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Keywords:

  • bacterial overgrowth;
  • gastrointestinal motility;
  • genealogy;
  • intestinal neuropathy;
  • intestinal pseudo-obstruction;
  • intestinal transit;
  • manometry

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References

Background  Few families with autosomal dominant forms of chronic idiopathic pseudo-obstruction (CIP) have been identified and reported.

Methods  We compared two families by clinical, laboratory, histopathologic, and genealogical investigations. Ten patients (pts) (five women) from two families, A and B, both with a family history suggesting autosomal dominant CIP, were investigated.

Key Results  All pts had chronic diarrhea, nine of ten pts had chronic abdominal pain and seven of ten chronic vomiting. Median age for onset of symptoms was 23 (A) and 34 years (B). None had dysphagia, urogenital, neurologic, or ocular symptoms. Small bowel transit and jejunal culture were abnormal in eight of nine. Manometry showed severe jejunal hypomotility in the fasting and fed state and absence of normal phase III in all nine pts and neuropathy-like duodenal alterations in eight of nine. Progress to overt CIP had occurred in six pts. Histopathologic re-evaluation (three pts) showed that criteria of visceral degenerative neuropathy were fulfilled in both families including intranuclear inclusions in all three pts. Genealogic exploration using the unique Swedish Register for Catechetical Meetings disclosed that the two families with all likelihood shared a male ancestor in the 1890s.

Conclusions & Inferences  The compiled results with striking similarities between family A and B together with genealogy findings indicate that this is one, large kindred with a familial autosomal dominant form of intestinal degenerative neuropathy often progressing to CIP but without extra-intestinal manifestations. This is the fourth and, so far, the largest family reported with these characteristics.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References

Chronic intestinal pseudo-obstruction (CIP) is a syndrome presenting with symptoms mimicking intestinal obstruction in the absence of mechanical obstruction. In idiopathic forms of CIP the intestinal propulsion is defective due to intestinal neuropathy or myopathy. Combined myoneuropathies also occur.1,2 The symptoms are often disabling: severe abdominal pain, diarrhea, nausea/vomiting, and constipation. Chronic pseudo-obstruction is the end stage of the disease but many patients with intestinal neuropathy or myopathy may have symptoms like disturbed defecation and abdominal pain without developing overt chronic pseudo-obstruction.

Apart from idiopathic forms, CIP may be secondary to neurologic, systemic and other diseases or due to clinical interventions such as radiation or surgical therapy.3 In gastroenterological practice most cases of CIP are sporadic, but familial forms, both myopathic and neuropathic, have been described. Rare autosomal dominant,4–10 autosomal recessive11 as well as X-linked forms have been reported.12 With a few exceptions, e.g.,13,14 little is known about underlying mutations of genes in these familial forms of CIP.

Given the present limited understanding of the genetic base for primary intestinal neuromuscular diseases leading to CIP, it should be of importance to find well-characterized families with hereditary CIP for further research with e.g., genetic linkage studies. The aim of this study was to compare clinical traits and gastrointestinal (GI) motility characteristics in two families from southern Sweden. Furthermore, the outcome of these steps motivated a re-evaluation of intestinal histopathology and an exploration of the genealogy of the two families.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References

Family material

In 1991–92, two members from a family (Family A, Fig. 1A, Subjects III:1 and IV:2) were referred to Sahlgrenska University Hospital for motility examination on the suspicion of intestinal pseudo-obstruction that was confirmed. The first patient’s father (II:1), born 1898, had died from intestinal failure in 1967. Histopathology from colonic resection material in one family member (IV:2) in 1990 had shown ‘degenerative changes and reduction of ganglionic cells in Auerbach’s plexus’.

image

Figure 1.  The two families from which patients were referred for evaluation of gastrointestinal motility. (A) Pedigree of family A, as it appeared after the first referrals to the GI Motility Unit. (B) Pedigree of family B, as it appeared after the first referral.

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From 2003, several patients from a second family (Family B, Fig. 1B) in southern Sweden were referred for GI motility examination. The mother (II:2) of the first referred patient in family B had died from intestinal failure in 1974 and a full thickness jejunal biopsy from this first investigated patient (Fig. 1B, III:11) was reported to show visceral inflammatory neuropathy.

