Research CMAJ

Congenital –isomaltase deficiency: identification of a common Inuit founder mutation

Julien L. Marcadier MD, Margaret Boland MD, C. Ronald Scott MD, Kheirie Issa MD, Zaining Wu, Adam D. McIntyre BSc, Robert A. Hegele MD, Michael T. Geraghty MD, Matthew A. Lines MD

See also research article on page E68 and at www.cmaj.ca/lookup/doi/10.1503/cmaj.140840 and commentary on page 93 and at www.cmaj.ca​ /lookup/doi/10.1503​/cmaj.141509

Competing interests: None Abstract declared. Background: Congenital sucrase–isomaltase Results: In the proband, we identified a This article has been peer deficiency is a rare hereditary cause of chronic novel, homozygous frameshift mutation, reviewed. diarrhea in children. People with this condi- c.273_274delAG (p.Gly92Leufs*8), predicted The authors have obtained tion lack the intestinal brush-border to result in complete absence of a functional patient consent. required for digestion of di- and oligosaccha- protein product. This change was very rides, including and , lead- ­common among the Inuit controls, with an Correspondence to: ing to malabsorption. Although the condition observed allele frequency of 17.2% (95% con- Matthew Lines, mlines​@cheo.on.ca is known to be highly prevalent (about fidence interval [CI] 12.6%–21.8%). The pre- 5%–10%) in several Inuit populations, the dicted Hardy–Weinberg prevalence of con- CMAJ 2015. DOI:10.1503​ genetic basis for this has not been described. genital sucrase–isomaltase deficiency in Inuit /cmaj.140657 We sought to identify a common mutation for people, based on this single founder allele, is congenital sucrase–isomaltase deficiency in the 3.0% (95% CI 1.4%–4.5%), which is compara- Inuit population. ble with previous estimates. Methods: We sequenced the sucrase–isomaltase Interpretation: We found a common muta- gene, SI, in a single Inuit proband with congen­ ­ tion, SI c.273_274delAG, to be responsible for ital sucrase–isomaltase deficiency who had the high prevalence of congenital sucrase–­ severe fermentative diarrhea and failure to isomaltase deficiency among Inuit people. Tar- thrive. We then genotyped a further 128 anon- geted mutation testing for this allele should ymized Inuit controls from a variety of locales in afford a simple and minimally invasive means the Canadian Arctic to assess for a possible of diagnosing this condition in Inuit patients founder effect. with chronic diarrhea.

ongenital sucrase–isomaltase deficiency cents and adults with undiagnosed congenital (Online Mendelian Inheritance in Man sucrase–­isomaltase deficiency may be misdiag- C database no. #222900; www.omim.org​ nosed with irritable bowel syndrome.3–5 If the /entry​/222900) is a rare autosomal recessive condition is recognized, relief can be obtained form of malabsorption caused by by limiting the offending sugars, for instance, reduced or absent activity of sucrase–isomaltase, by giving a carbohydrate-free infant formula, a heterodimeric intestinal brush-border enzyme and/or by oral digestive enzyme replacement required for digestion of di- and oligosaccha- (e.g., sacrosidase).6,7 rides, including sucrose and isomaltose (Fig- Although congenital sucrase–isomaltase ure 1). In infants and children with this condi- deficiency is rare (about 0.2%) in North Ameri- tion, exposure to specific , such as cans of European ancestry,8 it is relatively com- sucrose, results in profound fermentative diar- mon in northern regions. The prevalence in Inuit rhea, gaseous abdominal distention, malabsorp- people in Greenland has been estimated to be as tion, malnutrition and failure to thrive.1,2 Presen- high as 5%–10% in studies from 1972 and tation is generally after weaning, due to the 1987.9,10 In the region now known as Nunavut, introduction of sucrose-containing foods such the combined prevalence of congenital sucrase– as fruits; affected people may “self-treat” by isomaltase deficiency at 2 sites (Repulse Bay developing a dislike of sweet foods. Because and Chesterfield Inlet) has been estimated at 7% symptoms tend to improve with age, adoles- in a study from 1978.11 Small case series further

