Araujo APQC, Araujo IP, Araujo AQC. J Rare Dis Res Treat. (2018) 3(1): 1-5 Journal of www.rarediseasesjournal.com Rare Diseases Research & Treatment

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Autonomic dysfunction in diseases Alexandra Prufer de Queiroz Campos Araujo1*, Igor Prufer de Queiroz Campos Araujo2, Abelardo de Queiroz Campos Araujo3 1Institute of Pediatrics, Federal University of Rio de Janeiro (UFRJ). Rua Bruno Lobo 50, Cidade Universitária, Rio de Janeiro, RJ 21941-912, Brazil 2School of Medicine, Federal University of Rio de Janeiro (UFRJ) Rua Bruno Lobo 50, Cidade Universitária, Rio de Janeiro, RJ 21044-020, Brazil 3The Institute of , Federal University of Rio de Janeiro (UFRJ). Av Venceslau Braz, 215, Botafogo, Rio de Janeiro, RJ 22290-160, Brazil

Article Info ABSTRACT

Article Notes Background: Motor neuron disorders predominately result in progressive Received: October 04, 2017 weakness. Nevertheless a wider expression of symptoms and signs point to Accepted: January 30, 2018 a more multisystemic involvement. Autonomic nervous system findings have been reported in animal models, adult and child motor neuron diseases. *Correspondence: Dr. Alexandra Prufer de Queiroz Campos Araujo, Institute of Objective: Review the literature on autonomic findings in motor neuron Pediatrics, Federal University of Rio de Janeiro (UFRJ). Rua diseases. Bruno Lobo 50, Cidade Universitária, Rio de Janeiro, RJ 21941-912, E-mail: [email protected] Method: A PubMed literature search. © 2018 Araujo APQC. This article is distributed under the terms Results: In the present review, we will discuss the neuropathological and of the Creative Commons Attribution 4.0 International License. clinical features of dysautonomia reported in motor neuron disease in humans and animal models. Keywords autonomic nervous system Conclusion: The literature points to considering careful autonomic spinal muscular evaluation and management in patients with motor neuron disorders. motor neuron disease animal models

Background Autonomic nervous system (ANS) disorders are found either as a primary disease or in association with other nervous system disorders. Dysautonomia is a general term used to describe a

therefore these conditions are often misdiagnosed. The pathological involvementfailure of the can ANS. be Symptomseither central, are wide-ranginginvolving structures and unspecific; as the intermediolateral (IML) column, the dorsal nucleus of the vagus and other brainstem nuclei, or peripheral postganglionic path1. Until recently, acquired and hereditary motor neuron diseases have been considered disorders clinically and pathologically limited to the motor neurons. However, this well established knowledge has been challenged by new clinical and experimental data. Recent evidences have led to believe that these conditions may have a wider range of involvement, also affecting the ANS2. Finally, although expression of ANS occurs in primary motor disorders and 3, it was not until recently, that a anatomical intersection of those two neurologicalsympathicomimetics systems have may been show found benefit4. in motor performance

motor neuron diseases in general and in SMA, both in humans and in animalIn this models. review, we will focus on findings of dysautonomia in