Altogether, nine patients (four from family A and five from family B) underwent evaluation at the GI motility laboratory according to our standard protocol for severe motility disorders including total gut transit measurements, antroduodenojejunal manometry and small bowel bacterial culture. In addition, one further patient from family B was identified (III:14) and included in the clinical trait comparison and the histopathology parts of the study since he had undergone distal colectomy and ileostomy for intractable diarrhea and bowel resection material was available for histology. For the latter patient the year of histologic expert evaluation was set as ‘year of diagnosis’, for the nine other patients the year when manometry and small bowel transit/radiology with abnormal findings were performed.

Subjects were considered as ‘affected’ when they had underwent evaluation at the motility laboratory and found to have a severe motility disorder or, in one case (III:14), had the typical histopathologic findings. In addition, at least one of the symptoms chronic diarrhea, vomiting or abdominal pain with a duration of over 1 year was required. Cases were categorized ‘reported to be affected’ in deceased subjects where living family members reported the presence of the symptoms mentioned above, or in living cases who reported such symptoms but no evaluation at the motility laboratory had been performed. Subjects who did not report symptoms or, if deceased, were not reported to have symptoms, was categorized as ‘absence of disease’.

Symptoms

All patients were specifically asked about the symptoms abdominal pain, diarrhea, constipation, nausea/vomiting, and dysphagia, with duration of more than 1 year and the age at onset when applicable.

Manometry

Antroduodenojejunal manometry was performed for 5 h during fasting followed by 60 min after a meal with a total energy content of 500 kcal. For pressure recording, an assembly with a central lumen for guide wire and eight water perfused lumens with recording points in the antrum, the descending part of the duodenum, the distal duodenum close to the ligament of Treitz and in the proximal jejunum was used. The assembly was connected to pressure transducers and recordings made with a polygraph (PC Polygraph, Synectics, Stockholm, Sweden) as described in detail elsewhere.15,16

Gut transit measurements

Gastric emptying  In most of the patients measurement of the emptying of radiopaque markers (ROMs) was used to measure gastric emptying.17 Twenty ROMs were given with the test meal. The mean gastric retention at fluoroscopy 4, 5, and 6 h after the meal was calculated. Upper reference levels were: for men 25% and for women 65%.18 Gastric emptying was also measured by a standardized Swedish scintigraphic method in some patients. Imaging of gastric retention with a gamma camera was performed for 2 h after ingestion of a 400 Kcal omelette meal with technetium-99. With this method upper reference values for retention at 120 min are: for postmenopausal women 54%, premenopausal women 65% and men 50%.19

Small bowel and colonic transit  Small bowel transit and colon transit were evaluated by fluoroscopy and calculation of the transit of ROMs in the small bowel and the colon according to the standard procedure at our motility lab.20 In the two initial patients abnormally delayed small bowel transit and dilated bowel loops were diagnosed by barium follow through only.

Assessment of small intestine bacteria

Small bowel cultures were taken when manometry was performed by aspiration from the jejunum through the central lumen of the catheter as described previously.21 In the two initial patients a hydrogen breath-test was performed as well.22

Histopathology

All three specimens (right sided hemicolectomy from patient IV:2, full-thickness jejunal biopsy from patient III:11, and rectosigmoid resection from patient III:14 had been fixed in 4% neutral formalin overnight and embedded in paraffin. The hematoxylin and eosin (H&E)-stained sections had been examined by pathologists at the primary hospitals. The primary diagnoses were ‘degenerative changes and reduction of ganglionic cells in Auerbach’s plexus’ (IV:2), visceral inflammatory neuropathy (III:11), and diverticulosis (III:14). The strong similarities in clinical presentation and in laboratory findings of the affected patients from the two families motivated a re-examination of the original histological material by a pathologist with special interest in GI neuromuscular pathology (author BV).

Newly prepared, 4 μm thick sections from the original paraffin blocks were stained according to the special CIP-protocol with both conventional special stainings (H&E, PAS, PAS-diastase, Giemsa, cresylviolett, and Masson trichrome) and immunohistochemistry (α- and γ-actin, desmin, vimentin, CD3, CD34, CD117, PGP9.5, α-internexin, neurofilament, substance P (SP), vasoactive intestinal protein (VIP), synaptophysin, and bcl-2). The details of these stainings have been described in detail earlier.23 As negative controls the antibodies were replaced by serum. Positive control sections were always stained together with the target tissue. As controls for the quantitation of SP+ and VIP+ neurons 10 cases of small bowel resections due to non-obstructing carcinoma were used from macro- and microscopically normal parts of the specimens at least 10 cm from the tumor.