102 CMAJ, February 3, 2015, 187(2) ©2015 8872147 Canada Inc. or its licensors Research support a high prevalence of sucrose malabsorp- Methods tion in locales as geographically dispersed as northern Alaska, the northwest coast of Hudson Patient description Bay and southern Manitoba.12,13 The proband, a female newborn from Baffin The current diagnostic gold standard for con- Island, Nunavut, was admitted to hospital 5 days genital sucrase–isomaltase deficiency is demon- after birth for hemodynamic and ventilatory sup- stration of complete or near-complete absence of port in the context of suspected sepsis. Preg- sucrase and/or isomaltase activity in biopsy tis- nancy and delivery history were unremarkable sue of the small bowel.14 This method is direct, apart from slight prematurity (35 w, 3 d). Bottle but it is also invasive and poses technical chal- feeding with a standard cow’s-milk-based infant lenges in young patients. Also commonly used formula was established soon after birth. On are the oral sucrose tolerance test and hydrogen day 5, the patient was brought to the local nurs- breath test, in which blood glucose and breath ing station with decreased alertness, hypotonia hydrogen, respectively, are measured after an and hypothermia. During medical evacuation to oral sucrose load.15 Of note, oral sucrose loading Ottawa, she required multiple fluid boluses for inevitably provokes acute abdominal discomfort refractory hypotension. The patient received and diarrhea in patients with this condition. A aggressive treatment, including 7 days of intra- third option, a therapeutic trial of carbohydrate- venous antibiotics, for suspected pneumonia. By free foods, provides a clinically meaningful 9 days after birth, her condition had improved demonstration of disordered carbohydrate diges- such that feeding with a standard premature for- tion, but is not sufficiently specific to be diagnos- mula was restarted. Over the following 3 days, tic of congenital sucrase–isomaltase deficiency. abdominal distention (Figure 2) and copious Lastly, genetic testing of SI, the gene for this watery diarrhea developed; these symptoms per- condition, is now clinically available. To date, sisted despite a switch to elemental formula. the Human Gene Mutation Database contains a Multiple routine investigations to ascertain the total of 16 SI mutations.16 In people of European cause of the infant’s diarrhea were unrevealing. descent, 4 mutations account for most disease Evidence of an ongoing malabsorptive process alleles.17 We sought to identify a common muta- included failure to thrive despite hypercaloric tion for congenital sucrase–isomaltase deficiency feeding (190 kcal/kg/d), increased stool osmotic in the Inuit population. gap and transient improvement of symptoms

A. Sucrose C. Isomaltose

CH2OH CH2OH H O H O H CH2OH H 1 2 OH H O H HO H O H OH CH2OH H -1,2 glycosidic 1 -D-glucose OH H H OH linkage OH H OH -1,6 glycosidic O -D-glucose β-D-fructose linkage H OH

CH2 B. 6 O 2 H H CH OH CH2OH H -D-glucose H O H H O H OH H OH H 1 4 H OH OH H OH H O OH OH H OH -1,4 glycosidic linkage H OH H OH -D-glucose -D-glucose

Figure 1: Sucrase–isomaltase catalyzes the of the α-1,2 glycosidic bond in sucrose (A), α-1,4 glycosidic bond in maltose (B) and α-1,6 glycosidic bond in isomaltose (C), as well as α-1,4 and α-1,6 limit generated from dietary by α- (not depicted). Blue circles depict sites of hydrolysis.

