A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy
Graphical abstract
Introduction
Autoimmune autonomic ganglionopathy (AAG) is a rare disease that presents with various autonomic symptoms. The ganglionic neuronal nicotinic acetylcholine receptor (gAChR) mediates fast synaptic transmission in all peripheral autonomic ganglia in the autonomic nervous system, comprising two α3 subunits and three β4 subunits [1,2]. However, the frequency of symptoms, extra-autonomic manifestations (coexistence with autoimmune rheumatic diseases and tumours, brain involvement, sensory disturbance, and endocrine disorders), laboratory findings, and prognosis of AAG remain largely unknown [3,4]. Approximately 50% of patients with AAG possess autoantibodies (Abs) against the gAChR [5,6]. Originally, gAChR Abs found in patients with AAG were thought to be specific for acetylcholine receptors (AChRs) containing the α3 subunit and were not assumed to bind non-specifically to nicotinic AChRs (nAChRs). Several previous reports have described the autonomic symptoms of gAChR Ab-positive AAG as severe, widespread, and predominantly post-ganglionic in distribution. Moreover, such studies have revealed that Ab levels are correlated with disease severity and pathogenesis [7,8]. Our previous study was the first to identify a subunit-specific Ab for gAChR (i.e., anti-gAChRβ4) [6]. Another subunit-specific Ab for gAChR, anti-gAChRα3, has been associated with several autonomic dysfunctions in an experimental model of AAG [[9], [10], [11], [12]]. Despite our previous findings, the clinical characteristics of patients with AAG who are seropositive for the gAChRβ4 Ab remain unknown. Therefore, we evaluated the frequency of individual autonomic symptoms and extra-autonomic manifestations such as sensory disturbance, central nervous system (CNS) involvement, endocrine disorders, and comorbid diseases (i.e., autoimmune diseases, tumours) in patients with AAG testing positive for gAChRα3 Abs, gAChRβ4 Abs, or both [3,13].
Differentiating AAG from other neurological disorders presenting with autonomic dysfunction via clinical and laboratory tests is often difficult [14]. In addition to anti-gAChR Ab levels, effective clinical tools are required to improve AAG diagnosis and monitoring. Neuroimaging data may aid in identifying clinically relevant post-ganglionic denervation. Metaiodobenzylguanidine (MIBG) is a physiological analogue of noradrenaline, which is taken up by the myocardium and actively transported into the noradrenaline granules of sympathetic nerve terminals by the noradrenaline transporter. Indeed, 123I-MIBG myocardial scintigraphy may assist in evaluating damage to postganglionic fibres of the cardiac sympathetic nerve based on decreases in the heart-to-mediastinum (H/M) ratio. We previously mentioned the usefulness of 123I-MIBG myocardial scintigraphy for AAG diagnosis [3]. Myocardial scintigraphy is generally used to evaluate autonomic function in patients with suspected Lewy body disease or autonomic neuropathies such as diabetic neuropathy or familial amyloid polyneuropathy [[15], [16], [17], [18]]. However, no similar studies have been performed among patients with AAG. Therefore, the secondary aim of the present study was to determine the value of 123I-MIBG myocardial scintigraphy for AAG diagnosis, relative to other laboratory evaluations.
The present study aimed to determine the clinical characteristics of patients with AAG testing positive for gAChRβ4 Ab. We examined the frequency of autonomic and extra-autonomic manifestations in 179 patients with AAG testing positive for gAChRα3 Abs, gAChRβ4 Abs, or both Abs. Furthermore, our study highlights the value of 123I-MIBG myocardial scintigraphy for AAG diagnosis.
Section snippets
Standard protocol approvals and patient consent
All patients provided written, informed consent before participating in the present study. The Human Ethics Committees at the Nagasaki Kawatana Medical Center and Kumamoto University Hospital (Japan) approved this study (approval number 2011-21 and 1281, respectively).
Study design and participants
We obtained 1787 serum samples (from 1381 patients) from teaching and general hospitals throughout Japan between January 2012 and August 2018 (Supplementary data 1). Clinical diagnoses were made in each hospital. All hospitals
Clinical features of patients with seropositive AAG
Although patients were divided into subgroups based on the time course of their illness, chronic AAG was the predominant subtype in our study (133/179, 74%) (Table 1). Among those with chronic AAG, 12 patients (12/133, 9%) experienced an antecedent event, whereas 13 of 46 (28%) patients in the acute AAG group experienced an antecedent event. Twenty-five patients (14%) reported antecedent events shortly before the start of autonomic symptoms: flu-like symptoms (n = 11), enterocolitis (n = 9),
Discussion
In the present study, we investigated the clinical symptoms involving autonomic and extra-autonomic manifestations, and laboratory findings among a diagnosed cohort of 179 patients with AAG who tested positive for gAChRα3 Abs, gAChRβ4 Abs, or both. The gAChR Abs have the potential to physiologically block the ganglionic synaptic transmission in the both of sympathetic and parasympathetic nervous system [1,12]. Our findings indicated that autonomic and extra-autonomic dysfunction (i.e., sicca
Declaration of competing interest
None of the authors have any conflicts of interest to disclose.
Acknowledgements
The authors would like to thank Dr. S. Orimo (Department of Neurology, Kanto Central Hospital, Tokyo, Japan) for helpful discussions.
The authors are grateful to Drs. Masataka Umeda, Kunihiro Ichinose, Hideki Nakamura, Hitomi Minami, Hajime Isomoto, Akio Ido, Kiyoshi Migita, and Kazuhiko Nakao for useful discussions. The authors are indebted to members of Kumamoto University Hospital Department of Neurology and Nagasaki Kawatana Medical center Department of Neurology for discussing some issues
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Subunit-specific autoantibodies in autoimmune autonomic ganglionopathy
2022, Journal of NeuroimmunologyAutoimmune autonomic ganglionopathy: Ganglionic acetylcholine receptor autoantibodies
2022, Autoimmunity ReviewsCitation Excerpt :Finally, the introduction of any protein-based label (in this case, GL8990) can introduce sites for specific or non-specific binding of antibodies; indeed, false positive autoantibody results in Gaussia-luciferase LIP systems have been described [11]. Furthermore, from a clinical perspective, results of the LIP assay do not correlate with objective measures of autonomic failure [57]. These limitations for the LIP approach in detecting gnACHR antibodies may be responsible for the observed high rate of seropositivity for either α3 or β4 subunit autoantibodies in a wide range of unrelated disorders, many of which do not have objective findings consistent with true AAG (Table 2).