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Familial visceral neuropathy (FVN) is a heterogeneous group of disorders due to abnormalities of the myenteric plexus. FVN with neuronal intranuclear inclusions is one particular form of FVN with a variable phenotype that includes achalasia, gastro-esophageal reflux, intestinal dysmotility and pseudo-obstruction, dysarthria, peripheral neuropathy and pupillary defects, and the presence of intranuclear inclusions within the neurons of the enteric nervous system. We present a four-generation family in which 10 individuals (7 of whom have been examined) are affected with FVN. The family was previously reported as familial esophageal achalasia, an autosomal recessive condition (MIM200400). At that time, several individuals in a single sibship were affected and there were no manifestations in either parent. Since that report, two individuals have had affected children and the mother has developed symptoms and has abnormalities on electromyography, thus enabling us to reclassify the family. This family provides further evidence of autosomal dominant inheritance, with marked variation in expression. © 2005 Wiley-Liss, Inc.
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- MATERIALS AND METHODS
Familial visceral neuropathy is a poorly understood, heterogeneous disorder, caused by abnormalities of the intestinal myenteric plexus. It commonly presents with gastrointestinal symptoms, in particular chronic intestinal pseudo-obstruction and esophageal dysmotility. Non-intestinal abnormalities, including pupillary abnormalities and peripheral neuropathy, may be present [Faber et al., 1987; Arrindell et al., 1991; Barnett et al., 1992].
In 1992, O'Brien and Smart reported on a family with “familial achalasia and non-achalasic esophageal dysmotility” (MIM200400) [O'Brien and Smart, 1992]. At that time, five sibs had dysphagia; their parents were asymptomatic and it was presumed that they had an autosomal recessive condition. Since the initial report, two of the sibs have had affected children and their mother has developed symptoms, suggesting that they have an autosomal dominant condition. Further investigation of the family showed that 10 individuals (7 confirmed) over four generations have been affected. Histological investigation in one individual demonstrated neuronal eosinophilic intranuclear inclusions. Review of the English language literature demonstrated seven other families with a very similar phenotype, two of which also had neuronal intranuclear inclusions [Schuffler et al., 1978, 1985; Roy et al., 1980; Mayer et al., 1986; Faber et al., 1987; Arrindell et al., 1991; Camilleri et al., 1991; Barnett et al., 1992; Zannolli et al., 2002].
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The pedigree is shown in Figure 1 and the clinical findings are summarized in Table I. All affected relatives presented with dysphagia. The median age of presentation, of the seven family members examined, was 16 years (range 10–63 years). Esophageal manometry was performed in six patients; abnormalities were seen in all those who had symptoms at the time of the investigation and included diffuse esophageal spasm, absent peristalsis, and classical achalasia (Table II). IV-6 was unable to tolerate esophageal manometry. Three (III-5, III-6, and III-7) have developed recurrent aspiration pneumonia, for which one (III-5) required intensive care management.
