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1.  High degree of efficacy in the treatment of cyclic vomiting syndrome with combined co-enzyme Q10, L-carnitine and amitriptyline, a case series 
BMC Neurology  2011;11:102.
Cyclic vomiting syndrome (CVS), defined by recurrent stereotypical episodes of nausea and vomiting, is a relatively-common disabling and historically difficult-to-treat condition associated with migraine headache and mitochondrial dysfunction. Limited data suggests that the anti-migraine therapies amitriptyline and cyproheptadine, and the mitochondrial-targeted cofactors co-enzyme Q10 and L-carnitine, have efficacy in episode prophylaxis.
A retrospective chart review of 42 patients seen by one clinician that met established CVS diagnostic criteria revealed 30 cases with available outcome data. Participants were treated on a loose protocol consisting of fasting avoidance, co-enzyme Q10 and L-carnitine, with the addition of amitriptyline (or cyproheptadine in those < 5 years) in refractory cases. Blood level monitoring of the therapeutic agents featured prominently in management.
Vomiting episodes resolved in 23 cases, and improved by > 75% and > 50% in three and one additional case respectively. Among the three treatment failures, two could not tolerate amitriptyline (as was also the case in the child with only > 50% efficacy) and one had multiple congenital gastrointestinal anomalies. Excluding the latter case, substantial efficacy (> 75% response) was 26/29 at the start of treatment, and 26/26 in those able to tolerate the regiment, including high dosages of amitriptyline.
Our data suggest that a protocol consisting of mitochondrial-targeted cofactors (co-enzyme Q10 and L-carnitine) plus amitriptyline (or possibly cyproheptadine in preschoolers) coupled with blood level monitoring is highly effective in the prevention of vomiting episodes.
PMCID: PMC3163531  PMID: 21846334
2.  Carnitine Profile and Effect of Suppletion in Children with Renal Fanconi Syndrome due to Cystinosis 
JIMD Reports  2014;16:25-30.
Background: Cystinosis is an autosomal recessive disorder marked by intralysosomal cystine accumulation. Patients present with generalized proximal tubular dysfunction called renal Fanconi syndrome. Urinary carnitine loss results in plasma and muscle carnitine deficiency, but no clinical signs of carnitine deficiency have been described. Also, the optimal dose of carnitine supplementation is undefined. This study aimed to determine whether currently recommended carnitine doses result in adequate correction of plasma carnitine.
Methods: Five cystinosis patients with renal Fanconi syndrome, aged 2–18 years, were included. l-carnitine was prescribed 50 mg/kg/day since diagnosis: median 36 (range 18–207) months. Total and free plasma and urine carnitine and carnitine profiles were measured at study onset, after stopping l-carnitine for 3 months and 3 months after reintroducing l-carnitine 50 mg/kg/day.
Results: At study onset, plasma free carnitine was normal in all patients, total carnitine (1/5), acetylcarnitine (3/5), and several short- and medium-chain acylcarnitines ≤10 carbons (5/5) were increased indicating carnitine over-supplementation. Three months after cessation, carnitine profiles normalized and 3/5 patients showed plasma carnitine deficiency. Three months after reintroduction, plasma free carnitine normalized in all patients, however, carnitine profiles were disturbed in 4/5 patients. Urine free carnitine, acetylcarnitine, and acylcarnitines ≤10 carbons were increased in all patients independent of carnitine supplementation.
Conclusion: Administration of recommended doses l-carnitine (50 mg/kg/day) resulted in over-supplementation. Although the drug is considered to be rather safe, long-term effects of over-supplementation remain unknown warranting cautious use of high doses. Plasma carnitine profile might be used as a monitor, to prevent overdosing.
PMCID: PMC4221611  PMID: 24798266
3.  Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome. 
Journal of Clinical Investigation  1985;75(4):1124-1130.
