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Kinder- und Jugendmedizin 2007; 7(01): 10-16
DOI: 10.1055/s-0037-1617938
Gastroenterologie
Schattauer GmbH

Genetische Diarrhö bei mukosalen Enzym- und Transportproteindefekten

Genetic diarrhoea due to defects of mucosal enzymes and transport proteins
Peter Heinz-Erian
1   Department Kinder- und Jugendheilkunde, Medizinische Universität Innsbruck (Geschäftsführender Direktor: Univ.-Prof. Dr. med. G. Simbruner)
,
Thomas Müller
1   Department Kinder- und Jugendheilkunde, Medizinische Universität Innsbruck (Geschäftsführender Direktor: Univ.-Prof. Dr. med. G. Simbruner)
,
Sabine Scholl-Bürgi
1   Department Kinder- und Jugendheilkunde, Medizinische Universität Innsbruck (Geschäftsführender Direktor: Univ.-Prof. Dr. med. G. Simbruner)
› Author Affiliations
Further Information

Publication History

Eingegangen: 14 October 2006

angenommen: 27 October 2006

Publication Date:
11 January 2018 (online)

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Zusammenfassung

Neben hereditären Mukosastrukturdefekten können auch genetische Störungen der Enzymaktivität oder der Transportfunktion von Darmepithelmembranen eine chronische Diarrhö verursachen. Für die meisten hier beschriebenen funktionellen Defekte konnten bereits Genmutationen identifiziert werden. Klinisch verursachen sie entweder eine osmotische oder sekretorische Diarrhö. Die Abklärung erfordert eine genaue Familien- und Ernährungsanamnese sowie eine gezielte biochemische und molekularbiologische Diagnostikvon Blut- und Stuhlproben. Sehr hilfreich für die klinische Praxis ist die H2-Messung im Atemgas zur Evaluation von Mono- und Disaccharidresorptionsstörungen. Um die Pathogenese aufklären zu können, sind in spezialisierten Zentren Verfahren wie in situ-Hybridiserung zur zellulären Lokalisation von Gensonden, Studien des zellulären Transports mit radioaktiv markierten Tracern und elektrophysiologische Methoden an Darmschleimhautbioptaten von großem Wert. Therapeutisch lässt sich die klinische Symptomatik oft durch Vermeidung der krank machenden Noxe oder umgekehrt, durch Gabe eines fehlenden Substrats soweit kontrollieren, dass eine langzeitparenterale Ernährung nicht mehr notwendig ist.

Summary

Besides hereditary structural defects also genetic disorders of enzyme activity or transport function in gut epithelial membranes may cause a chronic diarrhoea. Gene mutations have been identified in most of the functional defects described here. The clinical course is characterized by either osmotic or secretory diarrhoea. Evaluation affords a concise history of familial diseases and dietary habits as well as targeted biochemical and molecular biologic investigations in blood and fecal specimen. Very helpful for clinical practice are hydrogen breath tests in the evaluation of absorption defects of mono- and disaccharides. For the elucidation of the immanent pathogenesis specialized centers apply methods such as in situ hybridization for the cellular localization of marker probes, studies of cellular transport using radioactive tracers and electrophysiological measurements in gut biopsies. As for treatment, clinical symptoms may be controlled in many cases by avoiding the etiologic agent or on the opposite substituting a missing nutritional substrate so that often long term parenteral nutrition will be unnecessary.

