|
1
|
Tebaibia A, Benmediouni F, Boudjella MEA, Lahcen M, Oumnia N. Familial achalasia isolated or syndromic: about 18 families. EXPLORATION OF DIGESTIVE DISEASES 2023:276-281. [DOI: https:/doi.org/10.37349/edd.2023.00030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/22/2023] [Indexed: 11/04/2023]
Abstract
Aim: Familial achalasia (FA) is a very rare condition. This work aims to evaluate its prevalence, characterize its clinical profile in a large series, and assess the efficacy and safety of pneumatic dilation (PD) in this context.
Methods: A total of 817 patients with achalasia were collected over a period of 20 years (1990–2010). All cases of FA: isolated or associated to Allgrove syndrome, were looked for in both parents and siblings.
Results: In this study, 18 families with FA were identified n = 41 patients (5%). Two members were affected in each family, in 14 families, three members per family in three others, and for the remaining family 04 members. All cases of achalasia were observed in siblings and parent to child transmission was unfound. Achalasia was associated to Allgrove syndrome in 15 families. It was isolated in 3 families. Consanguinity was found in 89% of patients, and death at a young age in the siblings was recorded in 27% of cases. Achalasia was present before the age of 5 years in 75% of cases. There was no difference between the two groups for age, age at onset, sex and the presence of the cardinal signs of achalasia. A total of 102 dilations were performed. Only one session in 31% of cases, two in 38%, three in 17% and more than three sessions in 14%. The long-term success rate of PD was low.
Conclusions: FA manifests almost exclusively in childhood. It is rarely isolated; most often falls under Allgrove syndrome. Alacrima is the earliest sign that should lead to the diagnosis. The long-term success rate of PD is rather low. This requires recourse to multiple sessions of PD or Heller’s cardiomyotomy which may be the best initial approach.
Collapse
Affiliation(s)
- Amar Tebaibia
- Internal Medicine Department, Algiers Medical Faculty, El Biar Hospital, El Biar, Algiers 16000, Algeria
| | - Farouk Benmediouni
- Internal Medicine Department, Laghouat Medical Faculty, Laghouat Mixed Hospital, Laghoua 03000, Algeria
| | | | - Mustapha Lahcen
- Internal Medicine Department, Algiers Medical Faculty, Baïnem Hospital, Baïnem, Algiers 16000, Algeria
| | - Nadia Oumnia
- Internal Medicine Department, Algiers Medical Faculty, Salim Zmirli Hospital, El Harrache City, Algiers 16000, Algeria
| |
Collapse
|
|
2
|
Tebaibia A, Benmediouni F, Boudjella MEA, Lahcen M, Oumnia N. Familial achalasia isolated or syndromic: about 18 families. EXPLORATION OF DIGESTIVE DISEASES 2023:276-281. [DOI: 10.37349/edd.2023.00030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/22/2023] [Indexed: 11/04/2024]
Abstract
Aim: Familial achalasia (FA) is a very rare condition. This work aims to evaluate its prevalence, characterize its clinical profile in a large series, and assess the efficacy and safety of pneumatic dilation (PD) in this context.
Methods: A total of 817 patients with achalasia were collected over a period of 20 years (1990–2010). All cases of FA: isolated or associated to Allgrove syndrome, were looked for in both parents and siblings.
Results: In this study, 18 families with FA were identified n = 41 patients (5%). Two members were affected in each family, in 14 families, three members per family in three others, and for the remaining family 04 members. All cases of achalasia were observed in siblings and parent to child transmission was unfound. Achalasia was associated to Allgrove syndrome in 15 families. It was isolated in 3 families. Consanguinity was found in 89% of patients, and death at a young age in the siblings was recorded in 27% of cases. Achalasia was present before the age of 5 years in 75% of cases. There was no difference between the two groups for age, age at onset, sex and the presence of the cardinal signs of achalasia. A total of 102 dilations were performed. Only one session in 31% of cases, two in 38%, three in 17% and more than three sessions in 14%. The long-term success rate of PD was low.
Conclusions: FA manifests almost exclusively in childhood. It is rarely isolated; most often falls under Allgrove syndrome. Alacrima is the earliest sign that should lead to the diagnosis. The long-term success rate of PD is rather low. This requires recourse to multiple sessions of PD or Heller’s cardiomyotomy which may be the best initial approach.