Plasma and urine free and acyl carnitine were measured in 19 children with nephropathic cystinosis and renal Fanconi syndrome. Each patient exhibited a deficiency of plasma free carnitine (mean 11.7 +/- 4.0 [SD] nmol/ml) compared with normal control values (42.0 +/- 9.0 nmol/ml) (P less than 0.001). Mean plasma acyl carnitine in the cystinotic subjects was normal. Four subjects with Fanconi syndrome but not cystinosis displayed the same abnormal pattern of plasma carnitine levels; controls with acidosis or a lysosomal storage disorder (Fabry disease), but not Fanconi syndrome, had entirely normal plasma carnitine levels. Two postrenal transplant subjects with cystinosis but without Fanconi syndrome also had normal plasma carnitine levels. Absolute amounts of urinary free carnitine were elevated in cystinotic individuals with Fanconi syndrome. In all 21 subjects with several different etiologies for the Fanconi syndrome, the mean fractional excretion of free carnitine (33%) as well as acyl carnitine (26%) greatly exceeded normal values (3 and 5%, respectively). Total free carnitine excretion in Fanconi syndrome patients correlated with total amino acid excretion (r = 0.76). Two cystinotic patients fasted for 24 h and one idiopathic Fanconi syndrome patient fasted for 5 h showed normal increases in plasma beta-hydroxybutyrate and acetoacetate, which suggested that hepatic fatty acid oxidation was intact despite very low plasma free carnitine levels. Muscle biopsies from two cystinotic subjects with Fanconi syndrome and plasma carnitine deficiency had 8.5 and 13.1 nmol free carnitine per milligram of noncollagen protein, respectively (normal controls, 22.3 and 17.1); total carnitines were 11.8 and 13.3 nmol/mg noncollagen protein (controls 33.5, 20.0). One biopsy revealed a mild increase in lipid droplets. The other showed mild myopathic features with variation in muscle fiber size, small vacuoles, and an increase in lipid droplets. In renal Fanconi syndrome, failure to reabsorb free and acyl carnitine results in a secondary plasma and muscle free carnitine deficiency.
PMCID: PMC425435  PMID: 3988933
4.  Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome. 
Journal of Clinical Investigation  1988;81(2):549-560.
11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome. After treatment with oral L-carnitine, 100 mg/kg per d divided every 6 h, plasma carnitine concentrations became normal in all subjects within 2 d. Initial plasma free fatty acid concentrations, inversely related to free carnitine concentrations, were reduced after 7-20 mo of carnitine therapy. Muscle lipid accumulation, which varied directly with duration of carnitine deficiency (r = 0.73), improved significantly in three of seven rebiopsied patients after carnitine therapy. One Lowe's syndrome patient achieved a normal muscle carnitine level after therapy. Muscle carnitine levels remained low in all cystinosis patients, even though cystinotic muscle cells in culture took up L-[3H]carnitine normally. The half-life of plasma carnitine for cystinotic children given a single oral dose approximated 6.3 h; 14% of ingested L-carnitine was excreted within 24 h. Studies in a uremic patient with cystinosis showed that her plasma carnitine was in equilibrium with some larger compartment and may have been maintained by release of carnitine from the muscle during dialysis. Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered. However, its efficacy in restoring muscle carnitine to normal, and the optimal dosage regimen, have yet to be determined.
PMCID: PMC329603  PMID: 3276734
5.  Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport. 
Journal of Clinical Investigation  1984;73(3):857-867.
The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and "other tissues") was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract.
PMCID: PMC425090  PMID: 6707204
6.  Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide-induced Fanconi Syndrome rat model 
In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for β-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4th, 5th and 6th groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH) content in cardiac tissues. In carnitine-depleted rats, IFO induced dramatic increase in serum creatinine, BUN, CK-MB, LDH, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH, as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical changes-induced by IFO to the control values. In conclusion, data from the present study suggest that: Carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, constitute risk factors and should be viewed as mechanisms during development of IFO-induced cardiotoxicity. Carnitine supplementation, using PLC, prevents the development of IFO-induced cardiotoxicity through antioxidant signalling and improving mitochondrial function.
PMCID: PMC2952087  PMID: 20972373
ifosfamide; Fanconi Syndrome; carnitine deficiency; cardiotoxicity; D-carnitine; mildronate; propionyl-L-carnitine
7.  Cyclic Vomiting Syndrome (CVS): is there a difference based on onset of symptoms - pediatric versus adult? 
BMC Gastroenterology  2012;12:52.
Cyclic Vomiting Syndrome (CVS) is a well-recognized functional gastrointestinal disorder in children but its presentation is poorly understood in adults. Genetic differences in pediatric-onset (presentation before age 18) and adult-onset CVS have been reported recently but their clinical features and possible differences in response to therapy have not been well studied.
This was a retrospective review of 101 CVS patients seen at the Medical College of Wisconsin between 2006 and 2008. Rome III criteria were utilized to make the diagnosis of CVS.