Genealogic studies

For the genealogy part of this study conventional Parish Registers listing family members were utilized as well as the Swedish registers for Parish Catechetical Meetings. The latter are careful registers valid especially for the 18th and 19th centuries and include not only family members but also persons employed, e.g., at farms, and for whom the owner of the farm had the responsibility for their knowledge in the Lutherian faith.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References

Clinical presentation

Ten patients were included in this part of the study (Table 1). They all had severe GI symptoms and they all came from southern Sweden. All patients studied had onset of symptoms at adult age, irrespective of gender. Median ages for start of symptoms were 23 and 34 years for family A and B, respectively, while median ages for diagnosis were 43 and 49 years, respectively. Thus, median elapse from the onset of symptoms to diagnosis was 20 and 15 years in the two families.

Table 1.   Clinical presentation of symptoms in ten patients from family A and B. Index numbers refer to the pedigree obtained after the genealogy study part
FamilyIndexGenderAge at presentationAge at diagnosePDCVDyCIPO
  1. +, present; −, absent; P, pain; D, diarrhea; C, constipation; V, vomiting; Dy, dysphagia.

AIII-1F3565+++++
AIV-2F1843+++++
AIV-5F2540++++
AIV-6M2042++++
BIII-8M6063++++
BIV-12F3042++++
BIV-13M3841+++
BIII-11F2557+++++
BIV-8M3042++
BIII-14M7078++

The most common symptoms in the ten patient’s history were chronic diarrhea (ten of ten), abdominal pain (nine of ten) and vomiting (seven of ten) while six of ten had suffered from periods of constipation. One patient in family A (IV:2) had a colectomy for constipation at the age of 43. One patient in family B (III:14) had a distal colectomy and ileostomy at the age of 77 for diverticulosis and intractable diarrhea. Six out of 10 patients had dilated small bowel at radiology interpreted as a sign of overt CIP. All patients denied dysphagia. There was no history of urogenital diseases except missed abortion in one subject in family A (IV:2). No patient reported extra-intestinal neurologic or ocular symptoms. In both families pupillary reflexes were normal. Among diseases reported were porphyria cutanea tarda 1, celiac disease 1, and chronic obstructive respiratory disease in one heavy smoker.

Laboratory findings

Gut transit measurements  Gastric emptying was normal in seven of eight patients (III:1 not tested, Table 2). Six of the patients had an emptying value more rapid than the median for healthy subjects. Eight of the nine patients had slow small bowel transit. Small bowel marker transit was severely abnormal in six of seven patients tested, outside of the measure range of the method. Despite gastric emptying of markers within 1 h in all subjects, none of these six patients had markers in the colon 8 h after the meal (upper reference <5 h in healthy subjects20). After 24 h, three patients still had all markers in the small bowel and in three patients only about half of the markers had reached colon. Colonic transit was normal in five of six patients tested. In one patient the colonic transit could not be assessed because all transit markers were still in the small bowel on day 7, and one patient had undergone hemicolectomy.

Table 2.   Laboratory findings in nine patients from family A and B. Index numbers refer to the pedigree obtained after the genealogy study part
FamilyIndexJejunal entero-pathogensGastric emptyingColonic transitSmall bowel transitManometry abnormal phase IIIManometry jejunal hypomotility
  1. +, present; −, absent; N, normal; Abn, abnormally delayed; ND, not done; NM, not measurable.

AIII-1+NDNDAbn++
AIV-2+AbnNDAbn++
AIV-5+NNMAbn++
AIV-6+NNAbn++
BIII-8+NAbnAbn++
BIV-12+NNAbn++
BIV-13+NNAbn++
BIII-11+NNAbn++
BIV-8NNN++

Manometry  All patients from both families had clear-cut abnormal findings at manometry (Table 2). No patient had normal phase III: seven patients with phase III had absence of progression of phase III from duodenum to jejunum (Fig. 2B) and two patients lacked phase III. All patients had a severe hypomotility in the jejunum during fasting (Fig. 2A) and after the test meal. In addition, eight patients showed abnormal, longlasting (>3 min) bursts and abnormally clustered pressure waves in duodenum suggestive of a neuropathic disorder. For the eight patients that had the test meal a change to more frequent pressure waves followed in proximal duodenum in all patients, indicating a change to postprandial patterns at this level, however with a neuropathic-like appearance in several patients.

image

Figure 2.  Antroduodenojejunal manometry with 8-channel recording (A1–A3: Gastric antrum; D1–D3: Descendent duodenum; DD: Distal duodenum close to ligament of Treitz; J: Jejunum). (A) Fasting phase II recording in a woman, age 40 with normal gastric emptying. Manometry shows severe hypomotility at the jejunum. (B) Fasting recording in a male patient, 63 years-old, showing absence of motility in the distal duodenal recordings and the jejunum and abnormal progression of phase III that migrates from antrum to proximal duodenum, but is not detectable in distal duodenum or jejunum.