Collapse
Affiliation(s)
- Amar Tebaibia
- Internal Medicine Department, Algiers Medical Faculty, El Biar Hospital, El Biar, Algiers 16000, Algeria
| | - Farouk Benmediouni
- Internal Medicine Department, Laghouat Medical Faculty, Laghouat Mixed Hospital, Laghoua 03000, Algeria
| | | | - Mustapha Lahcen
- Internal Medicine Department, Algiers Medical Faculty, Baïnem Hospital, Baïnem, Algiers 16000, Algeria
| | - Nadia Oumnia
- Internal Medicine Department, Algiers Medical Faculty, Salim Zmirli Hospital, El Harrache City, Algiers 16000, Algeria
| |
Collapse
|
|
3
|
Shah K, Raffa F, Naik RD. Obesity and esophageal dysmotility. OBESITY AND ESOPHAGEAL DISORDERS 2022:61-76. [DOI: 10.1016/b978-0-323-98365-5.00004-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
4
|
Hoshino M, Omura N, Yano F, Yamamoto SR, Matsuda M, Yanaga K. Simultaneous diagnosis of familial achalasia: report of two cases. Surg Case Rep 2017; 3:62. [PMID: 28485000 PMCID: PMC5422213 DOI: 10.1186/s40792-017-0340-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 05/01/2017] [Indexed: 11/27/2022] Open
Abstract
Background Achalasia is a rare disease with a morbidity of 1 in 100,000, for which the exact mechanism of pathogenesis has not been clarified due to the small total number of patients. We herein report on our experience with two cases of familial achalasia in which the involvement of genetic inheritance was suspected. Case presentation These cases consist of a man in his thirties and his mother in her sixties. The son consulted the Department of Gastrointestinal Medicine at our institute with dysphagia, and an upper gastrointestinal endoscopy revealed a gastric submucosal tumor with a maximal diameter of approximately 50 mm. Achalasia was also strongly suspected due to the enlargement of the esophagus to the maximum transverse diameter of 55 mm by esophagography along with delayed clearance of barium. A detailed interview revealed prolonged mild dysphagia in his mother. Therefore, high-resolution manometry was carried out in both patients. As a result, peristaltic disorder was observed in the esophageal body in both the mother and son, leading to a definitive diagnosis of achalasia. For the son, total gastrectomy including the lower esophagus with Roux-en-Y reconstruction was performed. His postoperative course was uneventful, and the patient was discharged from hospital in remission on the 9th day following surgery and is currently undergoing follow-up as an outpatient. Conclusions We hereby report on a very rare case of familial achalasia that we experienced which may suggest a genetic element in the onset of achalasia, and reviewed the literature.
Collapse
Affiliation(s)
- Masato Hoshino
- Department of Surgery, Kasukabe Central General Hospital, 5-9-4 Midoricho, Kasukabe city, Saitama, 344-0063, Japan. .,Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan.
| | - Nobuo Omura
- Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Fumiaki Yano
- Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Se Ryung Yamamoto
- Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Minoru Matsuda
- Department of Surgery, Kasukabe Central General Hospital, 5-9-4 Midoricho, Kasukabe city, Saitama, 344-0063, Japan
| | - Katsuhiko Yanaga
- Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan
| |
Collapse
|
|
5
|
Abstract
Idiopathic achalasia is a primary esophageal motor disorder characterized by loss of esophageal peristalsis and insufficient lower esophageal sphincter relaxation in response to deglutition. Patients with achalasia commonly complain of dysphagia to solids and liquids, bland regurgitation often unresponsive to an adequate trial of proton pump inhibitor, and chest pain. Weight loss is present in many, but not all patients. Although the precise etiology is unknown, it is often thought to be either autoimmune, viral immune, or neurodegenerative. The diagnosis is based on history of the disease, barium esophagogram, and esophageal motility testing. Endoscopic assessment of the gastroesophageal junction and gastric cardia is necessary to rule out malignancy. Newer diagnostic modalities such as high resolution manometry help in predicting treatment response in achalasia based on esophageal pressure topography patterns identifying three phenotypes of achalasia (I-III) and outcome studies suggest better treatment response with types I and II compared to type III. Although achalasia cannot be permanently cured, excellent outcomes are achieved in over 90 % of patients. Current medical and surgical therapeutic options (pneumatic dilation, endoscopic and surgical myotomy, and pharmacologic agents) aim at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Either graded pneumatic dilatation or laparoscopic surgical myotomy with a partial fundoplication are recommended as initial therapy guided by patient age, gender, preference, and local institutional expertise. The prognosis in achalasia patients is excellent. Most patients who are appropriately treated have a normal life expectancy but the disease does recur and the patient may need intermittent treatment.
Collapse
Affiliation(s)
| | - Hannah P Kim
- Department of Internal Medicine, Nashville, TN, USA
| | | | - Michael F Vaezi
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
| |
Collapse
|
|
6
|
Ates F, Vaezi MF, Fox M, Gyawali CP, Roman S, Smout AJPM, Pandolfino JE. The Pathogenesis and Management of Achalasia: Current Status and Future Directions. Gut Liver 2015; 9:449-63. [PMID: 26087861 PMCID: PMC4477988 DOI: 10.5009/gnl14446] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Achalasia is an esophageal motility disorder that is commonly misdiagnosed initially as gastroesophageal reflux disease. Patients with achalasia often complain of dysphagia with solids and liquids but may focus on regurgitation as the primary symptom, leading to initial misdiagnosis. Diagnostic tests for achalasia include esophageal motility testing, esophagogastroduodenoscopy and barium swallow. These tests play a complimentary role in establishing the diagnosis of suspected achalasia. High-resolution manometry has now identified three subtypes of achalasia, with therapeutic implications. Pneumatic dilation and surgical myotomy are the only definitive treatment options for patients with achalasia who can undergo surgery. Botulinum toxin injection into the lower esophageal sphincter should be reserved for those who cannot undergo definitive therapy. Close follow-up is paramount because many patients will have a recurrence of symptoms and require repeat treatment.
