Alternative titles; symbols
SNOMEDCT: 360854006, 78373000; ICD10CM: E74.31; ORPHA: 35122; DO: 0111633;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q26.1 | Sucrase-isomaltase deficiency, congenital | 222900 | Autosomal recessive | 3 | SI | 609845 |
A number sign (#) is used with this entry because of evidence that congenital sucrose-isomaltase deficiency (CSID) is caused by homozygous or compound heterozygous mutation in the SI gene (609845), which encodes sucrose-isomaltase, on chromosome 3q26.
Congenital sucrose-isomaltase deficiency (CSID) is an autosomal recessive disorder characterized by absence of sucrase and most of the maltase digestive activity within the sucrase-isomaltase enzyme complex, with the isomaltase activity varying from absent to normal. The large amounts of unabsorbed disaccharides create osmotic-fermatative diarrhea with symptoms such as vomiting, flatulence, and abdominal pain (summary by Sander et al., 2006).
A deficiency of sucrase-isomaltase, an integral protein of the small intestine brush-border membrane responsible for catalyzing the hydrolysis of dietary sucrose and some of the products of starch digestion, results in osmotic diarrhea when the disaccharide is ingested, because absorption cannot occur until after hydrolysis produces the component monosaccharides. Hauri et al. (1985) identified sucrase-isomaltase immunologically in biopsy specimens from a child with congenital deficiency of the enzyme. Since the size of the protein was consistent with incomplete glycosylation and the protein could not be identified in the brush-border membrane by immune electron microscopy, the authors suggested that the deficiency was the consequence of a defect in intracellular transport. Lloyd and Olsen (1987) demonstrated a severe defect in intracellular processing of the enzyme.
Newton et al. (1996) reported 4 infants with congenital sucrase-isomaltase deficiency. Whereas the onset of symptoms ranged from 2 to 16 weeks, delayed diagnosis led to severe malnutrition in these infants. The authors commented that the population prevalence may be more common than presently recognized. This entity deserves consideration in the differential diagnosis for infants with persistent, watery diarrhea upon ingesting formula that contains glucose polymer.
A symptomatic form of SI deficiency in adults and late in onset was described by Jansen et al. (1965). By studies at the subcellular and protein level with monoclonal antibodies against sucrase-isomaltase, Naim et al. (1988) identified at least 3 phenotypes among 8 cases: one in which sucrase-isomaltase accumulated intracellularly, probably in the endoplasmic reticulum, as a membrane-associated high-mannose precursor; one in which the intracellular transport of the enzyme was apparently blocked in the Golgi apparatus; and one in which catalytically altered enzyme was transported to the cell surface. In all patients, electrophoretically normal or near-normal high-mannose sucrase-isomaltase was demonstrated. Apparently, different mutations in the sucrase-isomaltase gene lead to the synthesis of transport-incompetent or functionally altered enzyme.
Starnes and Welsh (1970) noted association of intestinal sucrase deficiency with renal calculi. The stones were predominantly calcium oxalate in 1 case. Reports of multiple affected sibs (e.g., Kerry and Townley, 1965) and consanguineous parents (e.g., Jansen et al., 1965) support recessive inheritance. Homozygotes have severe enzyme deficiency with clinical symptoms throughout life. Heterozygotes have intermediate enzyme values and no symptoms in adulthood, but may have mild symptoms in infancy.
Gray et al. (1976) found complete absence of sucrase-isomaltase by both enzymatic and antigenic measures.
Treem (1995) provided a review.
Treem (1996) discussed phenotypic heterogeneity in patients, noting that presentation in patients with CSID can include severe diarrhea and failure to thrive in infancy, 'chronic nonspecific diarrhea' without growth failure in toddlers, and 'irritable bowel syndrome' in adolescents and adults. Studies of the sucrase-isomaltase enzyme in patients with CSID (e.g., Fransen et al., 1991) indicated abnormalities of intracellular processing (glycosylation and folding), intracellular transport, and homing and insertion of the enzyme into the brush-border membrane. In most patients, both sucrase and isomaltase activities are completely absent; however, in some the mature enzyme is found inserted into the brush-border membrane and the mutation affects only the catalytic site of sucrase, leaving sucrase activity absent and isomaltase activity reduced by 50 to 90%.
