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Original Articles: Gastroenterology

Sucrase-isomaltase Gene Variants in Patients With Abnormal Sucrase Activity and Functional Gastrointestinal Disorders

Deb, Chirajyoti; Campion, Stephani; Derrick, Veronica; Ruiz, Vanessa; Abomoelak, Bassam; Avdella, Angelina; Zou, Baiming; Horvath, Karoly∗,†; Mehta, Devendra I.∗,†

Author Information
Journal of Pediatric Gastroenterology and Nutrition: January 2021 - Volume 72 - Issue 1 - p 29-35
doi: 10.1097/MPG.0000000000002852


What Is Known/What Is New

What Is Known

  • Congenital sucrase-isomaltase deficiency is a rare genetic disorder caused by mutations in the sucrase-isomaltase gene.
  • Congenital sucrase-isomaltase deficiency causes classical symptoms of carbohydrate malabsorption from increased osmotic load to the intestines.
  • Traditionally congenital sucrase-isomaltase deficiency diagnosis is considered in cases with abnormal sucrase and normal lactase activities.
  • Pan-disaccharidase deficiency is interpreted as a sample handling problem in cases with normal intestinal histology.

What Is New

  • Thirteen sucrase-isomaltase gene mutations, that are known to be pathogenic in congenital sucrase-isomaltase deficiency, were highly prevalent in 29% (36/125; P < 0.001) of non-Hispanic white patients with abnormal sucrase activity and normal histology.
  • In the low sucrase group, 71% of patients did not have a known mutation.
  • Sucrase-isomaltase gene pathogenic variants, primarily heterozygous mutations, are more prevalent in cases with abnormal sucrase activity and functional gastrointestinal disorders symptoms than normal sucrase activity groups.
  • Concomitant decreased lactase activity is common in low sucrase activity group with pathogenic sucrase-isomaltase gene mutations and may work synergistically to cause symptoms.
  • Pan-disaccharidase deficiency is a presentation of sucrase-isomaltase deficiency.

Congenital sucrase-isomaltase deficiency (CSID) affects digestion of sucrose, maltose, short alpha 1–4 linked glucose oligomers, branched (1–6 linked) α-limit dextrins, and starches due to significant deficiency of sucrase and variable deficiency of isomaltase activity (1,2). CSID can cause severe diarrhea, accelerated motility, malnutrition, and failure to thrive in young children with homozygous mutations (3–6).

The underlying causes of impaired sucrase-isomaltase (SI) activities are pathogenic mutations in the SI gene (2,3,5,7–9).

In recent studies, compound and simple heterozygous CSID variants were detected in patients diagnosed with IBS (3,5). Other studies reported high prevalence of sucrase enzyme deficiency in duodenal biopsies from patients with functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and nausea (3,5,7,10,11).

Disaccharidase activities measured in duodenal biopsies are considered the criterion standard for CSID diagnosis (2,9,12). Treem (9) recommended normal small bowel morphology with reduced or no sucrase activity, varying isomaltase activity from zero to full normal activity and normal lactase activity, or in cases with decreased lactase activity, a sucrase:lactase ratio of <1.0. However, Nichols et al (12) reported that sucrase enzyme deficiency is also frequently associated with deficiencies in other disaccharidases. Cohen et al (13,14) recently reported that sucrase enzyme deficiency is more common than previously thought, including in cases with pan-disaccharidase deficiencies (PDDs). Neither study confirmed their findings by genetic analysis. The disaccharidase assay method developed by Dahlqvist (15,16) has a known limitation of significant overlap in substrate hydrolysis by enzymes. For example, measured maltase activity is a summed activity of both SI and MGAM (maltase-glucoamylase) gene products (17–20). The prevalence of SI gene exonic mutations in patients with normal histology and abnormal sucrase activity may help address this gap in knowledge.


This study was approved by the Institutional Review Board (IRB 2, Pediatric and Pregnant Woman IRB) of Orlando Health, Orlando, FL. See Supplemental Digital Content ( for detailed methods.


