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Mitochondrial Disorder Caused Charles Darwin's Cyclic Vomiting

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Mitochondrial Disorder Caused Charles Darwin's Cyclic Vomiting International Journal of General Medicine Dovepress open access to scientific and medical research Open Access Full Text Article HYPOTHESIS Mitochondrial disorder caused Charles Darwin’s cyclic vomiting syndrome Josef Finsterer1 Background: Charles Darwin (CD), “father of modern biology,” suffered from multisystem John Hayman2 illness from early adulthood. The most disabling manifestation was cyclic vomiting syndrome (CVS). This study aims at finding the possible cause of CVS in CD. 1Krankenanstalt Rudolfstiftng, Vienna, Austria; 2Department of Pathology, Methods: A literature search using the PubMed database was carried out, and CD’s complaints, University of Melbourne, Victoria, as reported in his personal writings and those of his relatives, friends, colleagues, biographers, Australia were compared with various manifestations of mitochondrial disorders (MIDs), known to cause CVS, described in the literature. Results: Organ tissues involved in CD’s disease were brain, nerves, muscles, vestibular appa- ratus, heart, gut, and skin. Cerebral manifestations included episodic headache, visual distur- bance, episodic memory loss, periodic paralysis, hysterical crying, panic attacks, and episodes of depression. Manifestations of polyneuropathy included numbness, paresthesias, increased sweating, temperature sensitivity, and arterial hypotension. Muscular manifestations included periods of exhaustion, easy fatigability, myalgia, and muscle twitching. Cardiac manifestations included episodes of palpitations and chest pain. Gastrointestinal manifestations were CVS, dental problems, abnormal seasickness, eructation, belching, and flatulence. Dermatological manifestations included painful lips, dermatitis, eczema, and facial edema. Treatments with beneficial effects to his complaints were rest, relaxation, heat, and hydrotherapy. Conclusion: CVS in CD was most likely due to a multisystem, nonsyndromic MID. This diag- nosis is based upon the multisystem nature of his disease, the fact that CVS is most frequently the manifestation of a MID, the family history, the variable phenotypic expression between affected family members, the fact that symptoms were triggered by stress, and that only few symptoms could not be explained by a MID. Keywords: hyperemesis, cyclic vomiting, fatigue, metabolic disease, mitochondrial disorder, multisystem disorder, respiratory chain Introduction Cyclic vomiting syndrome (CVS) is a rare, chronic, debilitating, functional, gastroin- testinal disorder initially described in children1 but increasingly recognized in adults.2,3 CVS is characterized by recurrent, stereotypic episodes of intense nausea, intractable nonbilious vomiting, and abdominal pain lasting hours or days.4,5 Between the attacks, patients remain symptom-free and return to baseline health, unless CVS has become coalescent.5 The most common prodromal symptoms are nausea and abdominal discomfort.6 In adults, CVS is commonly associated with anxiety and depression.7 Correspondence: Josef Finsterer KAR, PO Box 20, 1180 Vienna, Austria Triggering factors include stroke,6 intake of morning medication,6 or cannabis Tel +43 1 7116 592 085 abuse.8 Severity of CVS in adults ranges from mild disease with infrequent episodes Fax +43 1 4781 711 Email [email protected] to severe, life-disabling disease requiring multiple emergency department visits or submit your manuscript | www.dovepress.com International Journal of General Medicine 2014:7 59–70 59 Dovepress © 2014 Finsterer and Hayman. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted http://dx.doi.org/10.2147/IJGM.S54846 without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Finsterer and Hayman Dovepress frequent hospitalizations.9,10 Frequently, CVS is associated the frequent association of CVS with other typical clini- with migraine, particularly in children,11 or mitochondrial cal manifestations of a MID,11,36,37 the abnormal urinary dysfunction.12 Onset of CVS is earlier among those who organic acid profile in some CVS patients,32 and the benefi- develop migraine.11 In adults, CVS is frequently associated cial response of CVS to compounds such as L-carnitine or with autonomic dysfunction, more frequently with sympa- coenzyme-Q, which are frequently used as supportive mea- thetic than with parasympathetic dysfunction.13 Females with sures in MIDs.12 In a 20-year-old adult, CVS was attributed CVS frequently have hyperemesis during pregnancy. to the FAOD multiple