Our study population comprised of 29(29%) pediatric-onset and 72 (71%) adult-onset CVS patients. Pediatric-onset CVS patients were more likely to be female (86% vs. 57%, p = 0.005) and had a higher prevalence of CVS plus (CVS + neurocognitive disorders) as compared to adult-onset CVS patients (14% vs. 3%, p = 0.05). There was a longer delay in diagnosis (10 ± 7 years) in the pediatric-onset group when compared to (5 ± 7 years) adult-onset CVS group (p = 0.001). Chronic opiate use was less frequent in the pediatric-onset group compared to adult-onset patients (0% vs. 23%, p = 0.004). Aside from these differences, the two groups were similar with regards to their clinical features and the time of onset of symptoms did not predict response to standard treatment. The majority of patients (86%) responded to treatment with tricyclic antidepressants, anticonvulsants (topiramate), coenzyme Q-10, and L-carnitine. Non-response to therapy was associated with coalescence of symptoms, chronic opiate use and more severe disease as characterized by longer episodes, greater number of emergency department visits in the year prior to presentation, presence of disability and non-compliance on univariate analysis. On multivariate analysis, only compliance to therapy was associated with a response. (88% vs. 38%, Odds Ratio, OR 9.6; 95% Confidence Interval [CI], 1.18-77.05).
Despite reported genetic differences, the clinical features and response to standard therapy in pediatric- and adult-onset CVS were mostly similar. Most patients (86%) responded to therapy and compliance was the only factor associated with a response.
PMCID: PMC3443054  PMID: 22639867
Motility; Cyclic vomiting; Nausea; Abdominal pain
8.  Anticipatory nausea in cyclical vomiting 
BMC Pediatrics  2005;5:3.
Cyclical Vomiting Syndrome (CVS) is characterised by discrete, unexplained episodes of intense nausea and vomiting, and mainly affects children and adolescents. Comprehending Cyclical Vomiting Syndrome requires awareness of the severity of nausea experienced by patients. As a subjective symptom, nausea is easily overlooked, yet is the most distressing symptom for patients and causes many behavioural changes during attacks.
Case presentation
This first-hand account of one patient's experience of Cyclical Vomiting Syndrome shows how severe nausea contributed to the development of anticipatory nausea and vomiting (ANV), a conditioned response frequently observed in chemotherapy patients. This conditioning apparently worsened the course of the patient's disease. Anticipatory nausea and vomiting has not previously been recognised in Cyclical Vomiting Syndrome, however predictors of its occurrence in oncology patients indicate that it could complicate many cases.
We suggest a model whereby untreated severe and prolonged nausea provokes anxiety about further cyclical vomiting attacks. This anxiety facilitates conditioning, thus increasing the range of triggers in a self-perpetuating manner. Effective management of the nausea-anxiety feedback loop can reduce the likelihood of anticipatory nausea and vomiting developing in other patients.
PMCID: PMC1079876  PMID: 15790392
9.  Cyclic Vomiting Syndrome Developed after Stroke 
Annals of Rehabilitation Medicine  2012;36(1):141-143.
Cyclic vomiting syndrome is characterized by recurrent episodes of stereotyped vomiting separated by regular symptom-free periods. We describe a case of cyclic vomiting syndrome developed after stroke, which has not been reported to date. A 69-year-old woman experienced recurrent vomiting following left cerebral infarct. The patient's vomiting pattern was consistent with cyclic vomiting syndrome, and the diagnosis of cyclic vomiting syndrome was established by exclusion of other known disorders which could have resulted in vomiting. She was treated with imipramine hydrochloride and her symptom was well controlled.
PMCID: PMC3309328  PMID: 22506247
Cyclic vomiting syndrome; Stroke
10.  Medium chain acyl-CoA dehydrogenase deficiency. 
Archives of Disease in Childhood  1992;67(1):142-145.