Collapse
Affiliation(s)
| | - Michael F. Vaezi
- Correspondence to: Michael F. Vaezi, Division of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, C2104-MCN, Nashville, TN 37232, USA, Tel: +1-615-322-3739, Fax: +1-615-322-8525, E-mail:
| | | | | | | | | | | | | |
Collapse
|
|
7
|
Abstract
Dysphagia is a symptom of swallowing dysfunction that occurs between the mouth and the stomach. Although oropharyngeal dysphagia is a highly prevalent condition (occurring in up to 50% of elderly people and 50% of patients with neurological conditions) and is associated with aspiration, severe nutritional and respiratory complications and even death, most patients are not diagnosed and do not receive any treatment. By contrast, oesophageal dysphagia is less prevalent and less severe, but with better recognized symptoms caused by diseases affecting the enteric nervous system and/or oesophageal muscular layers. Recognition of the clinical relevance and complications of oesophageal and oropharyngeal dysphagia is growing among health-care professionals in many fields. In addition, the emergence of new methods to screen and assess swallow function at both the oropharynx and oesophagus, and marked advances in understanding the pathophysiology of these conditions, is paving the way for a new era of intensive research and active therapeutic strategies for affected patients. Indeed, a unified field of deglutology is developing, with new professional profiles to cover the needs of all patients with dysphagia in a nonfragmented way.
Collapse
|
|
8
|
Im SK, Yeo M, Lee KJ. Proteomic identification of proteins suggestive of immune-mediated response or neuronal degeneration in serum of achalasia patients. Gut Liver 2013; 7:411-6. [PMID: 23898380 PMCID: PMC3724028 DOI: 10.5009/gnl.2013.7.4.411] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 10/19/2012] [Accepted: 10/26/2012] [Indexed: 12/18/2022] Open
Abstract
Background/Aims The primary pathophysiologic abnormality in achalasia is known to be a loss of inhibitory myenteric ganglion cells, which may result from an immune-mediated response or neuronal degeneration. The aim of this study was to identify proteins suggestive of an immune-mediated response or neuronal degeneration in the serum of achalasia patients using a proteomic analysis. Methods Blood samples were collected from five symptomatic achalasia patients and five sex- and age-matched healthy controls. Serum proteomic analysis was conducted, and the protein spots were identified using matrix-assisted laser desorption ionization/time-of-flight and a proteomics analyzer. The serum level of C3 was measured by enzyme-linked immunosorbent assay in nine patients with achalasia and 18 sex- and age-matched healthy controls. Results Of the 658 matched protein spots, 28 spots were up-regulated over 2-fold in the serum from achalasia patients compared with that from controls. The up-regulated proteins included complement C4B5, complement C3, cyclin-dependent kinase 5, transthyretin, and alpha 2 macroglobulin. The serum levels of C3 in achalasia patients were significantly higher than those of controls. Conclusions The serum proteomic analysis of achalasia patients suggests an immune-mediated response or neuronal degeneration. Further validation studies in larger samples and the esophageal tissue of achalasia patients are required.
Collapse
Affiliation(s)
- Seon Kyo Im
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | | | | |
Collapse
|
|
9
|
Hoshino M, Omura N, Yano F, Tsuboi K, Kashiwagi H, Yanaga K. Immunohistochemical study of the muscularis externa of the esophagus in achalasia patients. Dis Esophagus 2013; 26:14-21. [PMID: 22309323 DOI: 10.1111/j.1442-2050.2011.01318.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The etiology of achalasia is believed to be the neuropathy associated with chronic inflammation of the nerve plexus, but the cause of plexus inflammation is unknown. The purpose of this study was to evaluate the pathophysiology of achalasia by examining the muscularis externa of the esophagus. We used the muscularis externa of the esophagus of 62 patients with achalasia (median 44 years, male : female 32:30) who underwent surgical treatment (achalasia group) and of 10 patients (median 65.5 years, male : female 9:1) who underwent esophagectomy for thoracic esophageal cancer (control group) to perform immunohistochemical staining with S-100, CD43, c-kit (CD117), n-NOS, vasoactive intestinal polypeptide (VIP), and ubiquitin. The cell counts that were positive for S-100, n-NOS, VIP, and ubiquitin were significantly lower in the achalasia group compared with the control group (P < 0.001, P= 0.001, P < 0.001, and P= 0.001, respectively). There were no statistically significant differences with respect to CD43 and c-kit staining (P= 0.586 and P= 0.209, respectively). In conclusion, the pathophysiology of achalasia is therefore considered to be an impaired production of NO and VIP, which both affect interstitial cell of Cajal and smooth muscles, and this impairment is therefore considered to play a role in the pathophysiology of achalasia.