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Small bowel culture  Eight of the nine investigated patients had growth of enteropathogens and only one patient (from family B) had a normal culture. The commonest strains were Escherichia coli and Klebsiella. In the initial two patients (III:1; IV:2) a hydrogen breath test was performed as well, showing markedly increased H2-values compatible with bacterial overgrowth.

Histopathologic examination

The main histopathologic findings are summarized in Table 3. Intranuclear inclusions were found in both families in neurons in patients III:11 (Fig. 3A) and IV:2, whereas strongly suspected inclusion was found in one myenteric neuron in bcl-2 stained section in patient III:14 (Fig. 3C). The characteristic signs of neuronal degeneration on conventionally stained sections were swollen enlargement (>40 μm in diameter) with chromatolysis, vacuolization of the cytoplasm like ‘bunch of grape’ (Fig. 3B, IV:2), shrinkage with nuclear hyperchromasia, and the presence of PAS-diastase resistant lipofuscin granules within vacuoles (autophagic vacuoles; Fig. 3D). In some myenteric ganglia ‘cavities’ were observed with remnants of degenerated neurons and glial cells (Fig. 3E). Immunohistochemistry showed abnormal pattern in all three cases: synaptophysin-neurons without pericellular positive ring, increased staining with α-internexin, and large vimentin+ granules. The counting of SP and VIP immunoreactive neurons in patients from family B containing >100 neurons in the sections showed diminished SP/VIP ratio: 0.58 and 0.72 in patient III:11 and III:14, respectively (normal mean of the ratio: 1.1; 95% confidential interval: 0.8–1.5). There were no signs of ganglioneuritis (means of T-cell per myenteric ganglion were <0.25 in all three cases and no T-lymphocytes were observed within ganglia or along small nerves). Neither mastocytosis, nor eosinophilic infiltration was seen at the neural plexus. The interstitial cells of Cajal showed no abnormality except hypertrophy in one patient (Table 3).

Table 3.   Histopathologic findings in full thickness intestinal preparations from three patients with a familial history of chronic intestinal pseudo-obstruction
Patients Family/index no.NeuronsICCs
VacuolisationSwellingShrinkageLipofuscin and vimentin+ granulesIntranuclear inclusionNegative bcl-2 IHS
  1. *strongly suspected because it was found in bcl-2 stained section

A IV:2++++++Hypertrophy
B III:11++++++
B III:14++++(+)*+
image

Figure 3.  Illustration of degenerative neuropathy in family A and B. A: Patient III:11. Shrunken neuron with an intranuclear inclusion (arrow) surrounded completely by a halo. (H&E, bar = 10 μm). B: Patient IV:2. The neuronal body is 60 μm in diameter and resembles a ‘bunch of grape’ due tovacuolisation. The glial cells form a ring around the neuron. (H&E, bar = 25 μm). C: Patient III:14. Three neurons within a myenteric ganglion. Two of these are negative for bcl-2 (thin arrows; all healthy neurons should be bcl-2 positive), inbetween a small weakly positive neuron. Thick arrow shows a strongly suspected intranuclear inclusion. (bcl-2 immunohistochemistry, bar = 10 μm). D: Patient III:14. Diastase-resistent PAS+ lipofuscin granules in autophagic vacuoles (arrow). (PAS-diastase; bar = 15 μm). E: Patient III:14. Within a cavity remnant of a neuron with nucleus (long arrow) and two glial cells. Short arrow shows the vacuolized perikaryon of a neuron. (H&E, bar = 10 μm).

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No pathological alterations were seen in the muscles, mucosa, or the submucosa.

Genealogic studies

Familial intestinal degenerative neuropathy without extra-intestinal manifestations is a rare disease with very few families described. Therefore, the outcome of the histopathology study suggesting two such families in a restricted geographic area prompted genealogy research for a possible relationship between family A and family B.