Five different phenotypes of sucrase-isomaltase deficiency have been identified (Hauri et al., 1985; Fransen et al., 1991). Ouwendijk et al. (1996) described phenotypes I and II as exhibiting intracellular accumulation of mannose-rich SI in the ER and the Golgi, respectively. In phenotype III, an enzymatically inactive, but transport-competent, SI is expressed. Phenotype IV expresses a partially folded, mannose-rich SI molecule that is missorted to the basal lateral membrane. Phenotype V shows an SI species that undergoes intracellular degradation leaving behind the isomaltase subunit that is correctly targeted to the brush border membrane.
Peterson and Herber (1967) found that intestinal sucrase deficiency is a cause of diarrhea in adults and has a frequency of almost 0.2%. According to McNair et al. (1972), 10% of Greenland Eskimos have sucrose intolerance and the frequency is probably increased in Alaskan Eskimos (Ament et al., 1973). Gray et al. (1976) suggested that the deficiency is present in 0.2% of North Americans.
Peterson and Herber (1967) noted that enzyme of fungal origin is effective treatment.
Harms et al. (1987) found that lyophilized yeast by mouth is an effective treatment for sucrase-isomaltase deficiency. The test they used for this, the sucrose hydrogen breath test, is based on the fact that hydrogen is released from the malabsorbed sucrose by the colonic microflora. In vitro, yeast has appreciable sucrase activity, a low isomaltase and maltase activity, and virtually no lactase activity. The sucrase activity is inhibited by undiluted gastric juice to a greater extent than by diluted gastric juice; therefore, the yeast should be given on a full stomach. Lyophilized yeast may be poorly accepted by young children. Treem (1996) reported preliminary results of using an invertase preparation as another possible treatment. The invertase (beta-fructofuranosidase) preparation had the advantage of being odorless and tasteless, stable with refrigeration, and effective at low pH. Invertase hydrolyzes only sucrose (in vitro) and reduced or eliminated symptoms in 14 patients.
Congenital sucrase-isomaltase deficiency is an autosomal recessive disorder (Ouwendijk et al., 1996).
In a patient with CSID, Ouwendijk et al. (1996) identified a homozygous mutation in the SI gene (Q1098P; 609845.0001).
Jacob et al. (2000) identified an L340P mutation (609845.0002) that resulted in an unusual intracellular cleavage of SI in the endoplasmic reticulum. Spodsberg et al. (2001) identified a Q117R mutation (609845.0003) that elicited missorting of the enzyme to the basolateral membrane. Ritz et al. (2003) detected an L620P mutation (609845.0004) that caused a block in the endoplasmic reticulum.
Sander et al. (2006) analyzed the sucrase-isomaltase gene in 11 patients of Hungarian origin with congenital sucrase-isomaltase deficiency who had none of the previously identified mutations. Their analyses revealed 43 SI variants in total, 15 within exons and 1 at a splice site. Amino acid exchanges resulted from 8 of the exonic mutations, causing hypomorphic or null alleles. The splice site mutation was predicted to result in a null allele. All potential pathologic alterations were present on 1 allele only. In 6 of the 11 patients, the phenotype of CSID could be explained by compound heterozygosity.
Dahlqvist (1967) gave a useful review of the small intestinal disaccharidases in man. He recognized 6 of these, so presumably 6 unitary defects plus many combined defects might occur. The 6 disaccharidases are maltase IA, maltase IB (invertase), maltase II, maltase III, lactase (603202), and trehalase (275360). Maltose and lactose are well tolerated in 'sucrose intolerance.' See Durand (1964) for a symposium on this group of disorders.
