Richard G. Boles

Cyclic vomiting syndrome in adults

Abstract  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.

Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy.

MPV17 is a mitochondrial inner membrane protein of unknown function recently recognized as responsible for a mitochondrial DNA depletion syndrome. The aim of this study is to delineate the specific clinical, pathological, biochemical, and molecular features associated with mitochondrial DNA depletion due to MPV17 gene mutations. We report 4 cases from 3 ethnically diverse families with MPV17 mutations. Importantly, 2 of these cases presented with isolated liver failure during infancy without notable neurologic dysfunction. Conclusion: We therefore propose that mutations in the MPV17 gene be considered in the course of evaluating the molecular etiology for isolated, rapidly progressive infantile hepatic failure. (HEPATOLOGY 2007.)

A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency

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.

Mitochondrial DNA control region sequence variation in migraine headache and cyclic vomiting syndrome

Migraine headache is a very common condition affecting about 10% of the population that results in substantial morbidity and economic loss. The two most common variants are migraine with (MA) and without (MO) aura. Often considered to be a migraine‐like variant, cyclic vomiting syndrome (CVS) is a predominately childhood condition characterized by severe, discrete episodes of nausea, vomiting, and lethargy. Disease‐associated mitochondrial DNA (mtDNA) sequence variants are suggested in common migraine and CVS based upon a strong bias towards the maternal inheritance of disease, and several other factors. Temporal temperature gradient gel electrophoresis (TTGE) followed by cyclosequencing and RFLP was used to screen almost 90% of the mtDNA, including the control region (CR), for heteroplasmy in 62 children with CVS and neuromuscular disease (CVS+) and in 95 control subjects. One or two rare mtDNA‐CR heteroplasmic sequence variants were found in six CVS+ and in zero control subjects (P = 0.003). These variants comprised 6 point and 2 length variants in hypervariable regions 1 and 2 (HV1 and HV2, both part of the mtDNA‐CR), one half of which were clustered in the nt 16040–16188 segment of HV1 that includes the termination associated sequence (TAS), a functional location important in the regulation of mtDNA replication. Based upon our findings, sequencing and statistical analysis looking for homoplasmic nucleotide changes was performed in HV1 among 30 CVS+, 30 randomly‐ascertained CVS (rCVS), 18 MA, 32 MO, and 35 control haplogroup H cases. Within the nt 16040–16188 segment, homoplasmic sequence variants were three‐fold more common relative to control subjects in both CVS groups (P = 0.01 combined data) and in MO (P = 0.02), but not in MA (P = 0.5 vs. control subjects and 0.02 vs. MO). No group differences were noted in the remainder of HV1. We conclude that sequence variation in this small “peri‐TAS” segment is associated with CVS and MO, but not MA. These variants likely constitute risk factors for disease development. Our findings are consistent with previous data demonstrating progression of CVS into MO in many cases, and the co‐segregation in a maternal inheritance pattern of CVS and MO within families. A mitochondrial component in the pathogenesis of migraine and CVS has therapeutic implications, especially concerning the avoidance of fasting.

Maternal inheritance in cyclic vomiting syndrome

Cyclic vomiting syndrome (CVS), characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a fairly common, disabling, predominately‐childhood condition most often associated with migraine and dysautonomic features. Our group recently reported that children with CVS and additional neuromuscular disease manifestations demonstrate strong maternal inheritance of multiple disease manifestations and abnormal urine organic acids, suggesting the presence of predisposing mitochondrial DNA (mtDNA) sequence variants. In order to determine if maternal inheritance is present in CVS in general, a clinical interview was administered regarding 80 unrelated individuals with CVS ascertained randomly from the database of the Cyclic Vomiting Syndrome Association (CVSA). Disease manifestations consistent with potential mitochondrial dysfunction were far more common in matrilineal (sharing the same mtDNA sequence) versus in non‐matrilineal relatives, including mothers versus fathers (P = 3 × 10−9) and maternal versus paternal grandmothers (P = 2 × 10−6). Maternal inheritance is suggested in 52% of the 23 subjects with two or more neuromuscular abnormalities (“CVS+”) and in 54% of the 44 subjects without any neuromuscular abnormalities (“CVS−”). In both the CVS+ and CVS− sub‐groups, subjects, and affected matrilineal relatives of all ages suffer at a far higher incidence from several dysautonomic‐related conditions, including migraine and irritable bowel, as well as depression and hypothyroidism, while neuromuscular and cognitive disorders such as hypotonia and ADHD are common only in affected children. We conclude that mtDNA sequences predispose towards the development of protean disease manifestations in CVS patients ascertained through a disease‐specific association, as well as among their matrilineal relatives, whether or not neuromuscular disease is present in the proband. Since CVS was absent in all but one matrilineal relative of our probands, CVS is apparently a rare clinical presentation in individuals carrying the predisposing mtDNA sequences. The four conditions reported most frequently among the matrilineal relatives of our cases, migraine, depression, irritable bowel, and hypothyroidism, are known to segregate together in families, and our findings suggest that a common predisposing genetic factor is likely present on the mtDNA.