Table I. Summary of Clinical Findings
|Patient||Age at onset (year)||Dysphagia||Intestinal pseudo-obstruction||Dysarthria||Pupillary abnormalities||Ptosis||Neurological examination||Electrophysiology|
|II-2||63||+||−||−||−||−||Weakness in hands, reduced ankle reflexes||Peripheral motor neuropathy|
|III-2||10||+||Chronic constipation||+||Irregular, unresponsive to light, very slow response to accommodation||−||Weakness of finger abduction and opposition, muscle wasting of hands, pes cavus, areflexia, loss of light touch and pin-prick sensation to mid-calf. Sensori-neural hearing loss||Peripheral motor neuropathy|
|III-4||36||+||−||+||Irregular, no response to light or accommodation||−||Early pes cavus, areflexia||Peripheral motor neuropathy|
|III-5||12||+||+||+||Irregular, no response to light or accommodation||+||Peripheral muscle wasting and weakness, areflexia, patchy loss of sensation in limbs||Normal|
|III-6||16||+||−||+||Irregular, unresponsive to light, very slow response to accommodation||+||Areflexia, no motor or sensory disturbance, mild cerebellar signs in upper limbs||Not done|
|III-7||16||+||+||+||Irregular, unresponsive to light, very slow response to accommodation||+||Weakness of finger abduction and opposition, areflexia||Peripheral motor neuropathy|
|IV-6||10||+||−||−||Irregular, unresponsive to light, very slow response to accommodation||+||Areflexia, no motor or sensory disturbance||Not done|
Table II. Esophageal Manometry
|Patient||Lower esophageal sphincter pressure (cm H2O)||LOS relaxation with swallowing||Motility|
|III-2||45||Normal||Repetitive, low amplitude simultaneous waves. No normal peristalsis|
|III-4||25||Normal||Repetitive simultaneous waves. Some normal peristalsis|
|III-5|| || ||Absent peristalsis|
|III-6||52||Normal||Repetitive, low amplitude simultaneous waves. No normal peristalsis|
Two of the patients (III-5 and III-7) have had repeated episodes of intestinal pseudo-obstruction. Both developed classical symptoms of bowel obstruction but no evidence of mechanical obstruction was found at laparotomy in either patient. These two patients have had barium swallows that showed very delayed passage of barium in the small intestine, and both have demonstrated evidence of bacterial overgrowth on hydrogen breath testing. III-2 and III-7 require gastrostomy feeding, due to severe dysphagia, and III-5 requires total parenteral nutrition, due to complete intestinal failure.
Five of the affected individuals examined had nasal speech that developed in the 3rd or 4th decade of life. The underlying cause of this is unknown.
Most have irregular, asymmetric pupils that are unreactive, or react very slowly, to light and accommodation. In patient III-5, the pupils constricted following pilocarpine, suggesting denervation hypersensitivity. Bilateral non-fatigable ptosis was seen in four of the patients examined.
All of those examined had reduced or absent deep tendon reflexes. Several described feeling dizzy on standing; however, results of cardiovascular autonomic nervous system examination were normal in III-2. Electromyography showed evidence of distally predominant, lower motor neuron degeneration with regeneration in four of five patients examined. There was no evidence of myopathy and results of nerve conduction studies were normal. In one patient (III-2), the sympathetic skin response was absent in the foot but present in the hand. In three other patients the responses in the arm and leg were normal. The results were normal in III-5 but only one nerve was studied; he has declined further testing.
I-1, III-1, and IV-8 were unavailable for study, but are reported by other relatives to be similarly affected. I-1 was described as having a long history of dysphagia, requiring water to aid swallowing, and frequent vomiting. His family was unable to comment on his speech or whether he had other symptoms. He died of lung cancer at the age of 69 years; his dysphagia preceded this by many years. III-1 is said to have dysphagia and nasal speech. IV-8 is described as having dysphagia and always having to drink water to help him swallow his food. His speech is said to be normal; however, his parents have declined any assessment or investigation.
III-2 and III-5, both had a normal karyotype and III-5 had normal mitochondrial DNA analysis, performed on DNA extracted from muscle. Histological examination of his muscle biopsy did not show any abnormality. III-5 and IV-6 have had normal short synacthen tests.
Esophageal and gastric histology from IV-6 documented thickened nerve trunks and eosinophilic intranuclear inclusions in the ganglion cells of the myenteric plexus (Fig. 2). The smooth muscle was histologically normal. Unfortunately, there was insufficient tissue available for further study into the nature of these inclusions and tissue was not available for examination from any of the other relatives.