Ament, M. E., Perera, D. R., Esther, L. J. Sucrase-isomaltase deficiency a frequently misdiagnosed disease. J. Pediat. 83: 721-727, 1973. [PubMed: 4742566] [Full Text: https://doi.org/10.1016/s0022-3476(73)80362-2]
Antonowicz, I., Lloyd-Still, J. D., Khaw, K. T., Shwachman, H. Congenital sucrase-isomaltase deficiency: observations over a period of 6 years. Pediatrics 49: 847-853, 1972. [PubMed: 5041318]
Dahlqvist, A. Localization of the small-intestinal disaccharidases. Am. J. Clin. Nutr. 20: 81-88, 1967. [PubMed: 4164045] [Full Text: https://doi.org/10.1093/ajcn/20.2.81]
Davidson, M. Disaccharide intolerance. Pediat. Clin. N. Am. 14: 93-107, 1967. [PubMed: 5333958] [Full Text: https://doi.org/10.1016/s0031-3955(16)31945-9]
Dubs, R., Steinmann, B., Gitzelmann, R. Demonstration of an inactive enzyme antigen in sucrase-isomaltase deficiency. Helv. Paediat. Acta 28: 187-198, 1973. [PubMed: 4579420]
Durand, P. Disorders Due to Intestinal Defective Carbohydrate Digestion and Absorption. Rome: Il Pensiero Scientifico (pub.) 1964.
Fransen, J. A. M., Hauri, H.-P., Ginsel, L. A., Naim, H. Y. Naturally occurring mutations in intestinal sucrase-isomaltase provide evidence for the existence of an intracellular sorting signal in the isomaltase subunit. J. Cell Biol. 115: 45-57, 1991. Note: Erratum: J. Cell Biol. 115: following 1473, 1991. [PubMed: 1717481] [Full Text: https://doi.org/10.1083/jcb.115.1.45]
Gray, G. M., Conklin, K. A., Townley, R. R. W. Sucrase-isomaltase deficiency: absence of an inactive enzyme variant. New Eng. J. Med. 294: 750, 1976. [PubMed: 1256470] [Full Text: https://doi.org/10.1056/NEJM197604012941403]
Greene, H. L., Stifel, F. B., Herman, R. H. Dietary stimulation of sucrase in a patient with sucrase-isomaltase deficiency. Biochem. Med. 6: 409-418, 1972. [PubMed: 5075694] [Full Text: https://doi.org/10.1016/0006-2944(72)90085-3]
Harms, H.-K., Bertele-Harms, R.-M., Bruer-Kleis, D. Enzyme-substitution therapy with the yeast saccharomyces cerevisiae in congenital sucrase-isomaltase deficiency. New Eng. J. Med. 316: 1306-1309, 1987. [PubMed: 3553946] [Full Text: https://doi.org/10.1056/NEJM198705213162104]
Hauri, H.-P., Roth, J., Sterchi, E. E., Lentze, M. J. Transport to cell surface of intestinal sucrase-isomaltase is blocked in the Golgi apparatus in a patient with congenital sucrase-isomaltase deficiency. Proc. Nat. Acad. Sci. 82: 4423-4427, 1985. [PubMed: 3925457] [Full Text: https://doi.org/10.1073/pnas.82.13.4423]
Holzel, A. Sugar malabsorption due to deficiencies of disaccharidase activities and of monosaccharide transport. Arch. Dis. Child. 42: 341-352, 1967. [PubMed: 4952790] [Full Text: https://doi.org/10.1136/adc.42.224.341]
Jacob, R., Zimmer, K.-P., Schmitz, J., Naim, H. Y. Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme. J. Clin. Invest. 106: 281-287, 2000. [PubMed: 10903344] [Full Text: https://doi.org/10.1172/JCI9677]
Jansen, W., Que, G. S., Veeger, W. Primary combined saccharase and isomaltase deficiency: report of two adult siblings of consanguineous parentage. Arch. Intern. Med. 116: 879-885, 1965. [PubMed: 5848222]
Kerry, K. R., Townley, R. R. W. Genetic aspects of intestinal sucrase-isomaltase deficiency. Aust. Paediat. J. 1: 223-235, 1965.