Schlüsselwörter

Genetische Diarrhö - Enzymdefekte - Transportstörungen

Keywords

Genetic diarrhoea - enzyme defects - transport disorders
 

  • Literatur

  • 1 Guarino A, de Marco G. Persistent diarrhea. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR. (eds). Pediatric Gastrointestinal Disease. 4. ed.. Hamilton: BC Decker; 2004: 180-93.
    Search in Google Scholar
  • 2 Martin MG, Wright EM. Congenital intestinal transport defects. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR. (eds). Pediatric Gastrointestinal Disease. 4. ed.. Hamilton: BC Decker; 2004: 898-921.
    Search in Google Scholar
  • 3 Shepherd R. Complications and management of chronic liver disease. In: Kelly DA. Diseases of the liver and biliary system in children. 2. ed.. Oxford: Blackwell; 2004: 259-81.
    Search in Google Scholar
  • 4 Naim HY, Zimmer KP. Genetically detetermined disaccharidase deficiency. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR. (eds). Pediatric Gastrointestinal Disease. 4. ed.. Hamilton: BC Decker; 2004: 880-97.
    Search in Google Scholar
  • 5 Desjeux JF, Taminiau JAJM, Abely M. Congenital intestinal transport defects. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB. Pediatric Gastrointestinal Disease. 3. ed.. Hamilton: BC Decker; 2000: 701-26.
    Search in Google Scholar
  • 6 Semenza G, Auricchio S, Mantei N. Small intestinal disaccharidases. In: Scriver CR, Beaudet AL, Sly WS, Valle D. (eds). The Metabolic & Molecular Basis of Inherited Disease. 8. ed.. New York: McGraw-Hill; 2001: 1623-50.
    Search in Google Scholar
  • 7 Kuokkanen M, Kokkonen J, Enattah NS. et al. Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency. Am J Hum Genet 2006; 78: 339-44.
    CrossrefPubMedSearch in Google Scholar
  • 8 Savilahti E, Launiala K, Kuitunen P. Congenital lactase deficiency: a clinical study on 16 patients. Arch Dis Child 1983; 58: 246-52.
    CrossrefPubMedSearch in Google Scholar
  • 9 Flatz G, Howell JN, Doench J. et al. Distribution of physiological adult lactase phenotypes, lactose absorber and malabsorber, in Germany. Hum Genet 1982; 62: 152-7.
    PubMedSearch in Google Scholar
  • 10 Naim HY, Roth J, Sterchi EE. et al. Sucrase-isomaltase deficiency in humans. Different mutations disrupt intracellular transport, processing, and function of an intestinal brush border enzyme. J Clin Invest 1988; 82: 667-79.
    CrossrefPubMedSearch in Google Scholar
  • 11 Lebenthal E, Khin Maung U, Zheng BY. et al. Small intestinal glucoamylase deficiency and starch malabsorption: a newly recognized alpha-glucosidase deficiency in children. J Pediatr 1994; 124: 541-46.
    CrossrefPubMedSearch in Google Scholar
  • 12 Holzinger A, Maier EM, Buck C. et al. Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency. Am J Hum Genet 2002; 70: 20-5.
    CrossrefPubMedSearch in Google Scholar
  • 13 Hadorn B, Tarlow MJ, Lloyd JK. et al. Intestinal enterokinase deficiency. Lancet 1969; I: 812-3.
    PubMedSearch in Google Scholar
  • 14 Townes PL. Trypsinogen deficiency disease. J Pediatr 1965; 66: 275-85.
    CrossrefPubMedSearch in Google Scholar
  • 15 Rowen L, Koop BF, Hood L. The complete 685-kilobase DNA-sequence of the human beta T cell receptorlocus. Science 1996; 272: 1755-62.
    CrossrefPubMedSearch in Google Scholar
  • 16 Figarella C, DeCaro A, Leupold D. et al. Congenital pancreatic lipase deficiency. J Pediatr 1980; 96: 412-6.
    CrossrefPubMedSearch in Google Scholar
  • 17 Davis RC, Diep A, Hunziker W. et al. Assignment of human pancreatic lipase gene (PNLIP) to chromosome 10q24-q26. Genomics 1991; 11: 1164-6.
    CrossrefPubMedSearch in Google Scholar
  • 18 Sellin JH. The pathophysiology of diarrhea. In: Schultz SG, Andreoli TE, Brown AM, Fambrough DM, Hoffmann JF, Welsh MJ. (eds). Molecular Biology of Membrane Transport Disorders. 1. ed.. New York: Plenum Press: 1996: 541-64.
    Search in Google Scholar
