Decreased density of ganglia and neurons in the myenteric plexus of familial dysautonomia patients

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Abstract

Background: Familial dysautonomia (FD) is a hereditary disease of the autonomic and sensory nervous system. A prominent manifestation of FD is gastrointestinal dyscoordination, which contributes to the morbidity and mortality in FD. Aim: As the myenteric plexus is an essential factor in gastrointestinal motility control, we compared its morphology in appendices of FD patients and controls. Methods: Appendices from FD patients (N=19) were obtained during surgery of fundoplication and gastrostomy; normal appendices (N=17) were obtained from patients suspected to suffer from acute appendicitis, in whom, however, the appendix was found to be normal. Specimens were stained histochemically for NADPH diaphorase (NADPH-d) and in a blinded manner examined under a light microscope for seven morphologic parameters: ganglionic density, neuronal density, ganglionic area, number of stained neurons per ganglion, nerve bundle width, ratio between nervous tissue area and total area, and neuronal area. Results: Ganglionic density was 10.13 per mm2 in controls versus 5.01 per mm2 in FD (p<0.05). Neuronal density was 70.12 per mm2 in controls, compared with 22.09 per mm2 in FD (p<0.01). The other parameters were not different between the two groups. Conclusion: Densities of myenteric ganglia and neurons of FD patients were significantly lower than in controls. This deficiency may contribute to the pathogenesis of FD gastroenteropathy.

Introduction

Familial dysautonomia (FD), first described in 1949 [1], is an autosomal recessive disorder characterized by complex clinical symptomatology related to abnormalities in the peripheral nervous system [2]. The disease occurs mainly among Ashkenazi Jews, and the incidence in this population is 1:3703 live births with a carrier rate of 1:32 [3]. The FD gene was first mapped to chromosome 9q31 [4], and was recently identified [5]. FD, also known as Riley Day syndrome or Hereditary Sensory Neuropathy type III (HSN-III), is the most common and widely recognized congenital sensory neuropathy. The pathogenesis of FD is still unknown. In FD patients, there is a deficiency in autonomic and sensory neurons, and there is a progressive neuronal degeneration throughout life, which affects the function of most body systems [2], [6], and is manifested by a variety of symptoms. The main ones are gastrointestinal dysfunction, vomiting crises, recurrent pneumonias, altered sensitivity to pain and temperature, cardiovascular instability, impaired corneal reflex, diminished deep tendon reflexes, developmental delay, convulsions and skeletal disorders [1], [2]. The clinical diagnosis of FD is based on the following cardinal criteria: absence of fungiform papillae on the tongue, absence of axonal flare after intradermal injection of histamine, decreased or absent deep tendon reflexes, absence of overflow tears, and Ashkenazi Jewish ancestry [7], [8].

The clinical characteristics of FD are a consequence of a progressive depletion of autonomic and sensory neurons and hypoplastic autonomic ganglia [9], [10]. This pathology is evident even in the youngest patients, indicating that the deficiency begins already during developmental stages [11]. The pathological findings have led to the suggestion that an FD gene, named IKBKAP, may encode a protein that is a member of the recently identified human elongator complex, which may be crucial for the embryonic development and postnatal survival of neurons [12], [13].

Malfunction in the gastrointestinal tract is a prominent clinical manifestation of FD. It includes feeding difficulties in infancy, drooling, vomiting, gastroesophageal reflux (GER), prolonged gastric emptying, abdominal distention, constipation, diarrhea, and in older patients—slow gut syndrome [2], [14]. The nasopharyngeal dyscoordination and GER lead to recurrent aspiration pneumonia with subsequent chronic pulmonary disease, which poses a serious threat to life [2]. The disturbances in the motility of the esophagus and stomach have been demonstrated by radiologic and manometric studies [14], [15], [16]. In most FD patients, antireflux procedure is recommended in early childhood in order to prevent the detrimental effects of aspirated gastric juice on the lungs. In addition, feeding gastrostomy is fashioned to bypass the dyscoordinated nasopharynx and to improve the fluid and nutritional intake [17].

As the myenteric plexus is a major factor in gastrointestinal motility control, it can be proposed that its abnormality might contribute to the symptomatology of FD patients. Very little information is available on gastrointestinal innervation pathology in FD patients, and the available studies are very small, containing one to three patients only [18], [19], [20], [21], [22]. In the present work, we studied the structure of the myenteric plexus in the appendix vermiformis from a much larger group (19 FD patients and 17 controls), and employed advanced methods for data analysis.

Section snippets

Materials and methods

Thirty-six patients were included in the study. The FD group (N=19) consisted of patients who fulfilled the diagnostic criteria for the disorder. There were 11 males and 8 female in this group with a median age of 30 months (range 8 months to 15 years). The diagnosis of all patients was confirmed clinically by one of the authors (CM), and genetically. The genetic testing was performed in a highly qualified genetic laboratory with extensive experience diagnosing FD, and all patients had the same

Results

Macroscopic examination revealed no difference between the appendices of the 19 FD patients and the 17 controls. All appendices (from FD and control groups) were normal on routine histopathological (H&E stain) examination, and there were no signs of early inflammation or peri-ganglionic lymphocytes.

Fig. 1A shows an example of normal appendiceal myenteric plexus, stained for NADPH-d. The whole mount preparation technique shows the mesh-like myenteric plexus, consisting of ganglia and

Discussion

Familial dysautonomia is an inherited disorder, characterized by disturbances of autonomic and sensory functions. Patients with FD suffer from severe gastrointestinal manifestations mostly because of dyscoordination and motility disorders, which increase their morbidity and mortality. Our experimental results demonstrate a 50.6% decrease in the density of ganglia in the appendiceal myenteric plexus of FD patients (p<0.05), as well as a 68.5% decrease in neuronal density compared with normal

Acknowledgements

This study was supported by the US–Israel Binational Science Foundation (BSF 98-00185).

This work is part of the requirements of the Hebrew University-Hadassah Medical School Jerusalem, for an M.D. degree (A.B-S).

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