Achalasia in an Adolescent With Fabry Disease

Fabry disease is a rare, X-linked inborn error of glycosphingolipid metabolism caused by a deficiency of the lysosomal enzyme α-galactosidase A. This enzymatic deficiency leads to the accumulation of glycosphingolipid in various tissues. Clinically the disease is characterized by cutaneous angiokeratomas, severe limb pain, renal insufficiency, myocardial infarction and conduction defects, corneal opacities, hypohidrosis, seizures, and stroke (1,2). Gastrointestinal symptoms have rarely been reported and include anorexia (3,4), vomiting (3,4), abdominal pain (4), and diarrhea (3–6). Small bowel perforation (7) and colonic stricture (8) have been listed as gastrointestinal complications. Achalasia, a motor disorder of the esophagus, has been reported only once in association with Fabry disease, in a 52-year-old man (9). We report a 15-year-old boy with achalasia subsequently diagnosed with Fabry disease. CASE REPORT A 15-year-old boy presented with a 3-month history of dysphagia for both liquids and solids. He had frequent complaints of heartburn but denied vomiting, regurgitation, weight loss, fevers, diarrhea, or abdominal pain. The patient also had a 9-year history of episodic, sharp metatarsal pain that increased with febrile illnesses, and a several-year history of similar pain in his metacarpals. His uncle and sister had similar complaints of limb pain. His parents reported that he did not perspire as much as other individuals, and that he had dry skin. On physical examination, the patient weighed 52.3 kg (30th percentile) and was 173.3 cm tall (70th percentile). His heart rate was 74 beats/min; blood pressure, 120/63; and respiratory rate, 14 breaths/min. He was a thin, well-developed young man in no acute distress. Head and neck examination revealed no abnormalities. Results of a cardiac examination were regular and without murmur. His lungs were clear to auscultation. His abdomen was nondistended, soft, nontender, and had active bowel sounds. No hepatosplenomegaly was palpated. His umbilicus had 20 to 30 small, 1-mm, raised red nodules. The patient's skin was dry but without rashes. Neurologic examination revealed no focal deficits. An upper gastrointestinal series revealed a smooth tapering of the distal esophagus with proximal esophageal dilatation. Esophagogastroduodenoscopy and biopsies revealed reflux esophagitis. Esophageal manometry revealed aperistaltic wet swallows, elevated lower esophageal sphincter pressure of 35 mm Hg (normal, 22 ± 8 mm Hg), and incomplete relaxation of the lower esophageal sphincter, consistent with achalasia. Pneumatic dilatation was performed, and treatment with the proton pump inhibitor Omeprazole was initiated. The patient did well for several months until symptoms of dysphagia redeveloped and pneumatic dilatation was repeated. The patient has since been without dysphagia but continues with complaints of heartburn. Referral to a rheumatologist for evaluation of extremity pain revealed the probable diagnosis of Fabry disease based on a history of painful hands and feet, and a physical examination finding of periumbilical angiokeratomas. This diagnosis was confirmed by demonstrating absence of detectable serum α-galactosidase A (0.000 U/L; normal, 0.016–0.200 U/L). DISCUSSION Fabry disease is a rare metabolic disorder of sphingolipid metabolism with an estimated incidence of approximately 1 in 40,000 (10). It is an X-linked recessive sphingolipid storage disease caused by a deficiency of the lysosomal enzyme α-galactosidase A. Glycosphingolipid, predominantly globotriaosylceramide and to a lesser extent galabiosylceramide, accumulates within various tissues, leading to an array of symptoms. Diagnosis is made by documenting a deficiency of α-galactosidase A in plasma, serum, white blood cells, or cultured skin fibroblasts. This disease has an array of clinical manifestations. In male patients, Fabry disease usually presents in childhood or early adolescence with severe pain crises involving the fingers and toes, and is exacerbated by fever, cold, heat, or exercise. Angiokeratomas—tiny dark-purple–blue angiectases, which erupt around the umbilicus, genitalia, buttocks, back, hips, thighs, and oral mucosa—are characteristic of this disorder. Corneal opacities and lenticular opacities as well as hypohidrosis can also be seen early during the course of this disease. Heterozygous female patients are usually asymptomatic but may show a mild form of the disease with a normal life expectancy. Eighty percent of these patients have corneal opacities, and approximately 30% have angiokeratomas. Cardiac, central nervous system, and renal involvement occur in less than 1% of heterozygous patients (2). Complications of Fabry disease are caused by the progressive accumulation of glycosphingolipids in the endothelium of various tissues, leading to ischemia and infarction (2). Glycosphingolipids also accumulate in smooth muscle cells of the cardiovascular and renal systems, as well as in dorsal root ganglia, peripheral autonomic ganglia, salivary nuclei, the nucleus ambiguus, the substantia nigra, the hypothalamus, and the myenteric plexus (11–13). With increasing age, progressive accumulation of glycosphingolipid in vessels leads to cardiac disease, cerebrovascular attacks, and renal insufficiency. The