  • 19 Binder HJ. Disorders of absorption. In: Kasper DL, Braunwald E, Fauci A, Hauser S, Longo D, Jameson L. (eds). Harrisons Principles of Internal Medicine. 16 ed.. New York: McGraw-Hill: 2004: 1763-76.
    Search in Google Scholar
  • 20 Martin MG, Turk E. Lostao et al. Defects in Na+ glucose cotransporter (SGLT1) trafficking and function cause glucose galactose malabsorption. Nat Genet 1996; 12: 216-20.
    CrossrefPubMedSearch in Google Scholar
  • 21 Meeuwisse GW, Melin K. Glucose-galaktose malabsorption. A clinical study of 6 cases. Acta Paediatr Scand 1969; (Suppl) 188: 1-4.
    Search in Google Scholar
  • 22 Santer R, Steinmann B, Schaub J. Fanconi-Bickel syndrome – a congenital defect of facilitative glucose transport. Curr Mol Med 2002; 2: 213-27.
    CrossrefPubMedSearch in Google Scholar
  • 23 Santer R, Schneppenheim R, Dombrowski A. et al. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet 1997; 17: 324-6.
    CrossrefPubMedSearch in Google Scholar
  • 24 Wassermann D, Hoekstra JH, Tolia V. et al. Molecular analysis of the fructose transporter gene (GLUT5) in isolated fructose malabsorption. J Clin Invest 1996; 98: 2398-402.
    CrossrefPubMedSearch in Google Scholar
  • 25 Palacin M, Estevez R, Bertran J. et al. Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev 1998; 78: 969-1054.
    CrossrefPubMedSearch in Google Scholar
  • 26 Torrents D, Mykkänen J, Pineda M. et al. Identification of SLC7A7, encoding y+LAT-1 as the lysinuric protein intolerance gene. Nat Genet 1999; 21: 293-6.
    CrossrefPubMedSearch in Google Scholar
  • 27 Rajantie J, Simell O, Perheentupa J. Basolateral membrane transportdefect for Lysine in lysinuric protein intolerance. Lancet i: 1219-21.
  • 28 Hoglund P, Haila S, Socha J. et al. Mutations of the down-regulated adenoma (DRA) gene cause congenital chloride diarrhea. Nat Genet 1996; 14: 316-9.
    CrossrefPubMedSearch in Google Scholar
  • 29 Holmberg C, Perheentupa J. Congenital Na+ diarrhea: A new type of secretory Diarrhea. J Pediatr 1985; 106: 56-61.
    CrossrefPubMedSearch in Google Scholar
  • 30 Booth IW, Stange G, Murer H. et al. Defective jejunal brush-border Na/H+ exchange: a cause of congenital secretory diarrhoea. Lancet 1985; i: 1066-9.
    PubMedSearch in Google Scholar
  • 31 Müller T, Wijmenga C, Phillips AD. et al. Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes. Gastroenterology 2000; 119: 1506-13.
    CrossrefPubMedSearch in Google Scholar
  • 32 Walder R, Landau D, Meyer P. et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 2002; 31: 171-4.
    CrossrefPubMedSearch in Google Scholar
  • 33 Aggett PJ. Acrodermatitis enteropathica. J Inherit Metab Dis 1983; 6 (Suppl. 01) 39-43.
    CrossrefPubMedSearch in Google Scholar
  • 34 Kury S, Dreno B. Bezieau et al. Identification of SLC39A4 a gene involved in acrodermatitis enteropathica. Nat Genet 2002; 31: 239-40.
    CrossrefPubMedSearch in Google Scholar
  • 35 Oelkers P, Kirby LC, Heubi JE. et al. Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2) . J Clin Invest 1997; 99: 1880-7.
    CrossrefPubMedSearch in Google Scholar
  • 36 Hofmann AF, Scheingart CD, Lilienau J. Biological and medical aspects of ileal transport of bile acids. Ann Med 1991; 23: 169-75.
    CrossrefPubMedSearch in Google Scholar
  • 37 Wetterau JR, Aggerbeck LP, Bouma ME. et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 1992; 258: 999-1001.
    CrossrefPubMedSearch in Google Scholar
  • 38 Ohashi K, Ishibashi S, Osuga J. et al. Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia. J Lipid Res 2000; 41: 1199-204.
    PubMedSearch in Google Scholar
  • 39 Linton MF, Farese RV, Young SG. Familial hypolipoproteinemia. J Lipid Res 1993; 34: 521-41
    PubMedSearch in Google Scholar
  • 40 Roy CC, Levy E, Green PHR. et al. Malabsorption hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B. Chylomicron retention disease. Gastroenterology 1987; 92: 390.
    CrossrefPubMedSearch in Google Scholar