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Methods in the SMA mouse model. This animal model For this review, the literature search was based SMNDelta7 producesPTN) deficiency drier and was fewer examined fecal pellets on gastroenteric when compared function to on PubMed using the Mesh terms “Motor Neuron the control mice. Also mice had delayed gastric Disease”,“Bulbo-Spinal Atrophy, X-Linked”, “Muscular SMNDelta7 emptying and slow liquid transit in the small intestine. Atrophy, Spinal”, “Spinal Muscular of Childhood”, Central nervous system gene therapy did not rescue the gastroenteric dysfunction, suggesting a direct effect of “Autonomic Nervous System Diseases”, “Adrenergic Fibers”, 8. “Parasympathetic“Autonomic Nervous Nervous System”, System”, “Autonomic “Sympathetic Dysreflexia”, Nervous System”, “Cholinergic Fibers”. Articles that did not refer to SMN-PTNAdditionally, deficiency distal in thenecrosis, enteric a nervous feature system of SMA mice models, is thought to be a result of ANS dysfunction were not retrieved by the search were included as they producing impaired vascularization9. werethe specific cited in topics others were and/or not considered included. to Four have articles important that Finally, in mice, receives innervation and pertaining results. The review is divided into three from sympathetic neurons at the neuromuscular junction, topics: Dysautonomia in motor neuron diseases in animal where beta2-adrenreceptors are depicted on confocal models, in Motor Neuron Diseases in adults and in Spinal microscopy and a trophic role for this interaction is Muscular Atrophies of Childhood. postulated4. Results In summary, a number of animal models provided Animal models strong evidences of the involvement of the ANS in SMA. Using animal models is an excellent way to test and Dysautonomia in Motor Neuron Diseases of adults prove an etiopathogenic hypothesis. To this end, the Amyotrophic lateral sclerosis (ALS) is a progressive involvement of the ANS in motor neuron diseases has been explored particularly in (SMA) genetic mutations, that involves motor neurons in the 4-9 mouse models . cerebralneurodegenerative cortex, brain disorder, stem and rarely spinal associated cord. Degeneration with specific Heier et al5 found evidence of both myocardial and ANS of both lower motor neurons and upper motor neurons disturbances present in SMNDelta7 SMA mouse model. are crucial neuropathological features of ALS 8. ALS has Bradyarrhythmia was present in SMA mice relative to traditionally been considered to be a pure motor disease, in unaffected heterozygous littermates from a postnatal which sensory function and coordination remain intact10, and the existence of additional neurological manifestations at every time point electrocardiograms were recorded. or other organ involvements suggest an alternative Furthermore,second day and immunostaining PR interval wasfor sympathetic significantly innervation elongated diagnosis. However, it is increasingly recognized that non- showed a reduced number of branches in both ventral and motor manifestations may occur11. dorsal heart views. Thus a decrease in sympathetic tone Symptoms of dysautonomia are not prominent in ALS could be responsible for an autonomic imbalance. but were recently reported in several studies. Evidence for Accordingly, slow heart frequency was also described involvement of the ANS has also accumulated12. by others, studying the same animal model6. Furthermore, Autonomic symptoms such as orthostatic hypotension delivery of a survival motor neuron-1 transgene using a or postural dizziness are rare in patients with ALS13. self-complementary adeno-associated virus serotype 9 However, advanced cases exhibit blood pressure abolished this symptom. Thus authors conclude that this feature is most likely attributable to aberrant autonomic accompanied by tachycardia, as well as sudden falls in signaling. bloodfluctuations, pressure. including These frequently paroxysmal occur hypertensive during sleep episodes13,14. In In contrast, Biondi et al7, studying wild-type and type this way, a consistent body of evidences has suggested that 2 SMA-like mice (SmnDelta7/_7 SMN2+/ enhanced sympathetic drive of presumably central origin, also showing that cardiac and respiratory function are and possibly reduced parasympathetic drive, characterize 12 impaired in SMA-like mice, suggest that; there is−) no althoughdefect in the autonomic cardiovascular state in ALS . sympathetic activity and that differences in heart rate are ALS patients often report increased or reduced more likely due to cardiac conduction defects. They used sweating in their palms, reduced skin temperature, or pharmacological inhibition of both sympathetic (atenolol) skin discoloration and studies of sudomotor function and parasympathetic (atropine) branches and an exercise have provided evidence of sympathetic postganglionic protocol. cholinergic denervation in this disease15-17. The impact of Survival Motor Neuron Protein (SMN- Within the spectrum of neuropathology, the ANS