Careful studies of conventional Parish Registers added no new information to that already known and outlined in Fig. 1A, B. The father (subject I:2) of the first reportedly affected patient (II:1) was registered as ‘Unknown’. Careful scrutiny of the registers for Parish Catechetical Meetings in several parishes disclosed that the mother (I:1) of the first reportedly affected patient (II:1) in family A and the male ancestor in family B (I:4) had worked on neighboring farms in the same parish in 1897, i.e., the year before the birth of subject II:1. Thus, the genealogic research together with the outcome of the clinico-histopathologic studies strongly suggested that family A and B are linked together, sharing a common ancestor. Fig. 4 shows the widened pedigree of the kindred and the categorization of family members after the clinical and genealogic studies.

image

Figure 4.  Pedigree of family A and B. Genealogy investigations, together with clinical and histopathologic studies, revealed that family A and family B were, with all likelihood, parts of the same large kindred.

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Notes on clinical course

For all seven patients in family A and B who have been followed for at least 2 years after the diagnostic tests there has been a progress of gut symptoms, particularly abdominal pain. In most patients there was a decrease of diarrhea for months or years with antibiotics like ciprofloxacin. Three patients had decrease of drug refractory vomiting for 2–7 years with gastric electrical stimulation as reported elsewhere.24 Two patients in family A (III:1 and IV:2) died 6 and 13 years, respectively, after the diagnosis was made due to repeated septicemia, intestinal, and multi-organ failure.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References

The present study has identified a large kindred from the south of Sweden with familial intestinal degenerative neuropathy leading to CIP in the most severely affected family members. The characterization of the disease and the pedigree is based on clinical findings, laboratory investigations, histopathology, and genealogical studies in two ‘families’ originally thought to be separate family entities.

In most of the approximately eight families reported in the literature presenting hereditary intestinal degenerative neuropathy the disease is also combined with extensive extra intestinal involvement, particularly neurologic and ocular, as well as esophageal manifestations.5 Only three families6–8 have been reported with characteristics resembling our family, i.e., histopathologic evidence of degenerative neuropathy, no extra intestinal neurologic features, no esophageal symptoms and an age at presentation ranging from the first to seventh decade. The present family seems to be the largest one reported with respect to the number of patients with proven disorder. While two of the previously reported families had Irish and/or Scottish origin6,7 this is the first family reported from northern Europe.

From the pedigree of the family (Fig. 4) it can be concluded that the disease is inherited in an autosomal dominant manner. There are several examples of male to male transmission which rules out an X-linked inheritance. The age at onset is very variable with a median of 30 years in the ten subjects with proven disease (Table 1). One patient with documented degenerative neuropathy (III:14) had his first symptoms at the age of 70, while one boy (III:4) had died from intestinal failure in the 1930s when he was 3 years-old. Thus, family members that did not report symptoms may be at risk to develop the disease later on. In Fig. 4 all subjects depicted as ‘absence of disease’ (open symbols) were more than 32 years-old and without symptoms of chronic intestinal disease. There is no evidence of anticipation. Both sexes are affected equally.

The small bowel and colonic specimens from the three patients investigated in this study all fulfilled the relevant histopathologic criteria of degenerative visceral neuropathy as shown in Table 3.23 Neural inclusions were found in both family A and family B. This is in contrast to the three previous reports where inclusions were not reported.6–8 Mayer et al.7 observed swollen-vacuolar degeneration and pale neurons (sign of chromatolysis in H&E-stained sections) similar to our findings whereas in the other two reports degeneration of neurons was described only in sections prepared with silver-impregnation.6,8 No intranuclear inclusions (INI) were observed in these three reports6–8 in contrast to our findings. It is noteworthy, that familiar visceral neuropathy seems to be heterogeneous even with respect to INI. In the families with this disease INI were seen in the myenteric neurons in three families5,10,25 and in the submucosal neurons in one family.9 This variation can be explained by the findings in human cultured neurons26 and in transgenic mouse model of nuclear inclusion disease.27 In these studies, INI were found only in approximately 5% of the neurons.

