chronic intestinal pseudo - obstruction ( cipo ) is a high - morbidity syndrome that develops as a consequence of altered intestinal motility , which results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process . cipo is one of the most important causes of chronic intestinal failure both in pediatric ( 15% ) and adult cases ( 20% ) , since affected individuals are often unable to maintain normal body weight and/or normal oral nutrition , . the severity of the clinical picture , generally characterized by disabling digestive symptoms even between sub - occlusive episodes , contributes to deterioration of quality of life of the patients . furthermore , cipo often passes unrecognized for long periods of time , so that patients almost invariably undergo repeated , unnecessary and potentially invasive surgical procedures . fabry disease ( fd ) is an x - linked lysosomal storage disease characterized by the dysfunction of multiple systems , including significant gastrointestinal ( gi ) involvement such as diarrhea , abdominal pain , early satiety and nausea . the deficiency in lysosomal -gal a causes accumulation of globotriaosylceramide ( gl-3 ) within the lysosomes of multiple cell types throughout the body . this accumulation results in inflammation , ischemia , hypertrophy , and the development of fibrosis ultimately resulting in cellular damage and progressive organ dysfunction , . although fd was thought to be rare , only affecting 1 in 40,000 ; recent newborn screening data show it to be much more common , affecting up to 1 in 34004000 newborns . we report the occurrence of cipo in two unrelated patients with fabry disease and the possible explanation of a direct relation of these two disorders . case 1 : 62  years old female with classic phenotype of fd ( mutation : a292 t ) . at her initial visit for fd at the age of 59 , the patient described isolated bloating and sporadic diarrhea with intermittent abdominal colic pain since the age of 18 . medical records showed at least 4 hospitalizations for intestinal pseudo - obstruction during the last 20  years . she had echocardiographic evidence of left ventricular hypertrophy ( lvh ) and had a history of arrhythmias . she presented with a 5-day history of abdominal pain , primarily in the right lower quadrant and associated with intermittent fevers . abdominal ct reported distended bowel loops , thickening of the proximal colon wall and free fluid in adjoining fascias . the following day , physical exam revealed an absence of abdominal sounds and progressively worsening pain . the patient underwent abdominal surgery with right colonic resection and placement of colostomy due a suspicion of tumoral obstruction . pathological findings in h&e stained paraffin sections demonstrated enlarged ganglion cells with foamy cytoplasm present within meissner 's plexus of the submucosa present in the ileocecal valve sample . the foamy appearance likely represented the presence of gl-3 accumulation , lost in the paraffin processing . epoxy resin sections taken from this same area show enlarged ganglion cells filled with zebra bodies , further suggesting the accumulation of gl-3 . ganglion cells of auerbach 's plexus present between the two muscular layers of the muscularis propria were also engorged with gl-3 accumulation ( fig . substrate accumulation was also present in the smooth muscle cells of small arteries present in the submucosa ( fig . 1a : ganglion cells of auerbach 's plexus : ganglion cells appear markedly foamy due to the accumulation of gl-3 ( paraffin section , h&e , 600   ) . ( hrlm , 1  m epoxy resin , 1:1 richardson 's stain , 1000  ).fig . 1 a : ganglion cells of auerbach 's plexus : ganglion cells appear markedly foamy due to the accumulation of gl-3 ( paraffin section , h&e , 600   ) . ( hrlm , 1  m epoxy resin , 1:1 richardson 's stain , 1000   ) . case 2 : 37  years old male patient was diagnosed with classic fd ( mutation : d155h ) following a renal biopsy for proteinuria study . the patient had other classic symptoms of fd including chronic abdominal pain and episodes of diarrhea during childhood , neuropathic pain in the hands and feet associated with fever and exercise , angiokeratomas and cornea verticillata . furthermore , echocardiogram showed mild lvh and brain mri showed small periventricular ischemic lesions . at the age of 32 , the patient was hospitalized due abdominal pain and diverticulitis ; after 2  days of conservative treatment he made a full recovery . at the age of 38 , the patient developed fever and progressive left , lower - quadrant abdominal pain . after 3  days of conservative treatment , physical exam revealed severe abdominal distention , absence of abdominal sounds and progressively worsening pain . abdominal surgery showed sigmoid colon distention and a delustered appearance ; bowel resection with placement of colostomy was performed . pathological examination of h&e stained paraffin revealed neither obstructive process nor inflammatory infiltration . enlarged and vacuolated neurons in the meissner 's and auerbach 's plexuses ( fig . 2a ) and intracellular inclusions in the smooth muscle cells of small arteries were present in the submucosa . b : vascular arterial lumen narrowing due smooth muscle cells vacuolated cytoplasm . ( paraffin section , h&e , 600).fig . 2 a : vacuolated cytoplasm of submucosal and myenteric plexus colon cells . ( paraffin section , h&e , 600   ) . b : vascular arterial lumen narrowing due smooth muscle cells vacuolated cytoplasm . ( paraffin section , h&e , 600 ) . cipo may be primary , when it exclusively involves intestinal smooth muscle or enteric neural plexus , or secondary to other conditions . the histopathologic presentation of cipo can be divided in neuropathic , mesenchymopathic and myopathic forms based on abnormalities affecting the integrity of nerve pathways supplying the gut ( either intrinsic or extrinsic ) , interstitial cells of cajal ( icc ) or smooth muscle cells , respectively . neuropathic , mesenchymopathic and myopathic changes may contribute to gut dysmotility either individually or in combination ( e.g. neuro - myopathies or neuro - icc alterations ) .table 1causes of chronic intestinal pseudo - obstruction syndrome.table 1myopathicneuropathicmesenchymopathicvisceralmitochondrialcentral:parkinson diseasemultiple system atrophystrokeencephalitistumorloss of interstitial cells of cajalprimary:absence of or selective decrease in smooth - muscle alpha - actinfamilial or sporadic visceral myopathymyopathy from abnormal gut