acyl-coenzyme A dehydrogenase CVS occurs in all age groups, with a mean age of onset of deficiency, manifesting with anion gap metabolic acidosis, 4 years in children14 and 35 years in adults.5 The demographic nonketotic hypoglycemia, collapse, multiorgan failure, and profile and disease characteristics are similar in pediatric and death.18 adult-onset CVS; however, pediatric CVS more likely occurs Generally, CVS is diagnosed upon the history, clinical in females and has a higher prevalence of concomitant neuro- presentation, and after exclusion of other possible causes.38 In logical abnormalities.3 In a study of 101 CVS patients, 65% adults, CVS is diagnosed according to the Rome III criteria, were female and 29% were pediatric cases.3 The prevalence which include stereotypic, acute-onset episodes of nausea of cognitive impairment is higher in children as compared and vomiting lasting ,1 week, more than two episodes to adults.3 Latency between onset and diagnosis is longer in within the previous year, and absence of nausea or vomit- pediatric as compared to adult patients.3 CVS is a rare con- ing between the episodes.39 In children, CVS is diagnosed dition in adults but is regarded as the second most common according to essential criteria (recurrent, severe, discrete cause of recurrent vomiting after gastroesophageal reflux episodes of vomiting with varying intervals of normal in children, affecting 1.9% of school-aged children.15 CVS health between episodes) and supportive criteria (vomit- is present in about 2% of Scottish and Western Australian ing episodes and patterns which are similar to each other school children.16,17 Despite increasing awareness, CVS often within each individual case).40 Laboratory and radiographic remains unrecognized for months or even years in children studies are typically normal.32,35,40 Because of the lack of and adults. awareness, CVS is often diagnosed with delay, particularly The etiology is multifactorial and heterogeneous since in adults.5 The diagnosis may be also delayed because there CVS has been described in patients with mitochondrial dis- is no specific test to confirm the diagnosis. In cases in which orders (MIDs) and fatty acid oxidation disorders (FAODs).4,18 CVS remains unrecognized, patients undergo unnecessary In pediatric cases with migraine, CVS was associated with diagnostic procedures and treatment without benefit41 and the mitochondrial DNA single nucleotide polymorphisms may develop interepisodic nausea and loss of periodicity m.16519C.T and m.3010G.A.19–22 CVS was reported (coalescence of symptoms).3 Differential diagnoses include in a patient with Kearns–Sayre syndrome23 due to a 3 kb hydrocephalus, brain tumor, Budd–Chiari malformation,6 mitochondrial DNA deletion with a heteroplasmy rate of medium chain acyl-CoA dehydrogenase deficiency, late- 30%–40% in blood, and it was also a phenotypic feature in onset form of glutaric acidemia type II, short chain acyl-CoA seven of eleven patients with mitochondrial encephalomyo- dehydrogenase deficiency, short-chain 3-hydroxy acyl-CoA pathy, lactic acidosis, and stroke-like episodes (MELAS) dehydrogenase deficiency, gastrointestinal reflux, and chronic first described in the literature.24 Episodic vomiting is also a cannabis abuse.4 These diagnoses need to be excluded before frequent feature of other MELAS patients,12 mitochondrial diagnosing CVS. neurogastrointestinal encephalomyopathy,25 mitochondrial There is no standard, evidence-based, generally accepted depletion syndrome due to MPV17 or TYMP mutations,26 treatment of CVS.5 Only symptomatic measures are avail- Leigh-syndrome,27 or nonsyndromic MIDs.28 Additionally, able, which can be separated into prophylactic measures and maternal inheritance of symptoms and signs and abnormal treatment of the acute symptoms. Prophylactic treatment is urinary excretion of organic acid in children suggested MID usually carried out with cyproheptadine (age 5 years) or to have been causative.29–32 Some CVS patients may also amitriptyline (age .5 years). Some patients may benefit present with lactic acidosis.10,33 CVS has been regarded a from flunarizine, a selective calcium antagonist,34 and some manifestation of migraine by some authors34 since it evolves patients additionally respond to topiramate, coenzyme-Q, or to migraine in one third of the cases.32,35 Further arguments L-carnitine.3 The response rate to amitryptiline was reported for a mitochondrial defect as cause of CVS are the frequent as 52.7% in an open-label, subject recall-based study in chil- transmission of CVS via a maternal trait of inheritance,32 dren and adults.12
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