Non-Hispanic white pediatric patients were selected due to scarcity of samples of reported pathogenic mutations in other ethnic groups (9,21–23).

Power analysis with alpha 0.05, beta 0.2/power 0.8 gave a sample size of 109. We enrolled 125 abnormal sucrase cases, and 500 normal sucrase cases (250 with moderate and 250 with high sucrase activities; 4:1 ratio of normal vs abnormal sucrase cases). All 625 patients had normal duodenal histology and none had underlying diseases that would affect enzyme activities. The mean age was 12.6 ± 4.5 years in the abnormal sucrase activity group, 10.5 ± 5.3 years in the moderate normal sucrase and 9.7 ± 5.1 years in the high normal sucrase activity groups. Each group had similar gender distribution.

The prevalence of known pathogenic SI gene mutations was 1.2% in sequenced non-Hispanic whites (National Heart, Lung, and Blood Institute, Exome Variant Server, GO Exome Sequencing Project,, 2012) and the prevalence of heterozygosity in the SI gene in IBS was reported as twice higher (3,5,18); therefore, we expected that at least 5% of cases with abnormal sucrase will have a SI gene mutation.

Disaccharidase Assays

Disaccharidase activities were measured in the authors’ laboratory following a modified Dahlqvist method (15,16,24).

Next-generation Sequencing of SI Gene Exons Using Formalin-fixed Paraffin-embedded Tissue DNA

Next-generation sequencing (Illumina Inc. San Diego, CA, USA) of the entire coding sequence (48 exons) of the SI gene using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed to detect known pathogenic variants of the SI gene (Table 1, Supplemental Digital Content,

Study Design

Study subjects were selected from laboratory databases based on the sucrase activities. Electronic medical records were used to collect clinical histories. FFPE tissue samples of 625 cases from the past 12 years (2006–2018) were used for DNA extraction.

Subjects were classified into 3 sucrase activity groups: low or abnormal, moderate normal, and high normal. Selection criteria for the abnormal group were abnormal sucrase activity (≤25.8 U) and a primary FGIDs symptom based on Rome IV classification (25–27). Selection criteria for the moderate group were moderate sucrase activities (≥25.8–≤55 U), and FGIDs may or may not be present. High sucrase activity group required sucrase activity >55 U and FGIDs may or may not be present. Patterns of disaccharidase deficiencies and clinical management of low sucrase cases were also analyzed.

Statistical Analysis of Clinical and Sucrase-isomaltase Gene Variant Data

Pearson Chi-square was used to test cumulative frequency of pathogenic SI variants for low sucrase activity cases versus high normal sucrase activity patients.

We adopt the least absolute shrinkage and selection operator (LASSO) method to perform feature selection, which determined the variants most likely to predict whether a subject was a low sucrase case, a moderate sucrase case, or a high sucrase activity case. See Supplemental Digital Content ( for more details on LASSO. To perform these analyses, Python 3 was used with Pandas (28), NumPy (29), Scikit-learn (30), and Matplotlib (31).


Gastrointestinal Symptoms of the Patients

All subjects had normal histologies. All abnormal sucrase cases had clinical history of FGIDs (Table 1). About 30% (38/125) of low sucrase group had diarrhea. No subject had diarrhea among the high normal sucrase group, and 28% (70/250) moderate sucrase activity normal group had diarrhea. Abdominal pain was reported in 92% (115/125) of the abnormal sucrase group, 73.6% of the moderate sucrase group, and 70.4% of the high sucrase group (Table 1).

