Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation.

BACKGROUND: Congenital sucrase-isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%-10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase-isomaltase deficiency in the Inuit population. METHODS: We sequenced the sucrase-isomaltase gene, SI, in a single Inuit proband with congenital sucrase-isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect. RESULTS: In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%-21.8%). The predicted Hardy-Weinberg prevalence of congenital sucrase-isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%-4.5%), which is comparable with previous estimates. INTERPRETATION: We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase-isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea.

Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria.

Pentosuria is one of four conditions hypothesized by Archibald Garrod in 1908 to be inborn errors of metabolism. Mutations responsible for the other three conditions (albinism, alkaptonuria, and cystinuria) have been identified, but the mutations responsible for pentosuria remained unknown. Pentosuria, which affects almost exclusively individuals of Ashkenazi Jewish ancestry, is characterized by high levels of the pentose sugar L-xylulose in blood and urine and deficiency of the enzyme L-xylulose reductase. The condition is autosomal-recessive and completely clinically benign, but in the early and mid-20th century attracted attention because it was often confused with diabetes mellitus and inappropriately treated with insulin. Persons with pentosuria were identified from records of Margaret Lasker, who studied the condition in the 1930s to 1960s. In the DCXR gene encoding L-xylulose reductase, we identified two mutations, DCXR c.583ΔC and DCXR c.52(+1)G > A, each predicted to lead to loss of enzyme activity. Of nine unrelated living pentosuric subjects, six were homozygous for DCXR c.583ΔC, one was homozygous for DCXR c.52(+1)G > A, and two were compound heterozygous for the two mutant alleles. L-xylulose reductase was not detectable in protein lysates from subjects' cells and high levels of xylulose were detected in their sera, confirming the relationship between the DCXR genotypes and the pentosuric phenotype. The combined frequency of the two mutant DCXR alleles in 1,067 Ashkenazi Jewish controls was 0.0173, suggesting a pentosuria frequency of approximately one in 3,300 in this population. Haplotype analysis indicated that the DCXR c.52(+1)G > A mutation arose more recently than the DCXR c.583ΔC mutation.

Theodore E. Woodward Award: lactase persistence SNPs in African populations regulate promoter activity in intestinal cell culture.

Lactase-phlorizin hydrolase, lactase, is the intestinal enzyme responsible for the digestion of the milk sugar lactose. The majority of the world's human population experiences a decline in expression of the lactase gene by late childhood (lactase non-persistence). Individuals with lactase persistence, however, continue to express high levels of the lactase gene throughout adulthood. Lactase persistence is a heritable autosomal dominant condition and has been strongly correlated with several single nucleotide polymorphisms (SNPs) located ∼14 kb upstream of the lactase gene in different ethnic populations: -13910*T in Europeans and -13907*G, -13915*G, and -14010*C in several African populations. The coincidence of the four SNPs clustering within 100 bp strongly suggests that this region mediates the lactase non-persistence/persistence phenotype. Having previously characterized the European SNP, we aimed to determine whether the African SNPs similarly mediate a functional role in regulating the lactase promoter. Human intestinal Caco-2 cells were transfected with lactase SNP/promoter-reporter constructs and assayed for promoter activity. The -13907*G and -13915*G SNPs result in a significant enhancement of lactase promoter activity relative to the ancestral lactase non-persistence genotype. Such differential regulation by the SNPs is consistent with a causative role in the mechanism specifying the lactase persistence phenotype.

Disaccharide digestion and maldigestion.

All food carbohydrates are hydrolysed to monosaccharides before transport across the microvillus membrane. The digestion of disaccharides and some oligosaccharides is undertaken by a number of small intestinal brush border enzymes: sucrase-isomaltase, lactase phlorizinhydrolase, maltase-glycoamylase and trehalase. The distribution of the enzymes in the small intestine has been investigated. Different disaccharide maldigestion syndromes have been described. Lactase deficiency in adults is a condition found in the majority of inhabitants of the world. However, the prevalence varies widely between different populations. Sucrase-isomaltase deficiency is a very rare congenital condition except in Greenland. Trehalose maldigestion is likewise rare outside Greenland. Different hypotheses regarding the molecular background of the maldigestion syndromes are discussed.

Increased prevalence of hereditary metabolic diseases among native Indians in Manitoba and northwestern Ontario.

OBJECTIVE: To compare the prevalence of hereditary metabolic diseases in the native and non-native populations of Manitoba and northwestern Ontario. DESIGN: Retrospective analysis. SETTING: Children's Hospital, Winnipeg. PATIENTS: Patients were selected by three methods: laboratory tests designed to screen patients suspected of having a metabolic disease, laboratory investigation of newborn infants with abnormalities detected through screening, and investigation of near relatives of probands with disease. RESULTS: A total of 138 patients with organic acid, amino acid and carbohydrate disorders were seen from 1960 to 1990. Of these, 49 (36%) were native Indians (Algonkian linguistic group). This was in sharp contrast to the proportion of native Indians in the total study population (5.8%). Congenital lactic acidosis due to pyruvate carboxylase deficiency (13 patients), glutaric aciduria type I (14 patients) and primary hyperoxaluria type II (8 patients) were the most common disorders detected. Other rare disorders included glutaric aciduria type II (one patient), 2-hydroxyglutaric aciduria (one patient) and sarcosinemia (one patient). Underreporting, especially of glutaric aciduria type I and hyperoxaluria type II, was likely in the native population. CONCLUSIONS: Hereditary metabolic diseases are greatly overrepresented in the native population of Manitoba and northwestern Ontario. We recommend that native children who present with illnesses involving disturbances of acid-base balance or with neurologic, renal or liver disease of unknown cause by investigated for a possible metabolic disorder.