From 65 reported cases of medium chain acyl-CoA dehydrogenase deficiency, we found an average presenting age of 13.5 months and a mean age at death of 18.5 months. One quarter of patients died of a Reye-like syndrome and/or sudden infant death. In half the cases there had been at least one sibling death. Asymptomatic cases were not uncommon (12% of cases). The crises were generally induced by a prolonged fast and after a viral prodromal phase in three quarters of cases. The crises consisted of somnolence progressing to lethargy which could lead to coma. Vomiting was frequent (60% of cases). Seizures, which were found in 29% of cases, represented a bad prognosis. The physical examinations revealed frequently a variable and regressive anicteric hepatomegaly. Blood and urine analysis revealed in most instances hypoglycaemia (96% of cases) with hypoketonuria and sometimes metabolic acidosis. Hepatic and muscular cytolytic enzymes were frequently raised, as were plasma ammonia, urea, and uric acid. Plasma total or free carnitine concentrations, especially non-fasting, were diminished in most cases. Plasma saturated medium chain fatty acids and particularly unsaturated cis-4-decenoate were on the other hand raised during the crises or during fasting. Urinary organic acid analysis revealed a characteristic profile of medium chain aciduria: C6-C10 dicarboxylic acids, hydroxy acids, glycine conjugates, and carnitine conjugates. Oral loading tests with carnitine or phenylpropionate allow a precise diagnosis. The diagnosis is confirmed by specific assays in various tissues. Avoidance of prolonged fasting seems to be the mainstay of treatment.
PMCID: PMC1793557  PMID: 1739332
11.  A Case of Cyclic Vomiting Syndrome Responding to Gonadotropin-Releasing Hormone Analogue 
Cyclic vomiting syndrome (CVS) is a disorder characterized by recurrent episodes of incapacitating nausea and vomiting interspersed with symptom free periods. Common triggers of cyclic vomiting include noxious stress, excitement, fatigue and menstrual period. Here, we report a case of cyclic vomiting syndrome in adult patient characterized by stereotypical vomiting attack, occurring in every menstruation period. Recurrent vomiting episodes began 6 years ago and we treated this patient with subcutaneous injection of goserelin, a gonadotropin-releasing hormone analogue (GnRHa) and oral estrogen. After 4 months of therapy, she was symptom free for the following 5 years, even with the resumed normal menstruation. Recurrence of vomiting attack with same pattern occurred 1 month before readmission. Treatment with intravenous lorazepam aborted vomiting, but could not prevent recurrences of vomiting and epigastric pain. We treated the patient with GnRHa and oral estradiol again which effectively prevented recurrence of the symptoms.
PMCID: PMC2879835  PMID: 20535330
Cyclic vomiting syndrome; Menstrual period; Gonodotropin-releasing hormone analogue
12.  Adult Cyclic Vomiting Syndrome Successfully Treated with Intranasal Sumatriptan 
Cyclic vomiting syndrome is an increasingly recognized cause of nausea and vomiting in adults. We report the case of a 47-year-old man with recurrent episodes of intractable nausea and vomiting for one year. His symptoms persisted for 4–7 days and then resolved spontaneously, only to return after periods of time ranging from one week up to a month. After an extensive workup, which failed to determine any causative explanation for his symptoms, he was diagnosed with cyclic vomiting syndrome. His episodes of vomiting were successfully terminated with the use of intranasal sumatriptan. In this case, we highlight that sumatriptan effectively aborted symptoms in an adult patient with cyclic vomiting syndrome. Increasing physicians’ awareness of adult cyclic vomiting syndrome may improve care of patients suffering from this debilitating condition.
PMCID: PMC2811593  PMID: 19911235
adult cyclic vomiting syndrome; treatment; sumatriptan; triptan
13.  The Two Sides of Opioids in Cyclical Vomiting Syndrome 
Cyclical vomiting syndrome is increasingly recognized in adults, with recent reports suggesting ‘coalescing attacks’ in one third of the patients. We hypothesized that the common need for opioid treatment may contribute to coalescing attacks through development of opioid dependence and withdrawal, triggering cyclical vomiting syndrome.
This study was to review iatrogenic opioid dependence as the potential cause for triggering cyclical vomiting syndrome.
Materials and Methods:
A retrospective review was performed to identify patients treated for cyclical vomiting syndrome by a single physician between Jan and December of 2010. Demographic data, clinical presentation, treatment, cumulative opioid prescription during hospitalizations and emergency room visits and days of inpatient stay were abstracted from the chart.
Forty-one patients (mean age 37.5.6 ± 2.6 years; 66% female) were seen within this timeframe. In eleven patients (27%) with ongoing opioid use, the initial cyclical illness had progressed and eventually coalesced. A cohort of 23 patients was followed for at least 6 months (12.3 ± 1.7 months). The best single predictor of repeat hospitalizations was the cumulative opioid dosage.
Continued use of opioid therapy is a poor prognostic marker of cyclical vomiting syndrome and may contribute to disease coalescence, with dependence and withdrawal triggering recurrent episodes.