TABLE 1 - Prevalence of clinical symptoms and disaccharidase activities in the 3 sucrase activity groups
Symptom prevalence in the 3 sucrase activity groups, n (%)
Clinical symptoms Low (abnormal) (n = 125) Moderate (normal) (n = 250) High (normal) (n = 250)
Diarrhea (D) 38 (30.4) 70 (28.0) 0 (0)
Abdominal pain (AP) 115 (92.0) 184 (73.6) 176 (70.4)
D and AP 28 (22.4) 62 (24.8) 0 (0)
No D or AP 0 (0) 58 (23.2) 74 (29.6)
Low lactase 97 (77.6) 101 (40.4) 60 (24.0)
GI histology Normal Normal Normal
Disaccharidase activities
Sucrase 19.1 ± 6.0 (1.3–25.8) 41.9 ± 7.6 (26.0–54.3) 77.5 ± 19.9 (57.5–171.2)
Lactase 10.7/ ± 8.6 (1.0–51.6) 20.7/ ± 13.1 (1.7–72.4) 30.0/ ± 19.2 (0.8–84.5)
Maltase 87.7 ± 31.0 (25.−201.0) 195.2 ± 51.2 (80.5–409.5) 304.4 ± 86.4 (120.4–729.9)
Isomaltase (palatinase) 8.0 ± 2.6 (0.4–14.4) 15.3 ± 3.5 (7.1–29.2) 23.0 ± 6.0 (12.0–44.8)
Glucoamylase 18.9 ± 6.7 (5.9–44.7) 40.2 ± 10.4 (18.9–79.0) 63.0 ± 15.8 (31.0–115.0)
Clinical symptoms of patients in each group are presented in absolute numbers (n) with percentage in parenthesis (%).GI = gastrointestinal, n = number, SD = standard deviation.
Disaccharidase activities are presented as mean ± SD enzyme activity units (U) with minimum and maximum units in parenthesis.
U, unit; μM/min/g protein.

The 36 abnormal cases with a variant of the SI gene were classified using Rome IV criteria as shown in Table 2 (Supplemental Digital Content,

Disaccharidase Activities in the 3 Groups

Sucrase, lactase, maltase, isomaltase, and glucoamylase activities (mean ± SD, minimum-maximum) are summarized in Table 1. Sucrase activity was 19.1 ± 6.0 U (1.3–25.8) in the abnormal sucrase group, 41.9 ± 7.6 (26–54.3) in the moderate normal group, and 77.5 ± 20.0 (57.5–171.2) in the high normal group. Average sucrase activities across the 13 variants found in the low sucrase cases are presented in a bar plot (Fig. 1) and are approximately uniformly distributed across variants (Supplemental Digital Content,

Sucrase activities for case group across variants: we show a bar plot of the average sucrase activities across variants within the 36 low sucrase case group. Sucrase activities are presented as enzyme activity units (U, unit; μM/min/g protein). Error bars show standard deviation. We also plot the individual sucrase activities of cases within each variant on top of the bar plots. Variants with a star only have 1 patient with that variant and therefore have no standard deviation error bar.

The average lactase activity was also low in abnormal sucrase cases (10.7 ± 8.6 U; 1.0–51.6), but normal in the moderate (20.7 ± 13 U; 1.7–72.4) and high (30.0 ± 19.2; 0.8–84.5) normal groups (Table 1). The frequency of low lactase activity was 77.6% (97/125) within the abnormal sucrase group, and 40.4% (101/250) and 24.0% (60/250) in moderate and high normal sucrase groups, respectively (Table 1).

Among the 36 abnormal sucrase cases with SI gene mutations, maltase was low in 24 (66.7%), and palatinase in 22 (61.1%). Of these 36 cases, glucoamylase was measured in 32 cases, and found to be low in 18 of 32 (56.3%).

Prevalence of Congenital Sucrase-isomaltase Deficiency Pathogenic Mutations

Thirteen different SI gene exonic variants (p.Val577Gly, p.Gly1073Asp, p.Phe1745Cys, p.Pro348Leu, p.Val371Met, p.Ile1378Ser, p.Tyr975His, p.Val1667Leu, p.Glu801Ter, p.Arg1367Gly, p.Gly515Val, p.Ile799Val, and p.Leu914Ile) were detected in 36 of 125 abnormal sucrase cases (29%, P < 0.001; Table 2). Only 16 of the 250 moderate normal sucrase cases (6.4%, P < 0.05), and 5 of the 250 high sucrase cases (2.0%, P < 0.001) had 1 of the 13 pathogenic variants (Table 2).