Collapse
Affiliation(s)
- M Hoshino
- Department of Surgery, Jikei University School of Medicine, 3-19-18 Nishishinbashi, Minato-ku, Tokyo, Japan.
| | | | | | | | | | | |
Collapse
|
|
10
|
Ghoshal UC, Daschakraborty SB, Singh R. Pathogenesis of achalasia cardia. World J Gastroenterol 2012; 18:3050-7. [PMID: 22791940 PMCID: PMC3386318 DOI: 10.3748/wjg.v18.i24.3050] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Revised: 10/11/2011] [Accepted: 04/28/2012] [Indexed: 02/06/2023] Open
Abstract
Achalasia cardia is one of the common causes of motor dysphagia. Though the disease was first described more than 300 years ago, exact pathogenesis of this condition still remains enigmatic. Pathophysiologically, achalasia cardia is caused by loss of inhibitory ganglion in the myenteric plexus of the esophagus. In the initial stage, degeneration of inhibitory nerves in the esophagus results in unopposed action of excitatory neurotransmitters such as acetylcholine, resulting in high amplitude non-peristaltic contractions (vigorous achalasia); progressive loss of cholinergic neurons over time results in dilation and low amplitude simultaneous contractions in the esophageal body (classic achalasia). Since the initial description, several studies have attempted to explore initiating agents that may cause the disease, such as viral infection, other environmental factors, autoimmunity, and genetic factors. Though Chagas disease, which mimics achalasia, is caused by an infective agent, available evidence suggests that infection may not be an independent cause of primary achalasia. A genetic basis for achalasia is supported by reports showing occurrence of disease in monozygotic twins, siblings and other first-degree relatives and occurrence in association with other genetic diseases such as Down’s syndrome and Parkinson’s disease. Polymorphisms in genes encoding for nitric oxide synthase, receptors for vasoactive intestinal peptide, interleukin 23 and the ALADIN gene have been reported. However, studies on larger numbers of patients and controls from different ethnic groups are needed before definite conclusions can be obtained. Currently, the disease is believed to be multi-factorial, with autoimmune mechanisms triggered by infection in a genetically predisposed individual leading to degeneration of inhibitory ganglia in the wall of the esophagus.
Collapse
|
|
11
|
Panza E, Knowles CH, Graziano C, Thapar N, Burns AJ, Seri M, Stanghellini V, De Giorgio R. Genetics of human enteric neuropathies. Prog Neurobiol 2012; 96:176-89. [PMID: 22266104 DOI: 10.1016/j.pneurobio.2012.01.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 12/13/2011] [Accepted: 01/05/2012] [Indexed: 01/10/2023]
Abstract
Knowledge of molecular mechanisms that underlie development of the enteric nervous system has greatly expanded in recent decades. Enteric neuropathies related to aberrant genetic development are thus becoming increasingly recognized. There has been no recent review of these often highly morbid disorders. This review highlights advances in knowledge of the molecular pathogenesis of these disorders from a clinical perspective. It includes diseases characterized by an infantile aganglionic Hirschsprung phenotype and those in which structural abnormalities are less pronounced. The implications for diagnosis, screening and possible reparative approaches are presented.
Collapse
Affiliation(s)
- Emanuele Panza
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Gordillo-González G, Guatibonza YP, Zarante I, Roa P, Jacome LA, Hani A. Achalasia familiar: report of a family with an autosomal dominant pattern of inherence. Dis Esophagus 2011; 24:E1-4. [PMID: 21073617 DOI: 10.1111/j.1442-2050.2010.01124.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Esophageal achalasia is a well-known pathology with an autosomal recessive pattern of inherence described in the familiar cases. Its principal symptom is dysphagia, secondary to the poor relaxation of the lower esophageal sphincter. Chagas disease is one of the many causes involved in the development of this disease, being of great importance in our country because of the high prevalence of the vector. Various syndromes include achalasia in their symptomatology, such as the triple A syndrome or Allgrove syndrome (Addisonianism, achalasia, and alacrimia). We reported a family with a classical autosomal pattern of inherence with six affected members, four men and two women, with achalasia diagnosis as well as esophagus cancer in two of them, secondary to the disease, and no other findings.
