© Springer International Publishing Switzerland 2017Christophe Faure, Nikhil Thapar and Carlo Di Lorenzo (eds.)Pediatric Neurogastroenterology10.1007/978-3-319-43268-7_27
27. Familial Dysautonomia and Mitochondrial Disorders
Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II” Italy, via Pansini 5, Naples, 80131, Italy
KeywordsFamilial dysautonomiaMitochondrial disordersRiley-Day syndromeDysautonomic crisisOropharyngeal incoordination
Familial dysautonomia, also known as Riley-Day syndrome , is an autosomal recessive disorder , which occurs predominantly in the Ashkenazi Jewish population with an incidence of about 1 in 1370 individuals. It is associated with a complex neurological disorder that affects the sensory system and the autonomic nervous system functions . Although FD is caused by one gene and the penetrance is always complete, there is a great deal of variation in expression. The sensory dysfunction is characterized by alterations of small fiber neuronal populations such that patients with FD have impaired sensations of temperature, pain, and vibration. The autonomic dysfunction affects multiple systems, and it is characterized by cyclic manifestations of typical “dysautonomic crisis”; these crisis represent systemic reactions to physiologic and psychological stress. Gastrointestinal perturbations such as vomiting are the predominant part of the constellation of symptoms seen during an episode; other symptoms include hypertension, tachycardia, diaphoresis, personality changes, blotching of the skin, piloerection, functional ileus, and dilatation of pupils . Malfunction of the GI tract is the main clinical manifestation of FD with oropharyngeal incoordination being one of the earliest symptoms in the newborn. Discoordinated swallow is found in about the 60 % of patients with FD, and it is often responsible for the development of severe feeding alteration, malnutrition, and recurrent aspirations, which can lead to chronic lung disease . Impaired brainstem reflexes seem to underlie these abnormalities . Videofluorographic swallow studies allow for visualization of bolus flow throughout the upper aerodigestive tract in real time, and it is used to examine the presence and the timing of aspiration. In addition, cineradiographic swallowing studies may document the level of functional ability [5, 6]. However, the most prominent GI symptom is the propensity to vomit. Recurrent vomiting can be caused by peripheral as well as central autonomic dysfunction. Vomiting can occur cyclically as a part of dysautonomic crisis or daily in response to stress of arousal. When the vomiting is associated with a constellation of symptoms including hypertension, tachycardia, and diffuse sweating, the symptom is secondary to the autonomic crisis. The efficacy of diazepam in reducing vomiting during autonomic crisis suggests that the crisis is caused by a central phenomenon, probably developed from autonomic seizures . Gastroesophageal reflux is another common problem. Sundaram and colleagues found a prevalence of 95 % of GERD in a sample study of 174 patients with FD . Clinical symptoms can range from regurgitation to more atypical manifestations such as wheezing, apnea, or iron deficiency anemia secondary to severe esophagitis. A major contributor to the development of GERD is represented by the dysfunction and the increased relaxation of the lower esophageal sphincter (LES). The LES is controlled by postganglionic parasympathetic fibers within the vagus nerve and preganglionic sympathetic fibers. The parasympathetic circuits are able to control both the relaxation and the contraction of LES, while the sympathetic system evokes exclusively the contraction. The pathogenesis of GERD is correlated to the reported degeneration of sympathetic and the consequent prevalence of the parasympathetic nervous system. Thickened fluids and smaller, more frequent meals represent the first steps in management. Medical management includes use of H2-antagonists and proton pump inhibitors. However, if symptoms persist and events such as hematemesis occur, surgical intervention (such as a fundoplication) is strongly recommended. Up to 80 % of patients with FD undergo fundoplication surgery [9, 10]. The impact of the fundoplication wrap on the natural history of these patients compared with that of untreated patients has not been clarified. GERD can reoccur after the fundoplication, and up to 12 % of patients who receive the procedure require a second surgery . Esophageal dilatation and achalasia are possible recognized complications after fundoplication surgery [12, 13].