TABLE 2 - Prevalence of the 13 sucrase-isomaltase gene pathogenic variants in different sucrase activity groups, and in abnormal sucrase group with various disaccharidase patterns and symptoms
Patient groups Sample numbers (n) Number of cases with variants (frequency, %) P
Normal sucrase activity group
 High sucrase (>55 U§) 250 5 (2%)
 Moderate sucrase (>25.8–<55 U) 250 16 (6.4%) <0.001
Abnormal sucrase activity case group
 Abnormal (low sucrase) (<25.8 U) 125 36 (28.8%) <0.001
Cases subsets
 Abnormal sucrase cases with normal lactase ≥15.4 U 28 13 (46.4%) <0.001
 Abnormal sucrase cases with low lactase <15.4 U 97 23 (23.71%) <0.001
 Abnormal sucrase cases with PDD 51 13 (25.49%) <0.001
 Abnormal sucrase cases with D 10 2 (20%) <0.001
 Abnormal sucrase cases with AP 87 26 (22.22%) <0.001
 Abnormal sucrase cases with D and AP 28 8 (29.88%) <0.001
 Moderate normal sucrase cases with <32.8 U 38 6 (15.78%) <0.001
Thirteen SI gene pathogenic variants: p.Val577Gly, p.Gly1073Asp, p.Phe1745Cys, p.Pro348Leu, p.Val371Met, p.Gly515Val, p.Tyr975His, p.Val1667Leu, p.Glu801Ter, p.Ile799Val, p.Ile1378Ser, p.Leu914Ile, p.Arg1367Gly.AP = abdominal pain, D = diarrhea, PDD = pan-disaccharidase deficiency.
Sample number in different sucrase activity level groups consisting of normal (moderate and high) and abnormal case (low sucrase) groups, and the low sucrase case group subsets with different symptoms.
Number of patients in each group with at least 1 pathogenic congenital sucrase-isomaltase deficiency (CSID) variant.
P versus high normal sucrase group, meaning significantly higher mutation frequency is present in the low sucrase group.
§U, unit; μM/min/g protein.

Among the 36 abnormal sucrase cases with SI gene pathogenic variants, 29 had heterozygous mutations, 7 had CSID (5 compound heterozygous mutations, 1 homozygous mutation, and 1 with 2 different homozygous mutations; Table 3, Supplemental Digital Content, The carrier frequency of a pathogenic SI gene mutation in abnormal sucrase cases was significantly greater than in normal sucrase activity groups (P < 0.001; Table 2), regardless of gastrointestinal symptoms, lactase levels, or PDD (Table 2, Supplemental Digital Content,

Two moderate sucrase activity cases had compound heterozygous mutations. Both had sucrase activities between 25.8 and 32.8 U (Table 3, Supplemental Digital Content, A few other low frequency variants (p.Gly1760Val, p.Ser1795Leu, p.Thr1802Ser, p.Val1651Ile, p.Gly1476Ala, p.Arg1484His, p.Gly1760Asp, p.Ser186Pro) were detected in the normal sucrase groups (moderate and high) but not in the low sucrase group (Table 3, Supplemental Digital Content,

Important Variants for Classification of Sucrase-isomaltase Deficiency

Of the 13 pathogenic variants, LASSO analysis identified 5 primary pathogenic mutations: p.Val577Gly, p.Gly1073Asp, p.Phe1745Cys, p.Pro348Leu, and p.Val371Met (Table 3). These 5 primary SI gene pathogenic variants accounted for 31 of 36 (86%) of abnormal sucrase cases. These mutations were present in 31 of 125 (24.8%) abnormal sucrase cases, 7 of 250 (2.8%) moderate normal sucrase, and 0 of 250 (0%) high normal sucrase activity cases (P ≤ 0.001; Table 4, Supplemental Digital Content, Known inconsequential variants such as p.Met1523Ile or p.Thr231Ala are confirmed to be unimportant.