Collapse
Affiliation(s)
- G Gordillo-González
- Instituto de Genética Humana, Pontificia Universidad Javeriana Servicio de Gastroenterología, Departamento de Medicina Interna, Hospital San Ignacio, Pontificia Universidad Javeriana, Bogotá, DC, Colombia.
| | | | | | | | | | | |
Collapse
|
|
13
|
Demographic, clinical features and treatment outcomes in 700 achalasia patients in iran. Middle East J Dig Dis 2010; 2:91-6. [PMID: 25197519 PMCID: PMC4154830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 07/15/2010] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Achalasia is the most recognized motor disorder of the esophagus. Because it is an uncommon disease, most studies have reviewed small numbers of patients. Here, we report demographic, clinical features and treatment outcomes in 700 achalasia patients. METHODS In all patients, diagnosis was established based on clinical, radiological, endoscopic and manometric criteria. A questionnaire was completed for each patient and included the patient's age, gender, initial symptoms, frequency of different symptoms, presence of positive family history for achalasia, other accompanying diseases and treatment outcomes. RESULTS In our study men were affected more than women (54.3% vs. 45.7%). Patients' mean age was about 38 years. The most frequent symptoms noted were: dysphagia to solids and liquids, active regurgitation, passive regurgitation and weight loss, respectively. Women complained of chest pain more than men (59% vs. 47.1%, p=0.04). The vast majority of our patients were treated by pneumatic dilation (PD) of the LES and in long-term follow-up, 67% were in the responder group. Females responded better than males to PD. CONCLUSION Dysphagia to solids is the most common symptom in patients with achalasia. Chest pain was significantly higher among women. PD is an effective treatment for achalasia with long-term efficacy in the majority of patients.
Collapse
|
|
14
|
Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
Collapse
Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
| | | | | | | | | | | |
Collapse
|
|
15
|
Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010; 128:353-64. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Accepted: 08/02/2010] [Indexed: 12/15/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
Collapse
Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
| | | | | | | | | | | |
Collapse
|
|
16
|
de León AR, de la Serna JP, Santiago JL, Sevilla C, Fernández-Arquero M, de la Concha EG, Nuñez C, Urcelay E, Vigo AG. Association between idiopathic achalasia and IL23R gene. Neurogastroenterol Motil 2010; 22:734-8, e218. [PMID: 20367798 DOI: 10.1111/j.1365-2982.2010.01497.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology. Different evidences have been reported in support of achalasia as the result of an autoimmune and inflammatory process leading to neuronal cell loss. According to this, idiopathic achalasia has been significantly associated with specific alleles of the human leukocyte antigen system class II, although few reports studying association with other loci can be found in the literature. Recent studies have shown association of a non-synonymous polymorphism within the IL23R gene with different chronic inflammatory disorders, including Barrett's esophagus. The purpose of this study was to assess whether the IL23R coding variant Arg381Gln polymorphism is involved in susceptibility to idiopathic achalasia. METHODS We performed a case-control study including 262 patients with idiopathic achalasia and 802 healthy subjects, all of them white Spaniards. Achalasia patients were diagnosed on the basis of clinical, radiographic, endoscopic, and manometric criteria. All samples were genotyped for the IL23R Arg381Gln polymorphism using TaqMan technology. KEY RESULTS The minor allele of the Arg381Gln polymorphism was significantly increased in patients compared with healthy controls (OR = 1.46, 95% CI = 1.01-2.11, P = 0.036). This association seems to be specific to male patients with disease onset after 40 years (OR = 2.33, 95% CI = 1.29-4.16, P = 0.002). CONCLUSIONS & INFERENCES Our results suggest a role of IL23R in idiopathic achalasia predisposition and extend the evidence of the general influence of this gene in autoimmune and inflammatory diseases.
Collapse
Affiliation(s)
- A R de León
- Gastroenterology Department, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Suggested association of NOS2A polymorphism in idiopathic achalasia: no evidence in a large case-control study. Am J Gastroenterol 2009; 104:1326-7. [PMID: 19337240 DOI: 10.1038/ajg.2009.72] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
|
18
|
Abstract
Esophageal dysphagia can arise from a variety of causes such as motility disorders, mechanical and inflammatory diseases. Adequate management includes a detailed history, evaluation with upper endoscopy, barium radiography and manometry. Treatment is usually tailored to the underlying disease process and in some cases, as in inoperable cancer, palliative management may be necessary.
Collapse
Affiliation(s)
- Adeyemi Lawal
- Medical College of Wisconsin, Department of Medicine, Division of Gastroenterology and Hepatology, Froedtert East, FEC-4510, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | | |
Collapse
|
|
19
|
Abstract
Idiopathic achalasia is a primary esophageal motor disorder characterized by esophageal aperistalsis and abnormal lower esophageal sphincter (LES) relaxation in response to deglutition. It is a rare disease with an annual incidence of approximately 1/100,000 and a prevalence rate of 1/10,000. The disease can occur at any age, with a similar rate in men and women, but is usually diagnosed between 25 and 60 years. It is characterized predominantly by dysphagia to solids and liquids, bland regurgitation, and chest pain. Weight loss (usually between 5 to 10 kg) is present in most but not in all patients. Heartburn occurs in 27%-42% of achalasia patients. Etiology is unknown. Some familial cases have been reported, but the rarity of familial occurrence does not support the hypothesis that genetic inheritance is a significant etiologic factor. Association of achalasia with viral infections and auto-antibodies against myenteric plexus has been reported, but the causal relationship remains unclear. The diagnosis is based on history of the disease, radiography (barium esophagogram), and esophageal motility testing (esophageal manometry). Endoscopic examination is important to rule out malignancy as the cause of achalasia. Treatment is strictly palliative. Current medical and surgical therapeutic options (pneumatic dilation, surgical myotomy, and pharmacologic agents) aimed at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Although it cannot be permanently cured, excellent palliation is available in over 90% of patients.