PMCID: PMC3978933  PMID: 24741549
Cyclical vomiting syndrome; Coalescing attacks; Opioids
14.  Cyclic Vomiting Syndrome in a Male Patient With History of Renal Cell Carcinoma Status Post Nephrectomy 
Cyclic vomiting syndrome (CVS) is a condition whose symptoms are recurring attacks of intense nausea, vomiting and sometimes abdominal pain and/or headaches or migraines. Cyclic vomiting usually develops during the childhood ages of 3 - 7; whereas it often remits during adolescence, it can persist into adult life. We report a case of a 57 years old Caucasian male with a history of renal cell carcinoma status post left nephrectomy presenting with a 7 years history of intermittent nausea and vomiting with prodromal malaise, watery diarrhea, flushing and diaphoresis. Cyclic vomiting syndrome is a debilitating functional brain-gut disorder that was initially characterized in children, but now is increasingly recognized to occur also in adults.
Cyclic vomiting syndrome; Vomitting; Post nephrectomy
PMCID: PMC3299175  PMID: 22457701
15.  Identification and characterization of the caiF gene encoding a potential transcriptional activator of carnitine metabolism in Escherichia coli. 
Journal of Bacteriology  1996;178(5):1248-1257.
Expression of the Escherichia coli caiTABCDE and fixABCX operons involved in carnitine metabolism is induced by both carnitine and anaerobiosis. When cloned into a multicopy plasmid, the 3' region adjacent to the caiTABCDE operon was found to increase levels of carnitine dehydratase activity synthesized from the chromosomal caiB gene. The nucleotide sequence was determined, and it was shown to contain an open reading frame of 393 bp named caiF which is transcribed in the direction opposite that of the cai operon. This open reading frame encodes a protein of 131 amino acids with a predicted molecular mass of 15,438 Da which does not have any significant homology with proteins available in data libraries. In vivo overexpression consistently led to the synthesis of a 16-kDa protein. The caiF gene was transcribed as a monocistronic mRNA under anaerobiosis independently of the presence of carnitine. Primer extension analysis located the start site of transcription to position 82 upstream of the caiF initiation codon. It was preceded by a cyclic AMP receptor protein motif centered at position -41.5. Overproduction of CaiF resulted in the stimulation of transcription of the divergent cai and fix operons in the presence of carnitine. This suggested that CaiF by interacting with carnitine plays the role of an activator, thereby mediating induction of carnitine metabolism. Moreover, CaiF could complement in trans the regulatory defect of laboratory strain MC4100 impaired in the carnitine pathway. Expression of a caiF-lacZ operon fusion was subject to FNR regulator-mediated anaerobic induction and cyclic AMP receptor protein activation. The histone-like protein H-NS and the NarL (plus nitrate) regulator acted as repressors. Because of the multiple controls to which the caiF gene is subjected, it appears to be a key element in the regulation of carnitine metabolism.
PMCID: PMC177796  PMID: 8631699
16.  Carnitine and Coenzyme Q10 Levels in Individuals with Prader-Willi Syndrome 
Carnitine deficiency or coenzyme Q10 (CoQ10) deficiency may present with hypotonia, poor growth, easy fatigability, and apnea. This constellation of findings can also be seen in individuals with Prader-Willi syndrome (PWS). Animal studies indicate that increased fat mass due to obesity negatively correlates with both carnitine and CoQ10 levels in skeletal muscle. Increased body fat and obesity are characteristic of individuals with PWS. Currently there is no documentation of serum carnitine levels, and only one study investigating plasma CoQ10 levels, in individuals with PWS.
Fasting serum carnitine and plasma CoQ10 levels were measured in 40 individuals with molecularly confirmed PWS (ages 1–27 years; 19 F/21M), 11 individuals with early-onset morbid obesity of unknown etiology (ages 3–13 years; 5F/6M), and 35 control siblings from both groups (ages 1–24 years; 19F/16M).
There were no significant differences among the 3 groups in either total carnitine, free carnitine, or CoQ10 levels. However, individuals with PWS had higher serum levels of carnitine esters (p=0.013) and higher ester-to-free carnitine ratios (p=0.0096) than controls suggesting a possible underlying impairment of peripheral carnitine utilization and mitochondrial energy metabolism in some individuals with PWS.
Serum sampling identified no significant differences in total and free carnitine or CoQ10 levels between individuals with PWS, obese individuals, and sibling control groups. Muscle biopsy or measurement in leukocytes or cultured skin fibroblasts could be a better method to identify abnormalities in carnitine and CoQ10 metabolism in individuals with PWS than peripheral blood sampling.