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When this family was being re-investigated, several conditions were considered, including familial achalasia and non-achalasic esophageal dysmotility, Triple A syndrome, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), familial visceral neuropathy (FVN), and familial visceral myopathy. The family was previously reported as having familial achalasia and non-achalasic esophageal dysmotility and classified as “Achalasia–familial esophageal” (OMIM 200400) [O'Brien and Smart, 1992]. This would now seem an unlikely diagnosis as it is known to be inherited as an autosomal recessive condition and is not associated with neurological or ophthalmological signs and symptoms. The absence of confirmed male-to-male transmission means that we cannot formally prove autosomal dominant inheritance, but the pedigree suggests this is the most likely pattern. Triple A syndrome is an autosomal recessive condition, which causes achalasia, adrenocortical insufficiency, alacrima, and neurological abnormalities [OMIM, 2000; Handschug et al., 2001]. This condition has been excluded on the basis of the inheritance pattern, the absence of alacrima, and normal short synacthen tests in two individuals. MNGIE is another autosomal recessive condition that causes gastrointestinal dysmotility, ptosis, external ophthalmoparesis, peripheral neuropathy, and leucencephalopathy. Patients with MNGIE almost invariably have abnormalities on muscle biopsy, which were not seen in our patient whose muscle was examined, and none of our patients had ophthalmoparesis, which, together with the inheritance pattern, make this diagnosis unlikely.
There is considerable clinical overlap between FVN and familial visceral myopathy. The predominant manifestations in this group of conditions result from gastrointestinal dysmotility; patients commonly present with dysphagia or intestinal pseudo-obstruction. Chronic intestinal pseudo-obstruction is a term used to describe patients with symptoms, signs, and radiological findings suggestive of bowel obstruction but where no mechanical obstruction is found [Mann et al., 1997]. It may occur as part of a specific condition such as Chagas disease, caused by the parasite Trypanosoma cruzi, systemic sclerosis, amyloidosis or small cell carcinoma of the lung, or it may be idiopathic [Krishnamurthy and Schuffler, 1987]. Chronic idiopathic intestinal pseudo-obstruction can be inherited and these cases are divided broadly into FVN or familial visceral myopathy. In both conditions, patients often have esophageal dysmotility and, in the latter, patients commonly have urinary symptoms. The two conditions can be distinguished histologically; in familial visceral myopathy there are abnormalities in the smooth muscle of the gastrointestinal and renal tract, and the myenteric plexus is normal, whereas in FVN there are myenteric plexus abnormalities but normal smooth muscle. Although the gastrointestinal symptoms found in these conditions are similar, this histological distinction, and also the different extra-intestinal manifestations, may be important in defining the pathogenesis of these conditions. It is currently not possible to say how many underlying genes may be involved and we cannot rule out the possibility that the two conditions are allelic.
Seven families with very similar manifestations and abnormalities of the myenteric plexus have been described; details are summarized in Table III. The symptoms found in FVN vary depending, in part, on the severity of the myenteric plexus abnormalities and the degree of gastrointestinal tract involvement [Schuffler, 1981]. Eosinophilic inclusions in the ganglion cells were found in two families, but the nature of these inclusions was not identified. In the other reported families, the neurons were swollen and vacuolated, showed degeneration or were reduced in number. Hypertrophied nerve fibers were also seen in one family. It is unclear whether FVN with neuronal inclusions is a distinct condition or represents a sub-group.
Table III. Summary of Current and Previously Reported Cases
| ||Current case||Schuffler et al., 1978||Roy et al., 1980||Mayer et al., 1986||Faber et al., 1987||Camilleri et al., 1991||Barnett et al., 1992; Arrindell et al., 1991||Zannolli et al., 2002|
|Suggested inheritance pattern||AD||AR||AD||AD||AR||AD||AD||AD|
|Affected||10 (in 4 generations)||2 sibs||4 (father and 3 sons)||7 (in 2 generations)||5 (2 families- 3 sibs in 1 family and 2 1st cousins)||2 (mother and daughter)||6 (3/4 sibs, father and 2 of his sibs)||3 (mother and 2 sons)|
|Age at presentation||10–63 years (median 16 years)||2nd/3rd decade||8–18||1st–5th decades||2nd decade||1st decade||1st/2nd decades||1st/2nd decade|
