The Czech National Fabry Disease Screening Study in Patients Diagnosed With Non-infectious Inflammatory Bowel Disease, Functional Dyspepsia or Irritable Bowel Syndrome

Fabry disease screening study in patients diagnosed with gastrointestinal tract (GIT) disease, i.e. with the diagnosis of non-infectious inflammatory bowel disease, functional dyspepsia or irritable bowel syndrome in particular, is a project designed as a pilot study of Centre for Fabry disease, General University Hospital in Prague, and Clinical Centre ISCARE Prague, focused on improving the diagnosis and care of patients with Fabry disease in the Czech Republic.

Introduction Fabry (Anderson-Fabry) disease is a progressive multiorgan X-linked lysosomal storage disease. The disease is caused by a deficiency of the enzyme alpha-galactosidase A. The enzymatic defect leads to accumulation of enzyme substrate in various tissue types. The affected tissue types include the vascular endothelium of several organs involving kidneys, heart, nervous system, and GIT. Glycolipids accumulation triggers function impairment of affected organs and their subsequent failure. The disease is X-linked and most female heterozygotes develop milder symptoms or the disease manifests later in life than in affected hemizygous man. The disease burden is milder in women due to second X-chromosome.

A typical clinical picture can emerge in males as early as childhood. The onset of clinically evident symptoms manifests with attacks of neuropathic pain of the extremities, followed with early manifestation of hypohidrosis and development of skin lesions - angiokeratomata. In affected hemizygous males, sign of renal damage can be detected even in the second decade, representing already considerable renal damage leading to ultimate organ failure with the need for hemodialysis or kidney transplantation. The first gastrointestinal symptoms occur. From the third decade onwards, both males and females can present neurological symptoms such as white matter lesions as well as stroke, mostly of ischemic nature. Cardiac involvement is characterized by a thickening of the ventricular wall occurring in the third decade in men and approximately ten years later in women. The finding may remind of classical sarcomeric hypertrophic cardiomyopathy in its full extent, including left ventricular outflow tract obstruction. Patients suffer dyspnea, arrhythmias and chest pain. In some patients, other classical symptoms and manifestations of Fabry disease may be completely absent, and the patients with predominant or exclusive cardiac involvement are sometimes referred to as having a cardiac variant.

Most patients with Fabry disease report GI symptoms of diarrhea, with frequent abdominal pain attacks and increased flatulence. Defecation frequency varies, most often 4-6 times a day, which patients consider normal. However, more than 8-times-a-day evacuation episodes are common. Unlike in inflammatory bowel diseases such as Crohn's or ulcerative colitis, no blood or mucus in stool is present. Some patients, on the other hand, complain of severe constipation. Patients with Fabry disease may then be followed-up under diagnosis of non-infectious inflammatory bowel disease, functional dyspepsia or irritable bowel syndrome.

The diagnosis of Fabry disease is based on the evaluation of the defect enzyme activity level in plasma or leukocytes in males. In females, this test is less effective as the enzyme activity levels can reach near normal levels. Thus, sequencing of DNA of the GLA gene is necessary for a diagnosis in most females. they are diagnosed by DNA analysis for a mutation responsible for enzyme deficiency. In women Prior to sequencing, level of the lyso-Gb3 biomarker can be tested and the finding of elevated lyso-Gb3 should be the ultimate requirement for genetic testing.