PMCID: PMC3285456  PMID: 21337696
17.  Psychiatric Co-morbidity and Efficacy of Mirtazapine Treatment in Young Subjects With Chronic or Cyclic Vomiting Syndromes: A Case Series 
The aim of this case report was to evaluate the psychiatric co-morbidity and efficacy of mirtazapine treatment in young subjects with chronic or cyclic vomiting syndromes. This is a case series of 8 young subjects (age range of 6-16 years, 11.12 ± 3.52 years) who were referred or consulted to child psychiatry department. They were referred or consulted by pediatric gastroenterology or surgery departments for the presence of non-remitting and medically unexplained vomiting. They were investigated for co-morbid psychiatric disorders using a structured psychiatric interview. An open trial of mirtazapine was conducted for the treatment and/or prevention of vomiting. Primary outcome measure was Clinical Global Impression-Improvement scale. Subjects were diagnosed with chronic (n = 5) or cyclic (n = 3) vomiting syndromes. Duration of vomiting ranged from 6 months to 10 years (3.5 ± 3.2 years). All subjects received multiple psychiatric diagnoses with anxiety disorders being the most frequent. Maximum mirtazapine dosage was 7.5-30 mg/day (16.00 ± 6.16 mg/day). Three subjects showed complete remission and 5 subjects showed much to very much improvement in vomiting. Most frequent side effects were increased appetite, weight gain and sedation. Young subjects with chronic or cyclic vomiting may frequently suffer anxiety and/or depressive symptoms or disorders. Mirtazapine could be an effective treatment option for the treatment of vomiting and co-morbid anxiety or depressive disorders in these subjects. More systematic research are needed on this topic.
PMCID: PMC3155068  PMID: 21860824
Anxiety; Child; Familial cyclic vomiting syndrome; Gastrointestinal diseases; Mirtazapine
18.  The effect of homozygous deletion of the BBOX1 and Fibin genes on carnitine level and acyl carnitine profile 
BMC Medical Genetics  2014;15:75.
Carnitine is a key molecule in energy metabolism that helps transport activated fatty acids into the mitochondria. Its homeostasis is achieved through oral intake, renal reabsorption and de novo biosynthesis. Unlike dietary intake and renal reabsorption, the importance of de novo biosynthesis pathway in carnitine homeostasis remains unclear, due to lack of animal models and description of a single patient defective in this pathway.
Case presentation
We identified by array comparative genomic hybridization a 42 months-old girl homozygote for a 221 Kb interstitial deletions at 11p14.2, that overlaps the genes encoding Fibin and butyrobetaine-gamma 2-oxoglutarate dioxygenase 1 (BBOX1), an enzyme essential for the biosynthesis of carnitine de novo. She presented microcephaly, speech delay, growth retardation and minor facial anomalies. The levels of almost all evaluated metabolites were normal. Her serum level of free carnitine was at the lower limit of the reference range, while her acylcarnitine to free carnitine ratio was normal.
We present an individual with a completely defective carnitine de novo biosynthesis. This condition results in mildly decreased free carnitine level, but not in clinical manifestations characteristic of carnitine deficiency disorders, suggesting that dietary carnitine intake and renal reabsorption are sufficient to carnitine homeostasis. Our results also demonstrate that haploinsufficiency of BBOX1 and/or Fibin is not associated with Primrose syndrome as previously suggested.
PMCID: PMC4184381  PMID: 24986124
Carnitine; BBOX1; Fibin; CNV; Primrose syndrome
19.  Primary Carnitine Deficiency Presents Atypically with Long QT Syndrome: A Case Report 
JIMD Reports  2011;2:87-90.