TABLE 3 - Sucrase-isomaltase gene variant importance in sucrase-isomaltase deficiency
Low sucrase 0.4 2.5 1.9 2.4 1.0 0.0 0.0 0.0 0.3 0.2 1.4 –0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4
Moderate sucrase 0.0 –1.2 –0.6 –0.4 –0.1 0.0 0.0 –0.2 –0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
High sucrase –0.2 0.0 0.0 –0.9 0.0 0.0 0.0 0.1 0.1 0.0 –0.2 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 –0.2
Variants p.Val15Phe p.Val577Gly p.Gly1073Asp p.Phe1745Cys p.Pro348Leu p.Arg774Gly p.Ile1378Ser p.Tyr975His p.Thr231Ala p.Val1667Leu p.Val371Met p.Met1523Ile p.Glu801Ter p.Arg1367Gly p.Tyr1417Ter p.Gly1760Asp p.Gly1760Val p.Ser1795Leu p.Gly515Val p.Ser186Pro p.Thr1802Ser p.Arg1484His p.Ile799Val p.Val1651Ile p.Val1651Ile p.Leu914Ile p.Gly1476Ala
Importance is shown in this table as the resulting weights from a multinomial logistic regression of variant presence to patient group with LASSO (Least Absolute Shrinkage and Selection Operator; L1 regularization). Higher value weights from this regression represent variants more important for separating the low, moderate, and high sucrase patient groups using variant presence. Light gray denotes that a variant has high importance. Variants showed higher scores in abnormal or low sucrase group. List of variants are given in Table S1,

Prevalence of Sucrase-isomaltase Gene Mutations in the Abnormal Sucrase Groups With Concomitant Low Lactase Activity or Pan-disaccharidase Deficiency

Abnormal (low) lactase activity (≤15.4 U) was present in 97 of 125 (77%) of the abnormal sucrase cases, and 23.7% (23/97) had at least 1 of the 13 pathogenic SI gene variants (P < 0.001 vs normal sucrase cases; Table 2).

Twenty-eight of the 125 abnormal sucrase cases (22.4%) had normal lactase and at least 1 SI gene pathogenic mutation was detected in 13 of these 28 cases (46%; P < 0.001; Table 2).

Fifty-one abnormal sucrase cases (51/125; 40.8%) had PDD. Thirteen of these 51 PDD cases (25%; P < 0.001) had at least 1 pathogenic SI gene variants. Of those with heterozygous mutation, 31% (9/29) had PDD and 66% (19/29) had low lactase activity. No patterns of isolated sucrase deficiency or combinations with other enzymes helped identify pathogenic SI gene variants.

Clinical Presentation of the Abnormal Sucrase Cases With Sucrase-isomaltase Gene Variants

Of the 36 subjects with FGIDs, 12 were diagnosed with IBS (IBS-diarrhea = 7, IBS-mixed = 2, IBS-constipation = 3), 10 with functional abdominal pain, 7 with FD, and 7 with nonerosive reflux disease (NERD; Table 2, Supplemental Digital Content, Nausea (21/36; 58%) was the second most common symptom, followed by vomiting (11/36; 31%) and diarrhea (11/36; 31%).

Follow-up clinical data were available for 26 abnormal sucrase subjects. Surprisingly only 10 of 26 subjects (39%) had correct diagnosis and subsequent management of sucrase deficiency of CSID. In the remaining 16 subjects, 4 were treated with suspected small intestinal bacterial overgrowth, 4 had intervention for lactase deficiency only, and the final 8 had their decreased disaccharidase activities dismissed as possible laboratory errors. Among the 16 misdiagnosed cases, 12 (75%) had atypical NERD or FD presentations, whereas the 10 subjects with correct management of sucrase deficiency of CSID diagnosis had IBS and 7 of 10 had functional abdominal pain. It appears that concomitant PDD and lactase deficiency, with atypical presentation resulted in misdiagnosis of CSID.