CMAJ, February 3, 2015, 187(2) 103 Research

with brief bowel rest. Congenital sucrase–­ Sequencing of the SI gene in the proband isomaltase deficiency was considered at Genomic DNA was isolated from whole blood 3 months of age, and a therapeutic trial of carbo- using standard methods. Primers were designed for hydrate-free formula was started, resulting in each of the 48 exons of the SI gene and included stools rapidly returning to normal within the flanking intron boundaries. Each exon and its 48 hours. The patient was discharged on a carbo- flanking regions were amplified using polymerase hydrate-free formula with additional dextrose chain reaction (PCR), and the subsequent amplified supplementation. At last clinical follow-up (age nucleotides were sequenced using a 3130 Genetic 5 mo), the patient was asymptomatic and thriv- Analyzer (Applied Biosystems). Sequencing soft- ing, and her weight was between the 50th and ware was used to confirm the sequence against the 75th centiles for her age. GenBank entry NM_001041.3. The nucleotide of the translation initiation codon ATG constituted Control samples numbering 1 of the complementary DNA Hypothesizing a common founder allele among sequence. We followed the standard naming con- Inuit people, we genotyped 128 anonymized vention of the Human Genome Variation Society. samples from Inuit controls from a range of Canadian Arctic locales. The samples were col- Genotyping of control samples lected from healthy controls, who self-identified Genomic DNA samples isolated from whole as Inuit, as part of several independent studies blood were used in PCR amplifications that were screening for cardiovascular risk factors in performed employing oligonucleotide primers healthy populations. Controls were geographi- flanking the variant of interest in theSI gene. cally equally distributed from the western (Inuvi- Polymerase chain reaction was carried out in aluit), central (Kivalliq) and eastern (Nunavik) 30-µL mixtures containing 32 pmol of each Canadian High Arctic. Information regarding primer (sequences available in Appendix 1, current or past gastrointestinal disease was not available at www.cmaj.ca/lookup/suppl/doi​ available. :10.1503/cmaj.140657/-/DC1), 0.2 mM each of

Figure 2: Abdominal radiographs taken at 3 months of age showing severe bowel distension with multiple air-fluid levels in the small bowel. Severity of symptoms was such that the patient received a rectal biopsy for suspected Hirschsprung disease.

104 CMAJ, February 3, 2015, 187(2) Research deoxyadenosine triphosphate, deoxycytidine tri- expected Inuit prevalence of congenital sucrase– phosphate, deoxyguanosine triphosphate and isomaltase deficiency related to this specific deoxythymidine triphosphate, 1.5 mM magne- mutation is estimated to be 3.0% (95% CI 1.4%– sium chloride, 50 mM potassium chloride, 4.5%). The carrier rate is estimated to be 28.5% 20 mM tromethamine hydrochloride (pH 8.4) (delta-method 95% CI 22.4%–34.5%). and 1.0 units of Platinum Taq DNA polymerase (Invitrogen). Thirty amplification cycles were Interpretation performed, consisting of denaturation at 95°C, annealing at 60°C and extension at 72°C for 30 Our results show a common mutation, SI seconds each, followed by a final extension step c.273_274delAG, to be responsible for the high lasting 7 minutes at 72°C and cooling to 4°C. prevalence of congenital sucrase–isomaltase defi- Polymerase chain reaction amplification prod- ciency among people of Inuit descent. The pre- ucts were purified with Calf intestinal phospha- dicted homozygosity rate for this mutation, tase/Exonuclease I (New England Biolabs) and 1.4%–4.5%, is just below previous prevalence sequenced on an ABI 3730 DNA Analyzer estimates of 5%–10%.10,11 Factors likely to (Applied Biosystems). We analyzed DNA account for the difference could include sampling sequences using SeqScape v2.6 (Applied Bio- bias, geographic variations in allele frequency or systems) for allelic discrimination, which was the presence of other (as-yet unidentified) muta- used to determine genotypes (electropherograms tions. Although our study sample spanned the available in Appendix 1). Canadian Arctic, allele frequencies are likely to vary regionally and by population, and further Statistical analyses study is required to assess the geography of con- We assessed the deviation of genotype frequen- genital sucrase–isomaltase deficiency. The broad cies from the Hardy–Weinberg equilibrium geographic span of this condition in Inuit people using a χ2 analysis. The disease allele fre- suggests an ancient founder mutation, although quency in the population was estimated using the condition itself only recently emerged (in the the usual 95% confidence interval (CI) for a binomial proportion, without a continuity cor- rection. We used the delta method18 to estimate C population genotype frequencies. Calculations were performed using R ­software.19 Sucrase Results