|Intestinal pseudo-obstruction||+||+||Progressive disturbance of intestinal motility||Chronic abdominal pain, distension, constipation and diarrhea||+||+||2 individuals||Chronic diarrhea|
|Esophageal manometry||Diffuse esophageal spasm, absent peristalsis or classical achalasia||Vigorous achalasia|| ||Normal||N/R||Normal||Vigorous achalasia||N/R|
|Eyes||Ptosis. Asymmetric, irregular, unreactive pupils (denervation hypersensitivity)||Irregular poorly reactive pupils (denervation hypersensitivity)||Normal||Normal||Ptosis. External ophthalmoplegia||Normal||Pupils minimally responsive to light. Parasympathetic & sympathetic denervation hypersensitivity||Dysmetria|
|Reflexes||Reduced or absent||Absent||Normal||Normal||Absent||Normal||Normal||Increased|
|Peripheral neuropathy||Motor axonal peripheral neuropathy||Reduced vibration/position sense||N/R||−||Sensory and motor peripheral neuropathy||−||Large-fiber peripheral neuropathy||−|
|Histology of myenteric plexus||Thickened nerve trunks. Eosinophillic intranuclear inclusions in ganglion cells||Reduced number of neurons throughout GI tract. Eosinophilic intranuclear inclusions||Hyperplastic ganglia in myenteric plexus. Swollen, distorted, vacuolated neurons||Reduced number of neurons. Neurons swollen and vacuolated. Limited to jejunum and ileum||Hypertrophied nerve fibers. No ganglia||Degeneration of neurons||Eosinophillic intranuclear inclusions in submucosal ganglion cells||Eosinophilic intranuclear inclusions in neurons (rectal biopsy)|
|Other Features|| ||Ataxia|| || ||Bilateral sensori-neural hearing loss|| || ||Erectile dysfunction. Ataxia Cerebellar atrophy|
Some of the reported cases also had peripheral neuropathy and unreactive pupils. Electrophysiological studies in the previously reported cases with peripheral neuropathy showed a demyelinating pathology, rather than the axonal one demonstrated in our patients. The electromyographic abnormalities were severe in three of the patients we examined. (III-2, III-4, III-7) The degree of change in all patients seemed to be independent of the degree of gastrointestinal abnormality.
In four previously reported families, the disorder was inherited in an autosomal dominant pattern and in three it was thought to be autosomal recessive, based on single generations being affected. This condition shows extreme variability; in this family, II-2 and III-4 are minimally affected while III-5 has a severe, debilitating disease that has led to complete intestinal failure. It is possible that FVN is genetically heterogeneous with dominant and recessive forms, but it is also possible that the condition is dominantly inherited with wide variation in expression, reduced penetrance, or gonadal mosaicism accounting for the occurrence in single generations with apparently unaffected parents.
A common finding in this heterogeneous group of conditions is intestinal dysmotility, presenting as chronic idiopathic intestinal pseudo-obstruction or dysphagia, due to an abnormality of the myenteric plexus. This has led to the term FVN, but it may not be the best description as there are frequently extra-intestinal manifestations. Searching OMIM shows a number of different entries: intestinal pseudo-obstruction due to neuronal inclusion disease (243180), megaduodenum and/or megacystis (155310), and neuronal intranuclear inclusion disease (603472), showing that other names and classifications have also been used [OMIM, 2000].
There may be some overlap with other disorders that cause intranuclear inclusions. Neuronal Intranuclear Inclusion Disease (NIID) is a variable condition that can affect any part of the nervous system. The clinical manifestations depend on the sites involved, but it usually presents as a visceral neuropathy or a multisystem degenerative process with features such as ataxia, opthalmoplegia, oculogyric crises, dysarthria, and cognitive impairment. The enteric nervous system is only involved in some patients so gastrointestinal manifestations are not always seen. Most cases are sporadic but familial cases have been reported [Schuffler et al., 1978; Haltia et al., 1984; Kimber et al., 1998; Zannolli et al., 2002]. In 1998, Kimber et al. reported monozygotic female twins with neurogenic limb weakness, ataxia, and dysarthria and two adult sons of one of the twins with similar manifestations. Intranuclear inclusions typical NIID were found in the brains and spinal cords of both twins and immunostaining for ubiquitin was positive [Kimber et al., 1998].
The origin and nature of the inclusions seen in NIID and FVN remains unclear and further research is necessary to understand the pathogenesis of this condition. Identification of other families with similar phenotypes may allow further clarification of this rare group of conditions and possible gene localization through linkage analysis.