Lloyd, M. L., Olsen, W. A. A study of the molecular pathology of sucrase-isomaltase deficiency: a defect in the intracellular processing of the enzyme. New Eng. J. Med. 316: 438-442, 1987. [PubMed: 3807985] [Full Text: https://doi.org/10.1056/NEJM198702193160804]
McNair, A., Gudmand-Hoyer, E., Jarnum, S., Orrild, L. Sucrose malabsorption in Greenland. Brit. Med. J. 2: 19-21, 1972. [PubMed: 5015965] [Full Text: https://doi.org/10.1136/bmj.2.5804.19]
Moore, D., Lichtman, S., Durie, P., Sherman, P. Primary sucrase-isomaltase deficiency: importance of clinical judgment. (Letter) Lancet 326: 164-165, 1985. Note: Originally Volume 2. [PubMed: 2862366] [Full Text: https://doi.org/10.1016/s0140-6736(85)90279-x]
Naim, H. Y., Roth, J., Sterchi, E. E., Lentze, M., Milla, P., Schmitz, J., Hauri, H.-P. Sucrase-isomaltase deficiency in humans: different mutations disrupt intracellular transport, processing, and function of an intestinal brush border enzyme. J. Clin. Invest. 82: 667-679, 1988. [PubMed: 3403721] [Full Text: https://doi.org/10.1172/JCI113646]
Newton, T., Murphy, S., Booth, I. W. Glucose polymer as a cause of protracted diarrhea in infants with unsuspected congenital sucrase-isomaltase deficiency. J. Pediat. 128: 753-756, 1996. [PubMed: 8648532] [Full Text: https://doi.org/10.1016/s0022-3476(96)70325-6]
Ouwendijk, J., Moolenaar, C. E. C., Peters, W. J., Hollenberg, C. P., Ginsel, L. A., Fransen, J. A. M., Naim, H. Y. Congenital sucrase-isomaltase deficiency: identification of a glutamine to proline substitution that leads to a transport block of sucrase-isomaltase in a pre-Golgi compartment. J. Clin. Invest. 97: 633-641, 1996. [PubMed: 8609217] [Full Text: https://doi.org/10.1172/JCI118459]
Peterson, M. L., Herber, R. Intestinal sucrase deficiency. Trans. Assoc. Am. Phys. 80: 275-283, 1967. [PubMed: 6082247]
Prader, A., Auricchio, S. Defects of intestinal disaccharide absorption. Ann. Rev. Med. 16: 345-358, 1965. [PubMed: 14276572] [Full Text: https://doi.org/10.1146/annurev.me.16.020165.002021]
Ringrose, R. E., Preiser, H., Welsh, J. D. Sucrase-isomaltase (palastinase) deficiency diagnosed during adulthood. Digest. Dis. Sci. 25: 384-387, 1980. [PubMed: 7371476] [Full Text: https://doi.org/10.1007/BF01308064]
Ritz, V., Alfalah, M., Zimmer, K.-P., Schmitz, J., Jacob, R., Naim, H. Y. Congenital sucrase-isomaltase deficiency because of an accumulation of the mutant enzyme in the endoplasmic reticulum. Gastroenterology 125: 1678-1685, 2003. [PubMed: 14724820] [Full Text: https://doi.org/10.1053/j.gastro.2003.09.022]
Sander, P., Alfalah, M., Keiser, M., Korponay-Szabo, I., Kovacs, J. B., Leeb, T., Naim, H. Y. Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption. Hum. Mutat. 27: 119 only, 2006. [PubMed: 16329100] [Full Text: https://doi.org/10.1002/humu.9392]
Spodsberg, N., Jacob, R., Alfalah, M., Zimmer, K.-P., Naim, H. Y. Molecular basis of aberrant apical protein transport in an intestinal enzyme disorder. J. Biol. Chem. 276: 23506-23510, 2001. [PubMed: 11340066] [Full Text: https://doi.org/10.1074/jbc.C100219200]
Starnes, C. W., Welsh, J. D. Intestinal sucrase-isomaltase deficiency and renal calculi. New Eng. J. Med. 282: 1023-1024, 1970. [PubMed: 5436545] [Full Text: https://doi.org/10.1056/NEJM197004302821809]
Treem, W. R. Congenital sucrase-isomaltase deficiency. J. Pediat. Gastroent. Nutr. 21: 1-14, 1995. [PubMed: 8576798] [Full Text: https://doi.org/10.1097/00005176-199507000-00001]
Treem, W. R. Clinical heterogeneity in congenital sucrase-isomaltase deficiency. J. Pediat. 128: 727-729, 1996. [PubMed: 8648527] [Full Text: https://doi.org/10.1016/s0022-3476(96)70320-7]