Mitochondrial disorders (MD) refer to a clinically heterogeneous group of disorders that arise as a result of a dysfunction of the mitochondrial respiratory chain . They can be caused by either inherited or spontaneous mutations of nuclear (nDNA) or mitochondrial DNA (mtDNA) which lead to altered functions of the proteins or RNA molecules that normally reside in mitochondria. Defects in nDNA can be inherited from either parent, while defects in the genes of the mtDNA are maternally inherited. Mitochondria are present in virtually all cell types of human body, and their damage affects especially the main energy-dependent tissues such as the brain, heart, liver, skeletal muscles, kidney, and the endocrine and respiratory systems . MD primarily affect children, but adult onset is becoming more recognized. Over 100 mtDNA abnormalities associated to MD have been described in the literature, some resulting in profound disability and premature death . Gastrointestinal symptoms are reported in 15 % of patients with MD occurring usually in childhood, before the onset of more classical extraintestinal symptoms of MD . The major MD presenting with GI symptoms are mitochondrial neurogastrointestinal encephalomyopathy (MNGIE ) (peripheral neuropathy, ophthalmoparesis, leukoencephalopathy, muscle wasting, cachexia) , Leigh syndrome (subacute necrotizing encephalomyelopathy resulting in hypotonia, bulbar paresis, abnormal eye movements, lack of coordination of extremities, and regressive psychomotor development) , Kearns-Sayre syndrome (chronic progressive external ophthalmoplegia, atypical pigmentary retinopathy, ataxia, and heart block) , and MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) . MNGIE is a rare autosomal recessive disorder caused by mutations in the gene-encoding thymidine phosphorylase (TP), which lead to absolute or nearly complete loss of its catalytic activity, producing systemic accumulations of its substrates, thymidine (dThd) and deoxyuridine (dUrd) . MNGIE typically presents between the first and third decades with GI symptoms as presenting feature in approximately half of the cases . All patients will eventually develop GI symptoms during the course of the disease. Main symptoms attributable to GI dysmotility include dysphagia, early satiety, nausea, vomiting, abdominal pain and cramps, borborygmi, intestinal pseudo-obstruction, and bloating. These symptoms invariably lead to weight loss, which may manifest as extreme cachexia. Although the average age at presentation is approximately 18 years, GI symptoms have been reported earlier during the first year of life, including diarrhea at 5 months of age in one case and intussusception at 8 months in another infant . Different mtDNA mutations have been associated with GI disorders in MD. Recently Horvath et al. found a new heteroplasmic mutation in the anticodon-stem of mitochondrial tRNA of a girl presenting with clinical symptoms of MNGIE-like GI dysmotility and cachexia . Intestinal pseudo-obstruction is an increasingly recognized clinical feature in MNGIE and represents an important cause of chronic intestinal failure. The pathogenesis of intestinal pseudo-obstruction in MD is still unclear. Giordano et al. described the presence of smooth cell atrophy, mitochondrial proliferation, and mtDNA depletion in the muscularis propria of small intestine in two different studies, performed in one and four patients suffering from MNGIE, respectively [24, 25]. Their pathogenetic hypothesis is that the baseline low abundance of mtDNA molecules may predispose smooth muscle cells of the external layer of muscularis propria to the toxic effects of circulating dThd and dUrd. More recently, Zimmer et al. reported an alteration of the interstitial cells of Cajal (ICC) network in MNGIE . These findings support the hypothesis that ICC loss might be an early pathogenetic event in MNGIE-associated gut motor dysfunction before significant myopathic and/or neuropathic structural changes occur . Poor feeding and vomiting are often the initial presenting symptoms in Leigh syndrome [27, 28]. Mutations in more than 40 mtDNA and nuclear-encoded genes have so far been linked to this condition. Mutations in the nuclear gene-encoding SURF1, a mitochondrial protein involved in cytochrome c oxidase assembly, have been noted in many patients with Leigh syndrome and GI symptoms . Dysphagia is also common in patients affected by Leigh syndrome . Dysphagia seems to be due to primary esophageal dysmotility, neurogenic causes, or a combination of these two factors. Fifteen percent of patients with Kearns-Sayre syndrome, a MD characterized by progressive cytochrome c oxidase deficiency, presents with swallowing difficulties and dysphagia . Shaker et al. described the manometric characteristics of a cervical dysphagia in a patient with Kearns-Sayre observing the absence of pharyngeal peristalsis, abnormally low upper esophageal sphincter resting pressure, and the absence of proximal esophageal peristalsis . Eighty percent of patients with MELAS have the same mtDNA mutation, m.3243A>G, while the remaining cases are caused by a range of other mtDNA mutations. Diagnostic criteria include a stroke-like episode occurring before 40 years, neurological disturbance characterized by seizures and/or progressive dementia, lactic acidosis, and a ragged-red fibers myopathy . Other neurological features include severe migraines, sensorineural hearing loss, peripheral neuropathy, and psychiatric problems including depression. Gastrointestinal problems have been frequently reported in children affected by MELAS. Sproule et al. reported at least one GI disturbance in 64 % of a prospective cohort of 45 patients with a diagnosis of MELAS . Symptoms included abdominal discomfort, vomiting, constipation, diarrhea, gastroparesis, intestinal pseudo-obstruction, and recurrent pancreatitis . Other MD are characterized by nonspecific GI symptoms including dysphagia, delayed gastric emptying, feeding difficulties, GERD and/or vomiting, diarrhea, failure to thrive, and abdominal pain . GI symptoms are predominantly localized in the upper GI tract. Chitkara et al. reported the cases of six children with MD who presented upper GI symptoms such as vomiting, food aversion, poor suck, and feeding intolerance . Dysmotility disorders like delayed gastric emptying and intestinal pseudo-obstruction have been reported in children and adult patients with MD. Gastroparesis has been associated with various diseases and may occur as part of a MD [37, 38]. There is no consensus regarding management of patients with gastroparesis who do not respond to simple antiemetic or prokinetic therapy. Tatekawa et al. proposed a new surgical technique in a 12-year-old girl with pyruvate dehydrogenase complex deficiency with refractory gastroparesis .