Collapse
Affiliation(s)
- Farnoosh Farrokhi
- Division of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Michael F Vaezi
- Division of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| |
Collapse
|
|
20
|
Mearin F, García-González MA, Strunk M, Zárate N, Malagelada JR, Lanas A. Association between achalasia and nitric oxide synthase gene polymorphisms. Am J Gastroenterol 2006; 101:1979-84. [PMID: 16848803 DOI: 10.1111/j.1572-0241.2006.00762.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Our group previously reported the absence of nitric oxide synthase (NOS) in the gastroesophageal junction of patients with achalasia. NOS exists in three distinct isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible isoform (iNOS). Some studies have shown that NO production is regulated by NOS polymorphisms. AIM To assess whether some functional polymorphisms in the nNOS, iNOS, or eNOS genes are involved in susceptibility to suffer from achalasia. METHODS Genomic DNA from 80 unrelated Spanish Caucasian patients with sporadic achalasia and 144 healthy subjects matched for age (+/-5 yr) and gender was typed by PCR and RFLP methods for the 27-bp variable number of tandem repeat (VNTR) polymorphism in intron 4 of the eNOS gene, a CA microsatellite repeat and a Nla III (C-->T) restriction fragment length polymorphism (RFLP) in exon 29 of the nNOS gene, and two nucleotide substitutions located in exon 16 (C-->T) and exon 22 (G-->A) of the iNOS gene. RESULTS No significant differences in carriage, genotype, and allele frequencies of the nNOS, iNOS, or eNOS gene polymorphisms were found between patients with achalasia and controls. Individuals homozygous for genotype iNOS22*A/A tended to be more frequent in achalasia (20%vs 11%, odds ratio [OR] 1.79, 95% confidence interval [CI] 0.89-3.59, p= 0.09) as were those homozygous for the rare eNOS*4a allele (6.2%vs 1.4%, OR 4.5, 95% CI 0.89-22.67, p= 0.1) although the difference did not reach statistical significance. No differences in genotype and allele distribution were found with respect to epidemiological and clinical characteristics of patients with achalasia. CONCLUSION Our data suggest that NOS gene polymorphisms are not involved in the susceptibility to and nature of the clinical course of sporadic achalasia. However, studies in a greater number of patients are required to analyze the tendency toward a higher prevalence of genotypes iNOS22*A/A and eNOS*4a4a.
Collapse
Affiliation(s)
- Fermín Mearin
- Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain
| | | | | | | | | | | |
Collapse
|
|
21
|
Latiano A, De Giorgio R, Volta U, Palmieri O, Zagaria C, Stanghellini V, Barbara G, Mangia A, Andriulli A, Corinaldesi R, Annese V. HLA and enteric antineuronal antibodies in patients with achalasia. Neurogastroenterol Motil 2006; 18:520-525. [PMID: 16771767 DOI: 10.1111/j.1365-2982.2006.00772.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The aetiopathogenesis of primary achalasia is largely unknown, although an immunogenetic predisposition is suspected. To establish whether a correlation exists among possible aetiological factors, including class II human leucocyte antigen (HLA) alleles and autoantibodies to enteric neurones, and clinical features of patients with achalasia, a total of 60 patients and 200 healthy subjects were typed by high-resolution HLA-DQ and HLA-DR alleles. Circulating antineuronal antibodies were investigated by using indirect immunofluorescence on enteric neurones of rat ileum and colon and immunoblotting assay in a subset of achalasic patients and in all controls. The DQB1*0502 and DQB1*0601 alleles were significantly increased in patients with achalasia compared with controls (P < 0.03, P < 0.001, respectively). Moreover a negative correlation with the DQB1*0201 allele was found (P = 0.016). As a whole, 14 of 60 (23.3%) achalasia patients were carriers of HLA risk alleles, and 10 of 41 (24.4%) presented antineuronal antibodies. No significant correlation among HLA risk alleles, antineuronal antibodies and clinical features was found. In achalasia, no correlation exists among HLA alleles, antineuronal antibodies and clinical features. However, given the association between achalasia and HLA-DQ1, further research is needed to clarify the role of HLA antigens and antineuronal antibodies in this disease.
