Irreversible brain creatine deficiency with elevated serum and urine creatine: A creatine transporter defect?

Procainamide is a useful agent for management of ventricular arrhythmia, however its disposition and appropriate dosing during extracorporeal membrane oxygenation (ECMO) is unknown. We report experience with continuous procainamide infusion in a critically ill adult requiring venoarterial ECMO for incessant ventricular tachycardia. Pharmacokinetic analysis of procainamide and its metabolite, N-acetylprocainamide (NAPA), was performed using serum and urine specimens. Kidney function was preserved, and sequencing of the N-acetyltransferase 2 gene revealed the patient was a phenotypic slow acetylator. Procainamide volume of distribution and half-life were calculated and found to be similar to healthy individuals. However, despite elevated serum procainamide concentrations, NAPA concentrations remained far lower in the serum and urine. The magnitude of procainamide and NAPA discordance suggested alternative contributors to the deranged pharmacokinetic profile, and we hypothesized NAPA sequestration by the ECMO circuit. Ultimately, the patient received orthotopic cardiac transplantation and was discharged home in stable condition. Procainamide should be used cautiously during ECMO, with close therapeutic drug monitoring of serum procainamide and NAPA concentrations. The achievement of therapeutic NAPA concentrations while maintaining safe serum procainamide concentrations during ECMO support may be challenging.

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A novel mouse model of creatine transporter deficiency

F1000Research ◽

10.12688/f1000research.5369.2 ◽

2015 ◽

Vol 3 ◽

pp. 228

Author(s):

Laura Baroncelli ◽

Maria Grazia Alessandrì ◽

Jonida Tola ◽

Elena Putignano ◽

Martina Migliore ◽

...

Keyword(s):

Mouse Model ◽

Murine Model ◽

Deficiency Syndrome ◽

Speech Impairment ◽

Behavioral Disturbances ◽

Creatine Transporter ◽

Creatine Transporter Deficiency ◽

Creatine Deficiency ◽

Creatine Deficiency Syndrome ◽

Transporter Deficiency

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and behavioral disturbances, language and speech impairment ( OMIM #300352).CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT−/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.

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Quercetin, an Over-the-Counter Supplement, Causes Neuroblastoma-like Elevation of Plasma Homovanillic Acid

Pediatric and Developmental Pathology ◽

10.1007/s10024-003-5061-7 ◽

2003 ◽

Vol 6 (6) ◽

pp. 547-551 ◽

Cited By ~ 21

Author(s):

Josh Weldin ◽

Rhona Jack ◽

Kathryn Dugaw ◽

Raj P. Kapur

Keyword(s):

Dietary Supplement ◽

Homovanillic Acid ◽

Healthy Adult ◽

Elevated Serum ◽

Over The Counter ◽

Adult Volunteers ◽

Urine Levels ◽

Serum And Urine

A 22-month-old boy, who regularly consumed the oral dietary supplement, quercetin, was suspected erroneously of having a catecholamine-producing tumor, based on elevated serum and urine levels of the dopamine metabolite, homovanillic acid (HVA). Subsequent studies of healthy adult volunteers showed that significant elevations in plasma HVA are a consequence of quercetin ingestion.

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Zinc changes in blood and urine during cyclic pareteral nutrition: relationships with amino acid metabolism

British Journal Of Nutrition ◽

10.1079/bjn19940078 ◽

1994 ◽

Vol 72 (5) ◽

pp. 763-773 ◽

Cited By ~ 7

Author(s):

H. Faure ◽

X. Leverve ◽

J. Arnaud ◽

C. Boujet ◽

A. Favier

Keyword(s):

Parenteral Nutrition ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Elevated Serum ◽

