ABSTRACT: BACKGROUND: Cyclic vomiting syndrome (CVS), which is defined by recurrent stereotypical episodes of nausea and vomiting, is a relatively-common disabling condition that is associated with migraine headache and mitochondrial dysfunction. Co-enzyme Q10 (Co-Q) is a nutritional supplement that has demonstrated efficacy in pediatric and adult migraine. It is increasingly used in CVS despite the complete lack of studies to demonstrate its value in treatment. METHODS: Using an Internet-based survey filled out by subjects with CVS or their parents, the efficacy, tolerability and subject satisfaction in CVS prophylaxis were queried. Subjects taking Co-Q (22 subjects) were compared against those taking amitriptyline (162 subjects), which is the general standard-of-care. RESULTS: Subjects/parents reported similar levels of efficacy for a variety of episode parameters (frequency, duration, number of emesis, nausea severity). There was a 50% reduction in at least one of those four parameters in 72% of subjects treated with amitriptyline and 68% of subjects treated Co-Q. However, while no side effects were reported on Co-Q, 50% of subjects on amitriptyline reported side effects (P = 5 x 10-7), resulting in 21% discontinuing treatment (P = 0.007). Subjects/parents considered the benefits to outweigh the risks of treatment in 47% of cases on amitriptyline and 77% of cases on Co-Q (P = 0.008). CONCLUSION: Our data suggest that the natural food supplement Co-Q is potentially efficacious and tolerable in the treatment of CVS, and should be considered as an option in CVS prophylaxis. Our data would likely be helpful in the design of a double-blind clinical trial.

Major depressive disorder (MDD) is believed to have a genetic factor in its pathogenesis. On the basis of studies in MDD showing brain energy depletion and maternal inheritance in some families, we hypothesize that some of the genetic factor is likely maternally inherited on the mitochondrial DNA (mtDNA). Six hundred and seventy-two pedigrees from the Genetics of Recurrent Early-Onset Depression project were analyzed for matrilineal/nonmatrilineal pairs. Pairs were constructed to control for sex, age and autosomal gene contribution (e.g. maternal vs. paternal aunts). Individuals with and without any mood disorder were tallied and compared across five different pairs. Matrilineal relatives (with the same mtDNA sequence as the proband) were significantly more likely to suffer from a mood disorder than were nonmatrilineal relatives (with another mtDNA sequence; odds ratio 2.0, 95% confidence interval: 1.5-2.6, P = 3x10). Our data show a modest maternal bias in the susceptibility towards the development of depression, suggesting that predisposing genetic factors likely reside on the mtDNA. Thus, our data strengthen the hypothesis that energy metabolism may be involved in the pathogenesis of depression.

Abstract Pediatric cyclic vomiting syndrome (CVS) is associated with a high prevalence of co-morbid migraine and other functional disorders, and with two adult migraine-associated mitochondrial DNA (mtDNA) polymorphisms: 16519T and 3010A. These potential associations have not been studied in adult CVS. The objective of this study is to determine the prevalence of 16519T and 3010A mtDNA polymorphisms and other functional disorders in adult CVS patients. Adults with CVS recruited from the University of Kansas meeting Rome III criteria and a population control group completed a self-reported survey that included questions relating to the diagnostic criteria for several functional disorders. DNA was isolated from blood or saliva and genotyping was performed by standard methodologies. Adult CVS subjects, compared to controls, had significantly more symptoms consistent with several other functional disorders. 16519T was present in 22/31 cases (71%) of child-onset (<12 years) and 9/31 (29%) cases of adult-onset (18+ years) CVS (P = 0.01), vs 27% of controls. Among subjects with 16519T, 3010A was present in 30% of child-onset vs 0% of adult-onset CVS (P = 0.05) and 2% of controls. The conclusions drawn were:(i) unlike pediatric CVS, adult CVS is not associated with the 16519T and 3010A mtDNA polymorphisms, suggesting a degree of genetic distinction and (ii) similar to the pediatric setting, adult CVS is associated with a substantial burden of co-morbid functional disorders.

Mitochondrial dysfunction is a hypothesized component in the multifactorial pathogenesis of migraine without aura (MoA,'common migraine') and the related condition of cyclic vomiting syndrome (CVS). In this study, the entire mitochondrial genome was sequenced in 20 haplogroup-H CVS patients, a subject group studied because of greater genotypic and phenotypic homogeneity. Sequences were compared against haplogroup-H controls. Polymorphisms of interest were tested in 10 additional CVS subjects and in 112 haplogroup-H adults with MoA. The 16519C-->T polymorphism was found to be highly disease associated: 21/30 CVS subjects [70%, odds ratio (OR) 6.2] and 58/112 migraineurs (52%, OR 3.6) vs. 63/231 controls (27%). A second polymorphism, 3010G-->A, was found to be highly disease associated in those subjects with 16519T: 6/21 CVS subjects (29%, OR 17) and 15/58 migraineurs (26%, OR 15) vs. 1/63 controls (1.6%). Our data suggest that these polymorphisms constitute a substantial proportion of the genetic factor in migraine pathogenesis, and strengthen the hypothesis that there is a component of mitochondrial dysfunction in migraine.