Sequencing of SI identified a novel homozygous frameshift mutation in the proband NM_001041.3:​ c.273_274delAG (p.Gly92Leufs*8). No other pathologic variants were identified. This early frameshift in the fourth of SI’s 48 exons affects the Isomaltase gene’s only transcript and is therefore predicted to result in complete loss of enzyme expression (Fig- ure 3). This allele is not represented in the data set of the 1000 Genomes Project (www.1000genomes​ .org), nor in the National Heart, Lung, and Blood Institute’s Exome Variant Server (http://evs.gs​ p.Gly92Leufs*8 .washington.edu/EVS), which comprises data from 13 000 people of European or African descent. Intestinal lumen From the 128 anonymized samples from Inuit Cytosol controls living in the Canadian Arctic, we identi- fied a further 2 homozygous and 40 heterozy- N gous individuals. The observed allele frequency of this mutation in our sample is 17.2% (44 of Figure 3: Sucrase–isomaltase is located at the brush-border membrane of the 256 total alleles; binomial 95% CI 12.6%– small intestine. Enzymatic domains are in the gut lumen, connected to the 21.8%). The χ2 analysis confirmed the Hardy– cellular membrane by a short linker sequence. The c.273_274delAG mutation (red circle) results in disruption of the usual reading frame (p.Gly92Leufs*8), Weinberg equilibrium (p = 0.31). There were no significant between-region deviations from the completely abolishing both enzymatic activities (depicted in grey). Owing to nonsense-mediated decay, there is a high likelihood that the resulting above allele frequencies. If we assume the messenger RNA product is targeted for degradation (i.e., is not translated and absence of other common mutations, the is functionally null).