Treatment of cyclic vomiting syndrome with co-enzyme Q10 and amitriptyline, a retrospective study

BackgroundCyclic 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 treatmentMethodsUsing 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.ResultsSubjects/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 × 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).ConclusionOur 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.

Are pediatric and adult‐onset cyclic vomiting syndrome (CVS) biologically different conditions? Relationship of adult‐onset CVS with the migraine and pediatric CVS‐associated common mtDNA polymorphisms 16519T and 3010A

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.

Maternal inheritance in cyclic vomiting syndrome with neuromuscular disease

Cyclic vomiting syndrome (CVS), characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a predominately childhood condition associated with migraine and dysautonomic features. Disease‐associated mitochondrial DNA (mtDNA) sequence variants are suggested by a strong maternal bias in the inheritance of migraine, and the recent findings of mtDNA variants in a few children with CVS and additional neuromuscular disease manifestations (“CVS+”). A clinical interview using a questionnaire was administered (generally) to one parent of 62 children with CVS+. Non‐senile disease manifestations, including migraine, myopathy, seizures, and dysautonomia‐like symptoms, were far more common in matrilineal versus non‐matrilineal relatives, including being present in 75% of the mothers versus in only 11% of the fathers (P < 0.001). Overall, maternal inheritance is suggested in 86% of the families (in 65% strongly so). Disease manifestations in subjects and their affected matrilineal relatives are predominately intermittent and consistent with dysautonomia, including increased vital sign fluctuations. Body fluid metabolites and muscle biopsy findings are consistent with mitochondrial dysfunction in most cases tested. We conclude that mtDNA sequence variants are at least risk factors in the development of disease in most children at this “severe” end of the CVS spectrum, likely involving a maternally inherited propensity towards dysautonomia.

High degree of efficacy in the treatment of cyclic vomiting syndrome with combined co-enzyme Q10, L-carnitine and amitriptyline, a case series

BackgroundCyclic 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.MethodsA 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.ResultsVomiting 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.ConclusionOur 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.

Macular Pattern Retinal Dystrophy, Adult-onset Diabetes, and Deafness: A Family Study of A3243G Mitochondrial Heteroplasmy

PURPOSE To correlate mitochondrial DNA (mtDNA) mutation with phenotypic expression in three members of a Finnish family with macroreticular pattern dystrophy, non-insulin-dependent diabetes mellitus, and deafness. METHODS A multiplex polymerase chain reaction/allele-specific oligonucleotide method was used to screen 10 mtDNA point mutations known to cause mitochondrial DNA disorders, often characterized by myopathy, retinopathy, or both. Quantitative analysis of mutant mitochondrial DNA was performed in three tissue types in each of three family members by determining the percentage of mutant mtDNA in blood, buccal cells, and hair follicles. RESULTS A heteroplasmic A3243G mtDNA point mutation was found in each of the three family members studied. Heteroplasmy refers to the coexistence of normal and mutant mitochondria in the same cell. The average percentage of mutant heteroplasmy ranged from 11% to 25%. The severity of disease symptoms did not appear to correlate with the average degree of mutant heteroplasmy in the three tissues analyzed. CONCLUSIONS Molecular confirmation in this family emphasizes the importance of mitochondrial DNA mutation analysis in patients with macular pattern retinal dystrophy and other mitochondrial associated nonocular disease, such as non-insulin-dependent diabetes mellitus and deafness. The detection of a disease-associated mitochondrial DNA mutation warrants genetic counseling, appropriate patient follow-up, and possibly the molecular testing of other at-risk family members.