Primary carnitine deficiency (PCD) is an autosomal recessive disorder of fatty acid oxidation caused by mutations in the SLC22A5 gene encoding for the carnitine transporter OCTN2. Carnitine uptake deficiency results in renal carnitine wasting and low plasma levels. PCD usually presents early in life either with acute metabolic crisis or as progressive cardiomyopathy that responds to carnitine supplementation. PCD inclusion in the newborn screening (NBS) programs has led to the identification of asymptomatic adult patients ascertained because of a positive NBS in their offspring. We extensively reviewed the literature and found that 15 of 42 adult published cases (35.7%) were symptomatic. Cardiac arrhythmias were present in five patients (12%). Here, we report the ascertainment and long-term follow-up of the first case of PCD presenting with long QT syndrome. The patient presented in her early twenties with a syncopal episode caused by ventricular tachycardia, and a prolonged QT interval. Arrhythmias were poorly controlled by pharmacologic therapy and a defibrillator was installed. Syncopal episodes escalated during her first pregnancy. A positive NBS in the patient’s child suggested a carnitine uptake deficiency, which was confirmed by reduced carnitine transporter activity and by molecular testing. After starting carnitine supplementation, no further syncopal episodes have occurred and the QT interval returned to normal. As precaution, a low-dose metoprolol therapy and the defibrillator are still in place. Although rare, PCD should be ruled out as a cause of cardiac arrhythmias since oral carnitine supplementation is readily available and efficient.
PMCID: PMC3509843  PMID: 23430858
20.  Association of Marijuana Use and Cyclic Vomiting Syndrome 
Pharmaceuticals  2012;5(7):719-726.
Cannabis use has become one of the most commonly abused drugs in the world. It is estimated that each year 2.6 million individuals in the USA become new users and most are younger than 19 years of age. Reports describe marijuana use as high as 40–50% in male Cyclic Vomiting Syndrome patients. It is this interest in cannabis in the World, coupled with recognition of a cyclic vomiting illness associated with its chronic use that beckons a review of the most current articles, as well as a contribution from our own experiences in this area. The similarities we have demonstrated for both cannibinoid hyperemesis syndrome and cyclic vomiting make the case that cannibinoid hyperemesis syndrome is a subset of patients who have the diagnoses of cyclic vomiting syndrome and the role of marijuana should always be considered in the diagnosis of CVS, particularly in males.
PMCID: PMC3763664  PMID: 24281708
cyclic vomiting syndrome; marijuana; nausea; vomiting; cannabinoid hyperemesis syndrome
21.  Cannabinoid Hyperemesis Syndrome 
Current drug abuse reviews  2011;4(4):241-249.
Coinciding with the increasing rates of cannabis abuse has been the recognition of a new clinical condition known as Cannabinoid Hyperemesis Syndrome. Cannabinoid Hyperemesis Syndrome is characterized by chronic cannabis use, cyclic episodes of nausea and vomiting, and frequent hot bathing. Cannabinoid Hyperemesis Syndrome occurs by an unknown mechanism. Despite the well-established anti-emetic properties of marijuana, there is increasing evidence of its paradoxical effects on the gastrointestinal tract and CNS. Tetrahydrocannabinol, cannabidiol, and cannabigerol are three cannabinoids found in the cannabis plant with opposing effects on the emesis response. The clinical course of Cannabinoid Hyperemesis Syndrome may be divided into three phases: prodromal, hyperemetic, and recovery phase. The hyperemetic phase usually ceases within 48 hours, and treatment involves supportive therapy with fluid resuscitation and anti-emetic medications. Patients often demonstrate the learned behavior of frequent hot bathing, which produces temporary cessation of nausea, vomiting, and abdominal pain. The broad differential diagnosis of nausea and vomiting often leads to delay in the diagnosis of Cannabinoid Hyperemesis Syndrome. Cyclic Vomiting Syndrome shares several similarities with CHS and the two conditions are often confused. Knowledge of the epidemiology, pathophysiology, and natural course of Cannabinoid Hyperemesis Syndrome is limited and requires further investigation.
PMCID: PMC3576702  PMID: 22150623
Cannabinoid Hyperemesis Syndrome; Cannabis; Marijuana; Nausea; Vomiting
22.  Recent Concepts on Cyclic Vomiting Syndrome in Children 
Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder that can occur in both children and adults. Clinical courses of CVS manifesting recurrent severe vomiting episodes and interval illness may affect the long-term quality of life in children with CVS. Therefore, we should be careful in accessing a patient suggestive of CVS. Accurate diagnosis based on diagnostic criteria for CVS and the exclusion from other organic diseases mimicking clinical manifestations of cyclic vomiting is absolutely required. In patients diagnosed as CVS, optimal therapy should be performed to improve symptoms and to reduce complications in prodromal phase and emetic phase, and long-term prophylactic therapy should be tried to prevent the development of vomiting episodes. The identification of triggering factors which induce vomiting episodes might be helpful in preventing vomiting attacks. Systematic approach should be recommended to improve clinical outcome of CVS.
