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Congenital Sucrase–Isomaltase Deficiency: Identification of a Common Inuit Founder Mutation

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Congenital Sucrase–Isomaltase Deficiency: Identification of a Common Inuit Founder Mutation Research CMAJ Congenital sucrase–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 enzyme 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 sucrose and isomaltose, 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 carbohydrate 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 carbohydrates, 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% 11 symptoms tend to improve with age, adoles- in a study from 1978. 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. Maltose 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 hydrolysis 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 dextrins generated from dietary starch by α-amylase (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.
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