Visual Analysis Confirms Important Variants and Differences Between Abnormal (Low) and Normal Sucrase Activity Groups

We plotted frequency of low enzyme activity and symptoms versus variants in Figure 2, ignoring variants with sample sizes <5 and clinically silent variants (details in Supplemental Digital Content,

Enzyme and symptoms co-occurrence with variants: we show association of variants with normalized frequency of abnormal (low) enzyme activities and frequency of symptoms (how many patients with a given variant also have abnormal activity of a given enzyme or present a given symptom). The y axis shows normalized frequency and the x axis shows the variants. Notably, we see that frequencies of low activity and symptoms are highest for the most important variants predicted by LASSO (Table 2).

Abdominal pain is more common than diarrhea and thus has higher frequencies in this plot. Low sucrase activity/symptom frequency is higher for variants of high predicted pathogenic probability, and these variants match important variants from our LASSO regression (Table 3).

Finally, we plotted a receiver operating characteristic curve of sucrase:lactase ratio to predict deficiency. The optimal threshold was 1.43 with an accuracy of 75.2%, sensitivity of 86.5%, and specificity of 50.0% (Fig. 1, Supplemental Digital Content,


CSID was originally considered an autosomal recessive genetic disorder caused by homozygous mutations in the SI gene. Since the first CSID report by Weijers et al (4), many attempted to characterize the genetic basis of CSID. In a landmark study, the SI gene was sequenced in 33 previously diagnosed CSID patients and suspected pathogenic variants were identified (32). These cases had classic symptoms of presentation in early life with severe diarrhea, abdominal distension and cramps, and severely depressed sucrase activity on mucosal biopsies. Thus, the criteria standard for CSID diagnosis became disaccharidase assays using intestinal biopsy. Cellular expression of mutated proteins demonstrated that suspected pathogenic variants resulted in ineffective synthesis of the SI heterodimer enzyme and/or transport of the enzyme to the apical membrane of the brush border (32–34).

Recent studies suggest that partial deficiencies caused by heterozygous mutations in the SI gene could result in less severe presentations. Compound and simple heterozygous genotypes can have chronic symptoms such as IBS (3,5,13,35–37).

We assessed SI gene mutations prevalence in FFPE tissue DNA of non-Hispanic white pediatric and young adult patients with abnormal and normal sucrase activities, and normal histology. Known and previously unreported SI gene mutations were significantly more common in abnormal sucrase patients (29%), compared to moderate (6.4%) and high (2.0%) normal sucrase groups. Seven abnormal cases (5.6%) had CSID from multiple mutations (compound heterozygous, homozygous, or compound homozygous) and 29 (23.2%) had single heterozygous pathogenic SI gene variants. We also showed that these SI gene variants are either absent or significantly infrequent in normal sucrase groups.

Post hoc analysis of low sucrase cases indicated that the diagnosis of less severe sucrase isomaltase deficiency due to heterozygosity represents a challenge. The practitioners appropriately diagnosed and managed 10 of 26 (38%) cases. The association between pathogenic SI gene variants and symptoms such as chronic diarrhea and/or abdominal pain in both pediatric and adult patients has been reported (3,11,14).

Diarrhea, abdominal pain, dyspepsia, nausea, and vomiting were common symptoms in low sucrase cases. FD and NERD were commonly found in addition to IBS and RAP. Our results corroborate with that of Cohen et al (13,14), where nausea is a common symptom in children with abnormal sucrase. Similarly nausea and dyspepsia as presenting symptoms have also been reported in adults with lactase deficiency and SI deficiency (27,38,39).