Introduction: Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a disorder of oxidation of long chain fat, and can present as cardiomyopathy or fasting intolerance in the first months to years of life, or as myopathy in later childhood to adulthood. Expanded newborn screening has identified a relatively high incidence of this disorder (1:31,500), but there is a dearth of evidence-based outcomes data to guide the development of clinical practice protocols. This consensus protocol is intended to assist clinicians in the diagnosis and management of screen-positive newborns for VLCAD deficiency until evidence-based guidelines are available. Method: The Oxford Centre for Evidence-based Medicine system was used to grade the literature review and create recommendations graded from A (evidence level of randomized clinical trials) to D (expert opinion). Delphi was used as the consensus tool. A panel of 14 experts (including clinicians, diagnostic laboratory directors and researchers) completed three rounds of survey questions and had a face-to-face meeting. Result: Panelists reviewed the initial evaluation of the screen-positive infant, diagnostic testing and management of diagnosed patients. Grade C and D consensus recommendations were made in each of these three areas. The panel did not reach consensus on all issues, particularly in the dietary management of asymptomatic infants diagnosed by newborn screening.

Nerve, muscle and inflammatory cells involved in gastrointestinal (GI) function have high-energy requirements, and are affected in mitochondrial disorders. Familial aggregation of irritable bowel syndrome (IBS) frequently involves mothers and their children. Since mitochondrial DNA (mtDNA) is maternally inherited, mtDNA single nucleotide polymorphisms (SNPs) could confer risk to the development of IBS. The mtDNA SNPs, 16519C>T and 3010G>A, are associated with migraine and childhood cyclic vomiting syndrome. Our hypothesis is that these mtDNA SNPs are associated with functional GI disorders (FGIDs) and GI functions. The mt genome was first tested for the 7028C polymorphism (defining haplogroup H) in 699 patients or controls, and those with 7028C further genotyped at 16519 and 3010. Phenotypes were based on symptoms (validated questionnaires and criteria) and GI physiology using validated motor and sensory studies. IBS-C and IBS-Alt are less prevalent in individuals with the 7028C mtDNA polymorphism than in individuals with 7028T. Conversely, 7028C is associated with higher maximum tolerated volume (lower satiation) compared to 7028T. Among those with 7028C, non-specific abdominal pain (chronic abdominal pain or dyspepsia) was significantly associated with 3010A compared to 3010G (odds ratio 3.3, p=0.02), and slower gastric emptying was statistically associated with 3010G. There were no significant associations of mtDNA genotypes tested and stomach volumes, small bowel or colonic transit, rectal compliance, motor or sensory functions. Thus, variation in mtDNA may be associated with satiation, gastric emptying and possibly pain; further studies of mtDNA in appetite regulation and larger numbers of patients with FGIDs are warranted. Key words: 16519T, 3010A, irritable bowel syndrome, dyspepsia.

Cyclic vomiting syndrome (CVS) is a disorder noted for its unique intensity of vomiting, repeated emergency department visits and hospitalizations, and reduced quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. Because no accepted approach to management has been established, the task force was charged to develop a report on diagnosis and treatment of CVS based upon a review of the medical literature and expert opinion. The key issues addressed were the diagnostic criteria, the appropriate evaluation, the prophylactic therapy, and the therapy of acute attacks. The recommended diagnostic approach is to avoid "shotgun" testing and instead to use a strategy of targeted testing that varies with the presence of 4 red flags: abdominal signs (eg, bilious vomiting, tenderness), triggering events (eg, fasting, high protein meal), abnormal neurological examination (eg, altered mental status, papilledema), and progressive worsening or a changing pattern of vomiting episodes. Therapeutic recommendations include lifestyle changes, prophylactic therapy (eg, cyproheptadine in children 5 years or younger and amitriptyline for those older than 5), and acute therapy (eg, 5-hydroxytryptamine receptor agonists, termed triptans herein, as abortive therapy, and 10% dextrose and ondansetron for those requiring intravenous hydration). This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the diagnosis and treatment of CVS in children and adolescents.

Cyclic vomiting syndrome (CVS) was initially described in children but can occur in all age groups. Cyclic vomiting syndrome is increasingly recognized in adults. However, the lack of awareness of CVS in adults has led to small numbers of diagnosed patients and a paucity of published data on the causes, diagnosis and management of CVS in adults. This article is a state-of-knowledge overview on CVS in adults and is intended to provide a framework for management and further investigations into CVS in adults.

OBJECTIVE: Complex Regional Pain Syndrome Type I (CRPS-I), previously known as Reflex Sympathetic Dystrophy (RSD), is an idiopathic condition characterized by localized, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (i.e., swelling, skin color and temperature changes, altered perspiration) that usually appears following a "noxious" trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited mitochondrial disease, an association not previously published. METHODS: Medical records of about 500 clinic patients seen by one pediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria. RESULTS: CRPS-I was present in eight children in seven families, each of which also had additional functional/dysautonomic conditions, the most common (>/=4 cases per condition) being: gastrointestinal dysmotility, migraine, cyclic vomiting and chronic fatigue. All seven probands studied met Nijmegen (2002) diagnostic criteria for definite mitochondrial disease based upon the clinical signs and symptoms and biochemical analyses. Six of the seven families met our pedigree-based criteria for probable maternal inheritance. CONCLUSION: In one tertiary-care pediatric genetics practice, children meeting the CRPS-I diagnostic criteria frequently have additional autonomic-related conditions secondary to maternally-inherited mitochondrial disease, suggesting that mitochondrial DNA sequence variants can predispose towards the development of CRPS-I and other dysautonomias. CRPS-I should be considered in patients with mitochondrial disease who complain of idiopathic pain. Maternally inherited mitochondrial disease may not be a rare cause of CRPS-I, especially in children who present with other manifestations of dysautonomia.