PMCID: PMC2879837  PMID: 20535344
Cyclic vomiting syndrome; Diagnosis; Therapy; Child
23.  Serum metabolomic profiles suggest influence of sex and oral contraceptive use 
Aim: Considering that the effects of sex and oral contraceptives (OCs) on blood metabolites have been scarcely studied and the fact that protocol designs for clinical trials emphasise the use of contraception for women of childbearing potential, we examined if OCs and sex affect the serum levels of the physiologically relevant amino acids, carnitine and acylcarnitines, using metabolomics approaches. Methods: Healthy adult men and women were enrolled. They were drug free with the exception of women taking cyclic format OCs (ethinylestradiol + different progestins). OCs-free women were analysed during the follicular phase, and amino acids, free carnitine and acylcarnitines were measured using HPLC or LC-MS/MS, respectively. Results: Men had significantly higher leucine, isoleucine, methionine, asparagine, proline, valine, tyrosine, glutamine+glutamate, glutamate, histidine and citrulline than OCs-free women, while tryptophan was significantly lower in men. OCs use significantly decreased the levels of glycine, proline, histidine, lysine, hydroxyproline and ornithine and increased isoleucine levels when compared with non-user women. OCs use reduced, although not significantly, carnitine levels in women. Total esterified carnitines were higher in untreated women than in OCs users. Globally, the effect of OCs and sex was specific for the individual esterified carnitine. The observed metabolic changes were not attributable to renal or hepatic functions or to differences in body weight. Conclusions: The assessed parameters were specifically influenced by sex, highlighting the need to have reference values for women and men. The major novelty of this study is the demonstration that OCs specifically change the profiles of serum amino acids and carnitine, which suggests that OCs users and non-users should be represented in clinical trials.
PMCID: PMC4212935  PMID: 25360225
Amino acids; carnitine; acylcarnitines; metabolomics; oral contraceptives; sex
24.  Comparison of Vitamin E and L-Carnitine, Separately or in Combination in Patients With Intradialytic Complications 
Nephro-urology Monthly  2013;5(4):862-865.
The most common complications during dialysis are hypotension and muscle cramps. There are many strategies to prevent and treat these complications.
The aim of this study is to evaluate effects of vitamin E and L-carnitine supplementation alone and in combination on intradialytic complications.
Patients and Methods
In a prospective study, 20 patients with end stage renal disease on chronic hemodialysis that had intradialytic complications such as hypotension, muscle cramp, nausea, vomiting and headache were studied. These patients were studied in four 45 day periods, beginning with no treatment (step 1), receiving vitamin E (200 IU/d) (step 2), receiving L-carnitine (500 mg/d) (step 3) and their combination (step 4). Intradialytic complications were recorded in each step and compared between treatments.
All three treatments significantly reduced frequency of muscle cramps in comparison to baseline values. Vitamin E alone and in combination with L-carnitine reduced the frequency of muscle cramps more effectively. Hypotension was significantly lower in combination therapy in comparison to baseline values and vitamin E treatment.
Vitamin E and L-carnitine both have comparative effects on intradialytic complications. As the combination use of vitamin E and L-carnitine could more effectively reduce the intradialytic complications, it is recommended for daily use in hemodialysis patients.
PMCID: PMC3842554  PMID: 24350082
Renal Dialysis; Kidney Failure, Chronic; Vitamin E; Carnitine
25.  Cannabinoid hyperemesis syndrome: Clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse 
Cannabis is a common drug of abuse that is associated with various long-term and short-term adverse effects. The nature of its association with vomiting after chronic abuse is obscure and is underrecognised by clinicians. In some patients this vomiting can take on a pattern similar to cyclic vomiting syndrome with a peculiar compulsive hot bathing pattern, which relieves intense feelings of nausea and accompanying symptoms. In this case report, we describe a twenty-two year-old-male with a history of chronic cannabis abuse presenting with recurrent vomiting, intense nausea and abdominal pain. In addition, the patient reported that the hot baths improved his symptoms during these episodes. Abstinence from cannabis led to resolution of the vomiting symptoms and abdominal pain. We conclude that in the setting of chronic cannabis abuse, patients presenting with chronic severe nausea and vomiting that can sometimes be accompanied by abdominal pain and compulsive hot bathing behaviour, in the absence of other obvious causes, a diagnosis of cannabinoid hyperemesis syndrome should be considered.
PMCID: PMC2658859  PMID: 19291829
Cannabinoid; Cannabis; Cyclic vomiting; Hyperemesis; Marijuana; Vomiting

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