Page 2 of 5 Araujo APQC, Araujo IP, Araujo AQC. J Rare Dis Res Treat. (2018) 3(1): 1-5 Journal of Rare Diseases Research & Treatment appears to be the least frequently and systematically caused by a trinucleotide repeat expansion in the androgen studied, although modern morphological techniques may receptor gene. Affected males typically develop weakness be applied to evaluate its changes. This is partly due to in their mid-forties, as well as evidence of androgen limited access to the ANS via and partly because insensitivity with reduced fertility and gynecomastia. of lack of extensive sampling at autopsy. Nevertheless, SBMA causes a progressive degeneration of the lower in analogy to the loss of motorneurons, morphometric motor neurons and muscle. ANS involvement has not studies have detected neuronal loss in the thoracic18,19 been considered part of SBMA. Recently, however, Rocchi and sacral20 IML nucleus of the , which contain et al.24 assessed the autonomic cardiovascular function in sympathetic and parasympathetic preganglionic neurons, 5 SBMA patients. Autonomic function tests were abnormal respectively. On the other hand, atrophic neurons with in 4/5 patients, and plasma noradrenaline concentration intracytoplasmic inclusions such as Bunina bodies have been documented in Onuf’s nucleus21. Using a monoclonal controls. The impairment of cardiovascular responses in additionwas significantly to reduced reduced plasma in noradrenaline patients when concentration compared to 22 observed in those patients suggests subclinical involvement antibodyfound that thatthe IML specifically column neurons binds phosphorylatedin ALS also exhibited high of the ANS in Kennedy disease24 but this study awaits molecularincreased weightimmunoreactivity neurofilament compared proteins, with Itoh control et al. individuals. Sympathetic ganglion neurons exhibited similarly high immunoreactivity for phosphorylated high furtherSpinal muscularconfirmation. atrophies of childhood SMA is widely known as a motor neuron disorder and A unique patient with ALS and a SOD1 (V118L) mutation is the most common example of motor neuron disease in molecular weight neurofilament in all studied individuals. which has developed autonomic failure exhibited marked children and adolescents. SMA is an autosomal recessive neuronal loss in autonomic nuclei in the medulla and the disorder, which is the leading genetic cause of infantile 23 IML column death. It occurs as a result of homozygous mutation are involved in autonomic functions are vulnerable to the of the survival motor neuron gene (SMN1), marked by . These findings suggest that neurons that disease process in both sporadic and genetic ALS. progressive degeneration of motor neurons in the spinal There is evidence for subclinical involvement of both cord resulting in weakness and muscular atrophy. The sympathetic and parasympathetic nervous systems in severity of the disease is related to the residual amount of ALS. Decreased heart rate variability and baroreceptor SMN-PTN produced by the homologous gene (SMN2). SMN- sensitivity, as well as abnormalities in gastrointestinal PTN is ubiquitous and probably required for most tissues tract and salivary and lacrimal gland function indicate in normal development25. parasympathetic deterioration. Increased noradrenaline Signs and symptoms potentially related to levels and muscle sympathetic nerve activity support the dysautonomia have been reported in SMA, such as assumption of sympathetic hyperactivity, but evidence for postganglionic sympathetic deterioration, as indicated by cardiac sympathetic denervation, abnormal sympathetic tachycardia/bradycardia, fluctuation of blood pressure, emptying,hyperhidrosis, abnormalities abnormal infinger vascular cold-induced perfusion vasodilation,26-30. sympathetic deterioration. Most reported abnormalities gastroesophageal reflux, constipation and delayed gastric haveskin not response been found and to sudomotor correlate with dysfunction, disability reflectscore, disease duration, mode of involvement, or severity. Rather two young adults with SMA type III with atrial arrhythmias Probably the first report on ANS features in SMA was 31of limited numbers of patients were included in the studies and atrioventricular conduction disturbances . reviewed above. Furthermore, autonomic function may Atrioventricular conduction block and tachycardia were both also reported more recently by other authors32. in food intake and breathing problems, which are often It is in the longer survival SMA type I patients that be additionally compromised by inactivity, difficulties encountered in ALS patients, particularly in advanced the involvement of the ANS is more evident. Hachiya et stages. al26 of those children. Measurement of blood pressure, heart disturbances are infrequent in early ALS. Effective report the findings of autonomic function test on 3 compensatoryIn summary, mechanisms clinically in the significant ANS and diminished autonomic catecholamine during tachycardia and tilting, abnormal daily activity may explain why the subtle autonomic rate shows remarkable fluctuation, as well as high plasma dysfunction does not manifest clinically. these data suggest sympathetic hyperactivity and/or sympathetic-vagalfinger cold-induced imbalance. vasodilatation. Taken together, Another disease of the motor system, the spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, Further, in a large retrospective study of SMA type I is a slowly progressive X-linked ventilated patients, a quarter of them presented severe

Page 3 of 5 Araujo APQC, Araujo IP, Araujo AQC. J Rare Dis Res Treat. (2018) 3(1): 1-5 Journal of Rare Diseases Research & Treatment symptomatic bradycardia30. Finally, digital necrosis, reported in SMA type I patients, is, according to the authors, dependent of impaired regulation of vascular theautonomic consequences symptoms of ANS as well involvement. as specific Careful assessment autonomic of its tone, a function of the ANS28,29. evaluationfunction, would and helpmanagement to define strategiesare warranted to treat in or patientsprevent Despite this evidence, others, exploring cardiac with motor neuron disorders. evaluation with electrocardiogram and echocardiography Declarations in a case series of 37 SMA type II/III aged 6 to 65 years, found no dysfunction33. All authors participated in producing this work, from the literature review to article writing. Authors declare that Spinal muscular atrophy with respiratory distress (SMARD) is a rare motor neuron disease of infants that for this work. Since this work is a review, no original data can also result in dysautonomia. Autonomic crisis has been isthey available. have no conflict of interest. No funding was received reported34, in a child with SMARD and previous heart rate variability and absent typical circadian rhythm. References 1. Bannister R. Degeneration of the autonomic nervous system. Lancet. Neuropathological data also suggest the involvement of ANS in SMA. A recent neuropathological postmortem 2. 1971;Shababi 2(7717): M, Lorson 175-179. CL, Rudnik-Schöneborn SS. Spinal muscular study of SMA type 1 children revealed the wider spread atrophy: a motor neuron disorder or a multi-organ disease. J Anat. presence of neuronal degeneration35. The chromatolysis, degeneration and neuronophagia in the ventral thalamic 3. 2014;Pane M, 224(1): Staccioli 15-28. S, Messina S, et al. Daily salbutamol in young patients nuclei previously shown36,37 lesions in the posteroventral thalamic nuclei, Clarke’s 4. withKhan SMA MM, type Lustrino II. Neuromuscul D, Silveira Disord. WA, et 2008; al. Sympathetic 18(7): 536-540. innervation column and spinal ganglion, was38. Neurons confirmed, in asthe wellsacral as controls homeostasis of neuromuscular junctions in health and Onufrowicz’s nucleus exhibit central chromatolysis39,40. Additionally, neural tissue in the myenteric plexus of the 5. disease.Heier CR, Proc Satta Natl R, AcadLutz C,Sci. et 2016; al. Arrhythmia 113(3): 746-750 and cardiac defects are a

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