average life expectancy of male patients is 42 years (1). Death usually occurs from cardiac, renal, and/or cerebral complications of the vascular disease (10). Renal disease begins with proteinuria, which can start in childhood, and ends with renal failure, which usually occurs in the third or fourth decades of life. Cardiac abnormalities include myocardial infarction, congestive heart failure, conduction defects, and mitral insufficiency. Neurologic symptoms that usually present in the early 30s include headaches, seizures, dizziness/vertigo, ataxia, and hemiplegia (11). Hypertensive stroke can occur later as a complication of renal insufficiency. Mental deficiency is rare. Gastrointestinal manifestations of Fabry disease are rare but include diarrhea, anorexia, vomiting, and abdominal pain (3–6). Diarrhea is thought to be caused by the accumulation of glycosphingolipids in the myenteric plexus of the intestinal tract, resulting in dysmotility and subsequent bacterial overgrowth (8). Intestinal ischemia resulting from small-vessel disease or dysmotility has been reported previously (6,14). A 50-year-old man with Fabry disease died after a small bowel infarction (15). A small bowel perforation reported in a 51-year-old man likely resulted from a combination of severe vasculitis and thrombosis in the bowel wall, and involvement of autonomic ganglion cells leading to impaired motility (7). It is likely that abdominal pain in these individuals was related to intestinal ischemia. Our patient presented with several signs of Fabry disease and what appeared to be a previously unreported gastrointestinal manifestation of this disorder in children: achalasia. Achalasia, like Fabry disease, is a rare disorder with an incidence in children of less than 0.1 per 100,000 per year (16). It is an esophageal motility disorder characterized by increased resting lower esophageal sphincter pressure, incomplete relaxation of the lower esophageal sphincter with swallowing and aperistalsis of the esophageal body (17). Achalasia may be either primary (idiopathic) or secondary to an underlying disease such as Chagas disease or cancer (pseudoachalasia) (17). Primary achalasia usually presents between the ages of 25 and 60 years but can also present in childhood (18). Less than 5% of individuals develop symptoms before 15 years of age. Clinical manifestations include dysphagia, odynophagia, regurgitation of undigested food, noncardiac chest pain, failure to thrive, and recurrent pneumonia. Diagnosis is made by upper gastrointestinal series, esophagogastroduodenoscopy, and esophageal manometry. The characteristic upper gastrointestinal series shows a dilated esophagus with tapering at the gastroesophageal junction to the classic, narrowed “bird's beak” appearance. Esophageal manometry, the gold standard for diagnosing achalasia, reveals the diagnostic motility abnormalities mentioned earlier. Esophagogastroduodenoscopy is undertaken to rule out definitively an anatomic obstruction, malignancy, peptic stricture, or esophagitis. The cause of achalasia is unknown. Proposed mechanisms include degeneration or loss of nerve cells located in the dorsal motor nucleus of the vagus nerve, the myenteric plexus, or both sites (17–22). Inflammatory infiltration around the myenteric plexus and esophageal smooth muscle has been described (21–25). Eosinophilic infiltration with degranulation and release of the neurotoxic and cytotoxic protein, eosinophilic cationic protein, may cause neuronal damage that leads to the development of achalasia (22–24). Infectious etiologies have also been proposed including polio virus (26) and measles virus (27). In support of an infectious etiology is Chagas disease, in which the parasite Trypanosoma cruzi causes damage to the myenteric plexus and results in an esophageal motility pattern similar to primary achalasia. We postulate that sphingolipid deposition in the myenteric plexus and/or dorsal motor nucleus of the vagal nerve of patients with Fabry disease can result in achalasia by altering the normal central and enteric innervation of the esophagus. Because our mucosal biopsies are superficial and do not contain the submucosal and muscle layers, we cannot confirm this hypothesis. We hypothesize that achalasia and Fabry disease, both being very rare disorders, are related in our patient. Fabry disease should be considered in any male patient with pain crises involving the hands and feet, angiokeratomas, and with renal, cardiac, or central nervous system disease. Children with achalasia should be questioned about early manifestations of Fabry disease including pain involving the hands and feet and hypohidrosis, and should be examined for signs of this disorder, such as angiokeratomas and cataracts. Family members should also be questioned because this is an inheritable disorder. Our patient's mother, sister, and uncle have subsequently been diagnosed with Fabry disease. Currently, only symptomatic treatment is available for the painful crises, and acid-blocker therapy, pneumatic dilatation, botulinum toxin injection, or surgery is available to treat achalasia. Research for gene therapy (28–30) and enzyme replacement (31,32) is ongoing, but it is unknown whether it will help manifestations present in patients such as ours, once substantial vascular damage has occurred.