This study also confirmed presence of heterozygous SI gene mutations in symptomatic cases with varied disaccharidase deficiency patterns, including low sucrase with and without low isomaltase, and PDD (3,7,10,32,37). Moreover, 71% of abnormal cases had concurrent lactase deficiency. Two abnormal disaccharidases would lead to synergistic negative effects on carbohydrate digestion (32). Therefore, coexistence of lactase deficiency does not rule out CSID or pathogenic SI gene mutation associated sucrase deficiency. A sucrase:lactase ratio of <1.0 was proposed for CSID diagnosis in low lactase cases (9) based on index cases with severe early childhood presentations. Using receiver operating characteristic analysis we found a sucrase:lactase ratio of <1.43 is able to detect genetic SI deficiency in homozygous CSID or heterozygous SI gene pathogenic variants (Fig. 1, Supplemental Digital Content,, with sensitivity of 86.8% but a low specificity of only 50%. The original <1.0 ratio would result in a significant number of cases being misclassified (Fig. 1, Supplemental Digital Content,

Pan-disaccharidase deficiency with low lactase, maltase, sucrase, palatinase (isomaltase), and glucoamylase using a modified Dahlqvist method typically suggests mucosal injury (40). With normal histology, PDD, however, appears to be another presentation of CSID and heterozygous SI gene pathogenic mutation. In fact, 42.8% of patients with CSID or heterozygous pathogenic mutations were presented with PDD. There is a lack of strict substrate specificity in Dahlqvist method of disaccharidase assays (15,16,24). Sucrase contributes to the digestion of maltose and also partially hydrolyzes the available glucoamylase substrates (9,39). If combined with the concomitant lactase deficiency, this would result in PDD.

Technical aspects of confirming a genetic basis of sucrase deficiency including the more common heterozygous cases based solely on levels of activities of disaccharidases also pose a challenge. Obtaining samples without formalin contamination, and maintaining tissue in frozen condition are critically important. Most laboratories leave interpretation of such diverse disaccharidase activity patterns to the potentially unaware gastroenterologist. Reference laboratories use cut-offs set at the 10th percentile as they lack information on whether biopsy is histologically normal, likely increasing false positives. We use the more conventional third percentile of activities with normal histology.

Almost all pathogenic mutations were found in those under the third percentile, supporting this stringent approach.

This study has several strengths. Utilizing stored FFPE samples of 625 non-Hispanic white cases with previously measured disaccharidase assay made this the largest pediatric study to include genotyping of SI gene variants. The location of the specialty diagnostic laboratory near the endoscopy suite reduced chances of sample handling and transporting errors. Limitations include retrospective classification of FGIDs using Rome IV criteria, and including only non-Hispanic whites. This study is cross-sectional and further studies are warranted to support interventions.

In conclusion, high prevalence of heterozygous SI gene variants in patients with abnormal sucrase activity was found to be associated with FGIDs symptoms. Atypical symptoms such as dyspepsia, nausea, and vomiting were common. Concomitant lactase and pan-disaccharidase deficiencies were prevalent in subjects with abnormal sucrase and pathogenic SI gene variants. Limitations of the modified Dahlqvist method (15,16,24) as well as atypical presenting symptoms misled gastroenterologists. Guided interpretation of disaccharidases supported by genetic testing should be considered. Because 71% of low sucrase patients did not have a known mutation, this approach will help identify further mutations. Several previously uncharacterized mutations were identified as pathogenic by functional characterization (manuscript in preparation). Studies in other ethnicities are warranted for this treatable condition. Clinical trials on the role of enzyme therapy are supported by this cross-sectional prevalence study.


The authors acknowledge the funding support from QOL Medical, LLC. The authors also thank Lynne K. Honor for technical support in the lab, and Bertha A. Ben Khallouq for reading and editing the manuscript.


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congenital sucrase-isomaltase deficiency (CSID), functional gastrointestinal disorders, irritable bowel syndrome (IBS), lactase deficiency, pan-disaccharidase deficiency, sucrase-isomaltase (SI) gene variants

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