Total Serum ◽

Control Subjects ◽

Serum Zn ◽

M 12 ◽

Serum And Urine ◽

Serum And Urine Samples

Serum Zn, ultrafiltrable Zn and amino acids in serum and urine samples of twenty-seven patients receiving cyclic (12 h/24 h) parenteral nutrition were measured. These samples were collected in patients after a 12 h period of parenteral nutrition, and in the evening after 12 h without parenteral nutrition. The same determinations were performed in ten control subjects who followed the same sampling scheme. Total serum ultrafiltrable Zn showed no significant variations in the patients during parenteral nutrition, and was not significantly different in the two groups although the proportion of the Zn present in the ultrafiltrable fraction was elevated. Serum cystine levels were significantly higher (P= 0·05) in the patients than the control subjects, and cystine excretion was also higher in patients (P< 0·05) and increased after parenteral nutrition (56·0 (SE 6·5)v. 147·1 (SE 20·6) m/12 h;P< 0·001). Histidine levels did not vary significantly in serum after parenteral nutrition and were not different in the patients in comparison with the control subjects. Histidine excretion was not different in the two groups but increased significantly during parenteral nutrition (P< 0·05). Serum albumin was significantly depressed in the patients compared with the control subjects (45·3 (SE 1·5)v. 33·9 (SE 1·5) g/l;P< 0·001). These results suggest that cystine infusion and excretion relate to the changes occurring in serum Zn and in urinary Zn excretion.

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A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

10.1101/2020.08.11.246330 ◽

2020 ◽

Author(s):

Lara Duran-Trio ◽

Gabriella Fernandes-Pires ◽

Dunja Simicic ◽

Jocelyn Grosse ◽

Clothilde Roux ◽

...

Keyword(s):

Point Mutation ◽

Rat Model ◽

Energy Demand ◽

High Energy ◽

Behavioral Disorder ◽

Creatine Transporter ◽

Efficient Treatment ◽

Creatine Transporter Deficiency ◽

Creatine Deficiency ◽

Transporter Deficiency

ABSTRACTCreatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features. Slc6a8xY389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

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Prospective evaluation of serial 2-hydroxyglutarate in acute myeloid leukemia (AML) to determine response to therapy and predict relapse.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6606 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6606-6606

Author(s):

Amir Tahmasb Fathi ◽

Omar Ibrahim Abdel-Wahab ◽

Hossein Sadrzadeh ◽

Julia Foster ◽

Meghan Burke ◽

...

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Elevated Serum ◽

Response To Therapy ◽

Strongly Correlated ◽

Baseline Serum ◽

Non Invasive ◽

Mutant Idh1 ◽

A Prospective Study ◽

Serum And Urine

6606 Background: Mutations in isocitrate dehydrogenase (IDH1 and IDH2) occur in 10-20% of AML patients and result in production of 2-hydroxyglutarate (2-HG). We hypothesize that serial 2-HG quantification may be used to monitor response and predict relapse in patients with AML. Methods: We are conducting a prospective study at MGH and DFCI to (1) assess changes in serum and urine 2-HG levels during treatment in patients with newly diagnosed AML, (2) compare 2-HG levels in serum, urine, and bone marrow and, (3) serially compare 2-HG levels with IDH1/2mutant allele burden. In those with elevated serum 2-HG (≥1000ng/ml), 2-HG is monitored serially or at relapse. Results: To date, 20 patients have been enrolled, 5 (25%) of whom had elevated baseline serum 2-HG. All 5 were found to have IDH1/2 mutations. The serum 2-HG for these patients was significantly higher than for those who were IDH-wt (median 1933 vs 87ng/mL; p<0.001). Urine 2-HG was also higher in IDH-mutant patients (median 30500 vs 4230ng/mL; p<0.021), as was bone marrow 2-HG (median 9870 vs 309ng/mL; p<0.005). Serum 2-HG levels strongly correlated with that in urine (R2 0.987). Serum 2-HG decreased in all IDH mutant patients on therapy, but more rapidly in those receiving induction chemotherapy (Table), all of whom achieved remission, than those receiving hypomethylatingagents. Conclusions: Patients with IDH-mutant AML have markedly elevated serum and urine 2-HG. 2-HG levels decreased with therapy and there is a strong correlation between serum and urine 2-HG. Data on the sensitivity of serial 2-HG monitoring as well as comparison with mutant IDH1/2allele burden will be presented. This data suggests that serial 2-HG quantification may be a valuable non-invasive biomarker in this genetically defined subset of AML. [Table: see text]

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