Apart from familiar visceral neuropathy such as in the present family INI can also be observed in a variety of human diseases from polyglutamine-repeat expansion diseases (Huntington’s disease, spinocerebellar ataxia, neural, and inclusion disease) to synucleopathy, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis.28 The INI are also heterogeneous regarding their ultrastructural morphology depending on the thickness of the filaments and the presence or absence of granular material.29 Their chemical content is also complex, they can be ubiquitin+/−, αB-crystallin+, lamin A/C+, ataxin-7+, and TDP-43+.26–28 The role of INI is not clear. Some authors regard them as harmful causing neurodegeneration30 or disruption of the normal nuclear lamin pattern26 whereas others attribute an important protective function to INI.31–33 The latter possibility is supported by the findings of Clarke et al. who found in a murine model that cholinergic INI+ neurons were spared whereas NOS+/INI neurons were reduced in number.27

In the present study histopathology clearly demonstrated that the neuropathy involved not only the small bowel but also the colon and, furthermore, some patients had suffered from constipation. Nevertheless, the clinical and laboratory investigations demonstrated that the small bowel was the intestinal segment that was the most severely affected. This was evident both in the direct motility investigations (transit and manometry) as well as in occurrence of abnormal small bowel cultures usually coinciding with diarrhea. Particularly the manometry showed severe abnormalities in all patients investigated (Table 2). Interestingly one of the striking deviations, the hypomotility in the jejunum, could without doubt be classified as ‘not normal’ but this manometric abnormality is not specific for neuropathy because myopathic CIP usually show very similar patterns. Although the duodenal pressures in the present patients showed neuropathic-like alterations our findings emphasize the importance of taking full thickness biopsies in difficult cases with such abnormal jejunal pressure recordings. In the earlier reports, Mayer’s patient had a normal duodenojejunal manometry7 while the patient in Camilleri’s report showed jejunal hypomotility.8 It is of interest that myopathic forms of familial CIP often show involvement of the urinary bladder while in the present family urological symptoms did not occur.

Esophageal symptoms like dysphagia were not found in the present family. Furthermore, despite severe vomiting in several patients definite delay in gastric emptying was found in only one out of eight patients tested. Thus, the vomiting may well have been secondary to the small bowel disease rather than to a primary gastric disorder. This symptom profile with severe involvement of the small bowel and the colon could be compatible with a hereditary disorder affecting the midgut and the hindgut. More research directed to this problem, including gastric neuromuscular histopathology is warranted.

The present study demonstrates how genealogical studies can be of value in research on familial disorders. The conventional Parish Registers did not reveal any information about links between the two families A and B. In contrast, the Parish Catechetical Registers from the 19th century yielded a very plausible explanation for the occurrence of this rare disorder in two ‘families’ in a small geographic area. Parish Catechetical Registers are unique to Sweden and Finland and were in use from the end of the17th century for more than 200 years, regulated by the National Church Law.

Familial intestinal degenerative neuropathy is a very severe disease having a progressive course with the end stage being fulminant pseudo-obstruction. Treatment options are relatively limited and currently consist of nutritional support, antibiotic treatment of the small bowel bacterial overgrowth and symptomatic treatment for diarrhea and pain. Some of the patients have been treated with gastric electrical stimulation (GES) for vomiting with positive results.24 More research in well-characterized families may open new perspectives. Understanding the mechanisms involved in neuronal degeneration may provide the conceptual basis for treatment of ENS abnormalities, as pointed out by De Giorgio and Camilleri.34 We hope that further studies with genetic linkage in the reported family can help us to locate the responsible gene. Moreover, studies of the corresponding protein might hopefully produce knowledge about the pathophysiology of intestinal neuropathies with the ultimate goal to find curative treatments.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References

This study was supported by the Swedish Research Council (grant 13409) and by the Sahlgrenska Academy at University of Göteborg. The skilled genealogy work by the late Mrs. Fay Blomqvist was important for the outcome of this study.

Author contribution

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References

FA reviewed the CIP literature, checked documentation of patients’ history, collected data from the investigations, constructed pedigrees and wrote the first draft of manuscript; HL and ML performed the basal clinical work up investigations including endoscopies, referred patients for specialized laboratory investigations, handled the CIP treatment, and critically scrutinized the manuscript; BV performed the re-evaluation of histopathology, reviewed the literature on histopathology in CIP and wrote the manuscript parts on histopathology; HA initiated the comparisons between families A and B; was responsible for all motility investigations and their evaluation, initiated the research on genealogy links, performed the GES treatments and supervised manuscript writing.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. Author contribution
  9. Competing interests
  10. Conflict of interest
  11. References