Collapse
Affiliation(s)
- A Latiano
- U.O. Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Abstract
Idiopathic achalasia is an inflammatory disease of unknown etiology characterized by esophageal aperistalsis and failure of LES relaxation due to loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus. Proposed causes of achalasia include gastroesophageal junction obstruction, neuronal degeneration, viral infection, genetic inheritance, and autoimmune disease. Current evidence suggests that the initial insult to the esophagus, perhaps a viral infection or some other environmental factor, results in myenteric plexus inflammation. The inflammation then leads to an autoimmune response in a susceptible population who may be genetically predisposed. Subsequently, chronic inflammation leads to destruction of the inhibitory myenteric ganglion cells resulting in the clinical syndrome of idiopathic achalasia. Further studies are needed to better understand the etiology and pathogenesis of achalasia-such an understanding will be important in developing safe, effective, and possibly curative therapy for achalasia.
Collapse
Affiliation(s)
- Woosuk Park
- Department of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
| | | |
Collapse
|
|
23
|
Abstract
Absence or deficiency of tear volume (alacrima) is rarely seen in pediatric ophthalmology. It is often a part of the multiple systemic anomalies like Riley-Day syndrome and anhidrotic ectodermal dysplasia, or it may be associated with adrenal gland insufficiency, achalasia, and neurologic disorders like Allgrove's syndrome. We report on a 7-year-old girl presenting alacrima, achalasia, and mental retardation with normal adrenocortical function.
Collapse
Affiliation(s)
- Kemal Ornek
- School of Medicine, Department of Ophthalmology, Ankara University, Turkey
| | | | | |
Collapse
|
|
24
|
Abstract
Achalasia is a common primary oesophageal motor disorder. Treatment has been based traditionally on a surgical approach; however, there is new evidence that some medical strategies may be of benefit. The purpose of the present article was to review the current medical management of achalasia. A Medline search identified original articles and reviews published in the English-language literature between 1966 and 1998. This search has revealed that the pharmacological treatment of achalasia is limited to some subgroups of patients (for example, early stages of the disease and elderly patients), and that nitrates, nifedipine, and botulinum toxin are the best studied and most effective compounds.
Collapse
Affiliation(s)
- G Bassotti
- Gastrointestinal Motility Laboratory, GI & Hepatology Section, Department of Clinical and Experimental Medicine, University of Perugia School of Medicine, Italy.
| | | |
Collapse
|
|
25
|
Abstract
BACKGROUND The diagnosis and classification of oesophageal motility disorders is currently based on assessment of the phasic contractile activity of the oesophagus. Tonic muscular contraction of the oesophageal body (oesophageal tone) has not been well characterised. AIM To quantify oesophageal tonic activity in healthy subjects and in patients with achalasia. PATIENTS Oesophageal tone was measured in 14 patients with untreated achalasia and in 14 healthy subjects. In eight patients with achalasia, oesophageal tone was again measured one month after either endoscopic or surgical treatment. METHODS Tonic wall activity was quantified by means of a flaccid intraoesophageal bag, 5 cm long and of 120 ml maximal capacity, which was placed and maintained 5 cm above the lower oesophageal sphincter and connected to an external electronic barostat. The experimental design included measurement of oesophageal basal tone and compliance as well as the oesophageal tone response to a nitric oxide donor (0.5 ml amyl nitrite inhalation). RESULTS Oesophageal basal tone, expressed as the intrabag (intraoesophageal) volume at a minimal distending pressure (2 mm Hg), did not differ significantly between patients with achalasia and healthy controls (6.6 (2.5) ml versus 4.1 (0.8) ml, respectively). Oesophageal compliance (volume/pressure relation during intraoesophageal distension) was significantly increased in achalasia (oesophageal extension ratio: 3.2 (0.4) ml/mm Hg versus 1.9 (0.2) ml/mm Hg; p < 0.01). Amyl nitrite inhalation induced oesophageal relaxation both in patients and in controls, but the magnitude of relaxation was greater in the latter (intrabag volume increase: 15.3 (2.4) ml versus 36.2 (7.1) ml; p < 0.01). CONCLUSION In patients with achalasia, oesophageal tonic activity, and not only phasic activity, is impaired. Although oesophageal compliance is increased, residual oesophageal tone is maintained so that a significant relaxant response may occur after pharmacological stimulation.
Collapse
Affiliation(s)
- M González
- Digestive System Research Unit, Hospital General Vall d'Hebron, Autonomous University of Barcelona, Spain
| | | | | | | | | |
Collapse
|
|
26
|
Störungen der Ösophagus- und Magenmotilität bei Kindern. Eur Surg 1997. [DOI: 10.1007/bf02619745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
27
|
Kasirga E, Ozkinay F, Tütüncüoğlu S, Aydoğdu S, Colakoğlu Z, Musoğlu A, Yağci A, Taneli B, Yağci RV. Four siblings with achalasia, alacrimia and neurological abnormalities in a consanguineous family. Clin Genet 1996; 49:296-9. [PMID: 8884077 DOI: 10.1111/j.1399-0004.1996.tb03791.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Four siblings with achalasia, alacrimia and other problems involving the autonomic nervous system involvements are reported. Achalasia and alacrimia were present in all of them. Their parents are first cousins and have four other healthy children. Electrophysiological tests showed that autonomic dysfunction has progressed with age. Blood cortisol levels were normal in all four affected children. Depending on those findings of our case and previous reports, we conclude that triple-A syndrome and achalasia, alacrimia with or without neurological abnormalities could be variable manifestations of the same autosomal recessive gene defect.