CMAJ, February 3, 2015, 187(2) 105 Research

1960s) as a recognized health issue. This was Conclusion likely as a consequence of the changing diet of We identified a common mutation, SI the Inuit, which is traditionally (but not contem- c.273_274delAG, to be responsible for the high porarily) low in carbohydrates.20–22 In that prevalence of congenital sucrase–isomaltase defi- respect, congenital sucrase–isomaltase deficiency ciency among Inuit people. Our proband’s pre- presents a rare example of a gene–environment sentation shows congenital sucrase–isomaltase interaction under novel evolutionary pressures. deficiency to be a serious, potentially acute con- The severe presentation described in our pro- dition, for which timely recognition and start of band likely reflects an underlying genotypic vul- appropriate therapy are paramount. This condi- nerability (i.e., a complete lack of enzymatic tion should therefore be considered in the differ- activity caused by homozygous truncating muta- ential diagnosis of Inuit children and adults with tions) exacerbated by early and prolonged expo- compatible symptoms (e.g., chronic diarrhea, sure to dietary sucrose. Patients with milder failure to thrive and irritable bowel syndrome). mutations or lesser sucrose exposure would be Although breastfed infants with this condition expected to have variably milder phenotypes. are unlikely to present before weaning, some Whereas congenital sucrase–isomaltase defi- commercial formulas (including elemental and ciency is considered a recessive disorder, the lactose-free formulas used in the management of possibility of symptomatic carriers is an intrigu- suspected intolerance to cow’s milk protein) do ing and unanswered question. In the absence of a contain sucrose as their major carbohydrate com- second mutation, heterozygous carriers of the ponent. As in our patient, use of elemental for- c.273_274delAG mutation should have about mula containing sucrose may result in a paradox- 50% normal sucrase–isomaltase activity (i.e., ical worsening of symptoms. they should be able to cleave and absorb disac- Targeted mutation testing for the common SI charides to an extent). Nonetheless, reports of founder mutation may be a reasonable first-line gastrointestinal symptoms in small numbers diagnostic test for suspected congenital sucrase– of people with only a single identifiable SI muta- isomaltase deficiency in patients of Inuit descent. tion do raise the question of whether carriers Patients homozygous for the c.273_274delAG may have mild symptoms when exposed to mutation have a definite diagnosis of congenital sucrose.17,23 The availability of a noninvasive sucrase–isomaltase deficiency, and can be spared (molecular) test for congenital sucrase–isomaltase intestinal biopsy and sucrose tolerance tests. If deficiency raises the possibility of a more sys- there is a strong clinical suspicion for this condi- tematic study of the phenotype, if any, in hetero- tion, dietary management should not be delayed zygous people. while awaiting genetic results (i.e., it may be rea- sonable to consider empiric sucrose elimination Limitations while awaiting molecular confirmation). Because One major limitation of this study is that the con- the existence of other SI disease alleles in this pop- tribution of other SI mutations to the overall ulation has not yet been studied, negative or hetero- prevalence of congenital sucrase–isomaltase zygous (carrier) results should be viewed as incon- deficiency in Inuit people remains unknown. clusive, and must be considered in the clinical This could be addressed by sequencing SI com- context. At present, congenital sucrase–isomaltase pletely in a larger group of Inuit people. SI muta- deficiency is not a target of newborn or population- tions in various other populations are summa- based screening programs, although such screening rized in the Human Gene Mutation Database may be technically feasible, medically beneficial (www.hgmd.org) and the Leiden Open Variation and justifiable from a prevalence standpoint. At Database (www.lovd.nl/3.0/home). Other major minimum, physicians caring for Inuit patients may limitations include the following: the geographic wish to maintain a level of awareness of this com- distribution of the observed mutation, which is mon and readily treatable entity. likely to be nonuniform, has not been specifi- cally studied; the spectrum of clinical symptoms References to be found in people homozygous for the 1. Treem WR. Congenital sucrase isomaltase deficiency.J Pediatr Gastroenterol Nutr 1995;21:1-14. c.273_274delAG mutation remains to be studied 2. Semenza G, Salvatore A, Mantei N. Small-intestinal disacchari- systematically in a suitable cohort; and the clini- dases. In: Valle D, Beaudet AL, Vogelstein B, et al., editors. OMMBID: the online metabolic & molecular bases of inherited cal phenotype of heterozygous carriers, if any, diseases. New York: McGraw-Hill; 2013. Available: http​ has not yet been assessed in detail. These limita- ://ommbid​.mhmedical.com/content.aspx?bookid=474​&Sectionid​ =45374056 (accessed 2014 Sept. 4). tions could be addressed through a larger 3. Muldoon C, Maguire P, Gleeson F. Onset of sucrase-isomaltase founder mutation screening study, with collec- deficiency in late adulthood. Am J Gastroenterol 1999;​94:​ 2298-9. tion of pertinent clinical data regarding dietary 4. Ringrose RE, Preiser H, Welsh JD. Sucrase-isomaltase (palatinase) sucrose exposure and gastrointestinal symptoms. deficiency diagnosed during adulthood. Dig Dis Sci 1980;25:384-7.