morphogenesisautoimmune leiomyositisdiseases from defective genes coding for proteins indirectly related to oxidative phosphorylationperipheral:diabetic neuropathyneuropathies potentially involving the enteric nervous system :  amyloidosis  hirschsprung  chagas  paraneoplastic syndromes  autoimmune diseasessecondary:lupus , polymyositisamyloidosis ceroidosis ( vitamin e deficiency)progressive muscular dystrophy,drugs ( neuroleptics)diseases from genetically - induced mitochondrial dna stability disturbancediseases from defective nuclear genes coding for crm enzyme complex proteins causes of chronic intestinal pseudo - obstruction syndrome . multiple system atrophy absence of or selective decrease in smooth - muscle alpha - actin familial or sporadic visceral myopathy myopathy from abnormal gut morphogenesis autoimmune leiomyositis neuropathies potentially involving the enteric nervous system :  paraneoplastic syndromes amyloidosis ceroidosis ( vitamin e deficiency ) progressive muscular dystrophy , in fd , gastrointestinal symptoms occur in approximately 70% of male patients , , but the frequency ranges from 19% to 69% in different series , . in heterozygous patients ( females ) almost half of them may experience gi symptoms and some of those symptoms , such as constipation , are reported almost twice as often by female patients as by male patients . significant gi involvement has also been observed in children and can progress in severity with age . in a systematic review , laney and colleagues observed that gi symptoms even presented in very young children , aged 14  years old , most commonly complaining of abdominal pain . the symptoms present soon after the development of acroparesthesias and can be the initial symptom of fd in up to 20% of patients . abdominal pain is described as cramping mid - abdominal discomfort , frequently worsened with meals and increased stress . the possible local ischemia due endothelial deposits of gl-3 has led to the suspicion of . the diarrhea can be intake - triggered , frequently associated with significant urgency and frequency , and occurring up to 15 times daily . , colonic dysmotility can lead to the pseudo - obstruction syndrome , simulating intestinal necrosis . that is why up to this date colostomy has been performed in some cases , , even for children with fd without cardiac , renal or cerebrovascular compromise . intestinal perforation , secondary to diverticular disease , has been repeatedly described in the literature . the location of diverticula has been described as occurring at the duodenal , jejunal , and colonic levels , , . neuropathic pain ( acroparesthesias ) and gi involvement may be explained due a multifactorial cascade . substrate deposits of gl-3 in autonomic ganglia ( dorsal root ganglia -drg- and myenteric and submucosal ganglia ) may be the cellular alteration which results in the appearance of symptoms , , , , . intestinal ischaemia due myenteric vessel occlusion could also be correlated with the small fiber neuropathy as a result of vasa nervorum obliteration . animal models with fd showed mechanical hypersensitivity in the von- frey test and mechanical allodynia when compared with controls , . the same studies demonstrated that tissue involvement in drg and small nerve fiber loss are linked with upregulation of sodium channels type 1.8 ( nav1.8 ) and transient receptor potential vanilloid type 1 ( trpv1 ) . the upregulation of these channels in drg neurons causes an early depolarization of the resting potential , reduced threshold and increased frequency for evoked firing in these neurons , and increased fraction of drg neurons that fire spontaneously . the gi manifestations reported by patients with fd might be explained by the effect of the gl-3 deposits on visceral afferents that are known to express nav1.8 and trvp1 channels . a specific role for nav1.8 in regulating gastrointestinal function is supported by experimental evidence showing that this channel ( as well as nav1.9 also ) is important for responses to mechanical stimulation and mechanical hypersensitivity of visceral afferents innervating the colon when challenged by an inflammatory mediators or food intake . enzyme replacement therapy ( ert ) should be initiated in all affected patients with fd as soon as clinical signs and symptoms are observed . early treatment of asymptomatic or mildly symptomatic patients may be justified in order to prevent disease progression . this may be explained by a decrease of gl-3 accumulation in the endothelium of the intestinal vessels and by improved mesenteric circulation . ert is presently available in the form of agalsidase alfa ( replagal , shire hgt , inc . , cambridge , ma , usa ) and agalsidase beta ( fabrazyme , sanofi genzyme , cambridge , ma , usa ) , . agalsidase alfa is given at 0.2  mg / kg body weight every other week by intravenous ( iv ) infusion and is approved in many countries throughout the world , though not by the usa food and drug administration . agalsidase beta is administered at 1.0  mg / kg body weight once every 2  weeks as an iv infusion and is approved in europe , the usa and many other countries . there are no adequately powered head - to head studies that have compared the long - term effectiveness of the two enzyme preparations on clinical outcomes in well - characterized , phenotypically homogenous populations but evidence suggests that a higher agalsidase dose may be of clinical benefit in reducing gl-3 accumulation , . because of the shortage of agalsidase - beta in 2009 , many patients with fd were treated with lower doses or were switched from agalsidase beta to agalsidase alfa . one observational study assessed end - organ damage and clinical symptoms during dose reduction or switch from agalsidase beta to alfa . after 1  year , severity score index and frequencies of pain attacks , chronic pain , gastrointestinal pain , and diarrhea increased significantly in the dose - reduction and switch groups . because of the non - specific nature of the gi symptoms , diagnosis of fd is often delayed for several years . gastrointestinal involvement is often misdiagnosed ( usually as irritable bowel disease , visceral myopathy or inflammatory bowel disease ) or under - reported . the other authors declare that they have no competing interests in relation to this work . this research did not receive any specific grant from funding agencies in the public , commercial , or not - for - profit sectors . all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation of laboratorio de neuroqumica dr .