Collapse
Affiliation(s)
- E Kasirga
- Pediatric Gastroenterology Section, Department of Pediatrics, Faculty of Medicine, Ege University, Bornova-Izmir, Turkey
| | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
The Triple A syndrome is a rare condition comprising achalasia, alacrima and adrenocorticotrophic hormone (ACTH) insensitivity. A 12 year old Chinese girl with a variant of this syndrome (achalasia and alacrima), presenting with failure to thrive, is reported. Typical appearances of achalasia on barium swallow subsequently led to the correct diagnosis. The radiologist may be the first to recognize this syndrome and hence help anticipate its potentially life-threatening sequelae.
Collapse
Affiliation(s)
- P L Khong
- Department of Diagnostic Radiology, Queen Mary Hospital, Hong Kong
| | | | | | | |
Collapse
|
|
29
|
O'Brien CJ, Smart HL. Familial coexistence of achalasia and non-achalasic oesophageal dysmotility: evidence for a common pathogenesis. Gut 1992; 33:1421-3. [PMID: 1446873 PMCID: PMC1379617 DOI: 10.1136/gut.33.10.1421] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In five of seven siblings of healthy parents, dysphagia developed during adolescence or early adult life. A barium swallow was normal in one patient but showed appearances considered to be consistent with achalasia in all others. Oesophageal manometry was successfully performed in four of the five patients, including the patient with symptoms but normal radiological appearance. One patient had achalasia, two had oesophageal body motor dysfunction associated with a hypertensive, but normally relaxing lower oesophageal sphincter, and one had diffuse oesophageal spasm alone. The occurrence of three different oesophageal dysmotility disorders within members of a single sibship suggests that these conditions are intimately related and probably genetically determined as an autosomal recessive trait.
Collapse
Affiliation(s)
- C J O'Brien
- Gastroenterology Unit, Royal Hallamshire Hospital, Sheffield
| | | |
Collapse
|
|
30
|
Tuck JS, Bisset RA, Doig CM. Achalasia of the cardia in childhood and the syndrome of achalasia alacrima and ACTH insensitivity. Clin Radiol 1991; 44:260-4. [PMID: 1659963 DOI: 10.1016/s0009-9260(05)80192-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Achalasia of the cardia is an uncommon condition with an incidence of 0.1 cases per year per 100,000 population under 14 years. A review of experience at Booth Hall Children's Hospital over the past 10 years has revealed six cases of achalasia in children. This includes two cases of the rare syndrome of achalasia, alacrima and ACTH insensitivity (also known as Triple A syndrome) and its variants. There are 23 previously reported cases of Triple A syndrome and a further eight cases of its variants reported in the world literature. One-third of these cases (10 out of 31) have associated neurological abnormalities. The clinical and radiological features of achalasia are reviewed. The importance of barium studies in making the diagnosis is emphasized. However, early cases may show only spasm or incoordination, and manometry is required to confirm the diagnosis in these equivocal cases. In this series only three of the six barium studies were diagnostic and the remainder were diagnosed by manometry; all cases were subsequently confirmed by histology. Delay in diagnosis may result in severe lung damage due to repeated aspiration; this occurred in one of the six cases and was the cause of the child's death.
Collapse
Affiliation(s)
- J S Tuck
- Department of Radiology, Booth Hall Children's Hospital, Manchester
| | | | | |
Collapse
|
|
31
|
Affiliation(s)
- L J O'Donnell
- Department of Gastroenterology, St Bartholomew's Hospital, West Smithfield, London, UK
| | | | | |
Collapse
|
|
32
|
Marshall JB, Diaz-Arias AA, Bochna GS, Vogele KA. Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder. Report of a family study. Gastroenterology 1990; 98:1358-65. [PMID: 2323526 DOI: 10.1016/0016-5085(90)90357-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Although achalasia is usually of idiopathic origin, it may be secondary to another disease process such as neoplasia. The first description of a familial achalasia syndrome that appears to be secondary to diffuse esophageal leiomyomatosis with entrapment of nerve ganglia is presented. Documented in four generations of a family, the disease followed an autosomal dominant mode of inheritance. Long lower esophageal sphincter pressure zones and a high incidence of epiphrenic diverticula were interesting accompaniments of achalasia in this family. Many achalasia-affected family members have also had associated intestinal leiomyomas or neurofibromas. Affected family members also had urticaria pigmentosa, and some had systemic mast cell disease as well.
Collapse
Affiliation(s)
- J B Marshall
- Department of Medicine, University of Missouri-Columbia School of Medicine
| | | | | | | |
Collapse
|