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5. Karnsakul W, Luginbuehl U, Hahn D, et al. Disaccharidase activi- 21. Sheehy T, Roache C, Sharma S. Eating habits of a population ties in dyspeptic children: biochemical and molecular investiga- undergoing a rapid dietary transition: portion sizes of tradi- tions of -glucoamylase activity. J Pediatr Gastroenterol tional and non-traditional foods and beverages consumed by Nutr 2002;35:551-6. Inuit adults in Nunavut, Canada. Nutr J 2013;12:70. 6. Treem WR, McAdams L, Stanford L, et al. Sacrosidase ther- 22. Langlois KA, Findlay LC, Kohen DE. Dietary habits of apy for congenital sucrase-isomaltase deficiency. J Pediatr Aboriginal children. Health Rep 2013;24:3-7. Gastroenterol Nutr 1999;28:137-42. 23. Sander P, Alfalah M, Keiser M, et al. Novel mutations in the 7. Lücke T, Keiser M, Illsinger S, et al. Congenital and putatively human sucrase-isomaltase gene (SI) that cause congenital car- acquired forms of sucrase-isomaltase deficiency in infancy: bohydrate malabsorption. Hum Mutat 2006;27:119. effects of sacrosidase therapy. J Pediatr Gastroenterol Nutr 2009;49:485-7. Affiliations: Department of Genetics (Marcadier), Children’s . 8 Peterson ML, Herber R. Intestinal sucrase deficiency.Trans Hospital of Eastern Ontario; Division of Gastroenterology, Assoc Am Physicians 1967;80:275-83. Hepatology and Nutrition (Boland), Children’s Hospital of 9. McNair A, Gudmand-Hoyer E, Jarnum S, et al. Sucrose malab- Eastern Ontario; Department of Pediatrics (Boland, Issa, sorption in Greenland. BMJ 1972;2:19-21. Geraghty, Lines), University of Ottawa and Children’s Hos- 10. Gudmand-Høyer E, Fenger H, Kern-Hansen P, et al. Sucrase deficiency in Greenland: incidence and genetic aspects.Scand pital of Eastern Ontario Research Institute, Ottawa, Ont.; J Gastroenterol 1987;22:24-8. Department of Pediatrics (Scott, Wu), University of Wash- 11. Ellestad-Sayed JJ, Haworth J, Hildes J. Disaccharide malab- ington, Seattle, Wash.; Robarts Research Institute (McIntyre, sorption and dietary patterns in two Canadian Eskimo commu- Hegele), Schulich School of Medicine and Dentistry, West- nities. Am J Clin Nutr 1978;31:1473-8. ern University, London, Ont.; Metabolics (Geraghty, Lines), 12. Bell RR, Draper H, Bergan J. Sucrose, lactose, and glucose toler- Children’s Hospital of Eastern Ontario, Ottawa, Ont. ance in northern Alaskan Eskimos. Am J Clin Nutr 1973; 26:​ 1185-90. Contributors: Julien Marcadier, Margaret Boland, C. Ron- 13. Ellestad-Sayed JJ, Haworth J. Disaccharide consumption and mal- ald Scott, Kheirie Issa, Michael Geraghty and Matthew Lines absorption in Canadian lndians. Am J Clin Nutr 1977;​30:​698-703. contributed substantially to the study conception and design. 14. Treem WR. Clinical aspects and treatment of congenital C. Ronald Scott and Zaining Wu performed molecular analy- sucrase-isomaltase deficiency.J Pediatr Gastroenterol Nutr 2012;55(Suppl 2):S7-13 sis in the proband. Robert Hegele and Adam McIntyre per- 15. Perman JA, Barr RG, Watkins JB. Sucrose malabsorption in formed molecular analysis in the control samples. Julien children: noninvasive diagnosis by interval breath hydrogen Marcadier and Matthew Lines prepared the manuscript. All determination. J Pediatr 1978;93:17-22. of the authors revised the manuscript, gave final approval to 16. Stenson PD, Mort M, Ball EV, et al. The Human Gene Muta- the manuscript submitted for publication and agreed to act as tion Database: building a comprehensive mutation repository guarantors of the work. for clinical and molecular genetics, diagnostic testing and per- sonalized genomic medicine. Hum Genet 2014;133:1-9. Funding: Robert Hegele receives funding from the Canadian 17. Uhrich S, Wu Z, Huang J-Y, et al. Four mutations in the SI Institutes of Health Research. C. Ronald Scott and Zaining gene are responsible for the majority of clinical symptoms of Wu receive funding from QOL Medical. The funding CSID. J Pediatr Gastroenterol Nutr 2012;55(Suppl 2):S34-5. sources had no role in study design, data collection or analy- 18. Oehlert GW. A note on the delta method. Am Stat 1992;46:​27-9. 19. R Core Team. R: A language and environment for statistical sis, manuscript preparation, or the decision to submit the arti- computing. R Foundation for Statistical Computing, Vienna, cle for publication. Austria; 2014. Available: www.r-project.org (accessed 2014 Sept. 12). Acknowledgements: The authors wish to acknowledge the 20. Berti PR, Hamilton S, Receveur O, et al. Food use and nutrient contribution of the patient and family, without whom this work adequacy in Baffin Inuit children and adolescents.Can J Diet could not have been performed. The expert assistance of bio- Pract Res 1999;60:63-70. statistician Dr. Nick Barrowman is gratefully ­acknowledged.

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