used as an asparaginase activity surrogate and which patients may achieve equivalent efficacy with abridged dosing.
Subject(s)
Asparaginase/adverse effects , Bacterial Proteins/adverse effects , Dickeya chrysanthemi/enzymology , Hyperammonemia , Leukemia , Adolescent , Adult , Asparaginase/administration & dosage , Bacterial Proteins/administration & dosage , Child , Child, Preschool , Female , Humans , Hyperammonemia/chemically induced , Hyperammonemia/epidemiology , Leukemia/drug therapy , Leukemia/epidemiology , Male , Retrospective StudiesABSTRACT
INTRODUCTION: The hyperammonemic encephalopathy induced by causes different from inborn errors of metabolism is a relatively uncommon but severe complication. OBJETIVES: To study the characteristics of a secondary hyperammonemia episode to discern the triggering causes to get to the diagnosis, and the development in the therapeutic intervention. METHODS: A multicenter retrospective study of children with hyperammonemia unrelated to inborn errors of metabolism, conducted in Spanish hospitals. RESULTS: Nineteen patients were selected; hyperammonemia developed in infants under one year old in 47% of them, being diagnosed mostly with two or more symptoms. The most common clinical finding was an altered consciousness level similar to that of intoxication symptoms, followed by seizures. These clinical symptoms were present in 14 patients, with one of them or both. Twelve of the 19 patients were in treatment with more than two antiepileptic drugs routinely. All children were treated with protein restriction (n: 10), scavengers (n: 10) and/or carglumic acid (n: 12) for the treatment of hyperammonemia. CONCLUSIONS: This study suggests that secondary hyperammonemia could be underdiagnosed because it is only detected when severe symptoms appear. Risk seems to be higher in those patients receiving antiepileptic drugs or those critically ill with a restricted diet or incremented metabolism. The response to specific treatment is adequate but should be established earlier to avoid neurological sequelae of this entity.
INTRODUCCIÓN: la encefalopatía hiperamoniémica inducida por causas diferentes a los errores innatos del metabolismo es una complicación relativamente infrecuente, pero muy grave. OBJETIVOS: conocer las características de un episodio de hiperamoniemia secundaria, tratar de discernir las causas desencadenantes, cómo se llega al diagnóstico del episodio y cómo se desarrolla la actuación terapéutica. MÉTODOS: es un estudio multicéntrico retrospectivo de casos pediátricos con hiperamoniemia no relacionada con errores innatos del metabolismo, llevado a cabo en hospitales españoles. RESULTADOS: fueron seleccionados 19 pacientes y en un 47% el episodio de hiperamoniemia apareció en menores de un año, que fueron diagnosticados mayoritariamente con dos o más síntomas. La clínica más frecuente fue la de alteración del nivel de conciencia tipo intoxicación, seguida de las crisis convulsivas, sumando en ambas hasta 14 pacientes con alguna de ellas o las dos. Doce de los 19 pacientes utilizaban más de dos fármacos antiepilépticos de forma habitual. Todos los niños recibieron tratamiento con restricción proteica (n: 10), quelantes (n: 10) y/o ácido carglúmico (n: 12) para el tratamiento de la hiperamoniemia. CONCLUSIONES: este estudio sugiere que la hiperamoniemia secundaria puede estar infradiagnosticada y solo se detecta cuando aparece una sintomatología grave. Parecen ser pacientes de riesgo aquellos que reciben fármacos antiepilépticos o aquellos críticos con una alimentación restringida o un metabolismo elevado. La respuesta con tratamiento específico es adecuada pero debe ser precoz para evitar las secuelas neurológicas de esta entidad.
Subject(s)
Hyperammonemia/etiology , Metabolism, Inborn Errors/complications , Amino Acid Metabolism, Inborn Errors/complications , Anticonvulsants/adverse effects , Brain Diseases/etiology , Child , Child, Preschool , Female , Humans , Hyperammonemia/epidemiology , Hyperammonemia/therapy , Infant , Male , Metabolism, Inborn Errors/epidemiology , Retrospective Studies , Spain/epidemiologyABSTRACT
OBJECTIVE: To screen fatty acid oxidation disorders (FAOD) in newborns in Zhejiang province. METHODS: A total of 1 861 262 newborns were screened for FAOD in Neonatal Screening Center of Zhejiang Province during January 2009 and December 2016. The blood samples from newborns were screened by tandem mass spectrometry, and diagnosis of FAOD was confirmed by urine organic acid measurement combined with genetic analysis. The prognosis and follow-up of patients with FAOD were also evaluated. RESULTS: Of 1 861 262 newborns screened, 121 cases of FAOD were diagnosed. Among 121 cases of FAOD, primary carnitine deficiency (PCD) was the most common type (n=78, 64.5%), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD, n=27, 22.3%), medium-chain acyl-CoA dehydrogenase deficiency (n=5, 4.1%), multiple acyl-CoA dehydrogenase deficiency (MADD, n=4, 3.3%), very long-chain acyl-CoA dehydrogenase deficiency (n=3, 2.5%), carnitine palmitoyltransferase â deficiency(n=2, 1.7%)and carnitine palmitoyltransferase â ¡ deficiency (CPTâ ¡D, n=2, 1.7%). During 2-82 month follow-up, 15 patients were lost, 4 were dead (1 PCD, 1 MADD, and 2 CPTâ ¡D), and the remaining 102 subjects had normal intelligence and physical development without any clinical symptoms. CONCLUSIONS: PCD and SCADD are the most common FAODs in newborns in Zhejiang province. Most of FAOD patients are asymptomatic, and have normal growth and development after early intervention and management.