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Galactose Malabsorption

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Galactose Malabsorption Renal and intestinal hexose transport in familial glucose- galactose malabsorption Louis J. Elsas, … , Joseph H. Patterson, Leon E. Rosenberg J Clin Invest. 1970;49(3):576-585. https://doi.org/10.1172/JCI106268. Research Article Glucose transport by jejunal mucosa in vitro and kidney in vivo was investigated in a 3 yr old patient with congenital glucose-galactose malabsorption, her family, and 16 normal volunteers. Glucose transport by normal human jejunal mucosa was concentrative, saturable, sodium and energy dependent, and exhibited competitive inhibition. Biopsy specimens from six normal controls and an asymptomatic 5 yr old brother of the proband accumulated glucose to concentrations 16 times that in the incubation medium. The proband's mucosa was unable to concentrate glucose throughout a 60 min incubation period. Both of her parents and a half sister demonstrated impaired glucose transport. Their values fell between normal and those of the proband. Influx of glucose was impaired but efflux of glucose from the mucosa of these three heterozygotes was identical with that in three normal controls. A kinetic analysis indicated a reduced capacity (Vmax), but a normal affinity (Km) for glucose transport by their intestinal mucosa. All subjects accumulated fructose similarly. Renal glucose transport was investigated using renal glucose titration techniques. A partial defect in renal glucose reabsorption was found in the proband. Her brother's titration curve was similar to that of seven normal volunteers. We conclude that familial glucose-galactose malabsorption is inherited as an autosomal recessive trait, that heterozygotes for this disorder are detectable and demonstrate a reduced capacity for glucose […] Find the latest version: https://jci.me/106268/pdf Renal and Intestinal Hexose Transport in Familial Glucose -Galactose Malabsorption Louis J. ELSAS, RicHARD E. HILLMAN, JOSEPH H. PA1rERSON, and LEON E. ROSENBERG From the Division of Medical Genetics, Departments of Medicine and Pedia- trics, Yale University School of Medicine, New Haven, Connecticut 06510 A B S T R A C T Glucose transport by jejunal mucosa in INTRODUCTION vitro and kidney in vivo was investigated in a 3 yr old 14 patients have been reported previously with in- patient with congenital glucose-galactose malabsorption, testinal malabsorption of the sterically similar mono- her family, and 16 normal volunteers. Glucose transport saccharides D-glucose and D-galactose (1-14). The fa- by normal human jejunal mucosa was concentrative, milial nature of this disease was first determined by saturable, sodium and energy dependent, and exhibited Lindquist and Meeuwisse in a study of one large competitive inhibition. Biopsy specimens from six nor- Swedish family (2, 14, 15). They found first or second mal controls and an asymptomatic 5 yr old brother of cousin relationships in three out of four patients, several the proband accumulated glucose to concentrations 16 instances 'of consanguineous matings, and six deaths times that in the incubation medium. The proband's caused by idiopathic diarrhea in siblings of affected mucosa was unable to concentrate glucose throughout a patients. Subsequent authors have noted similar findings. 60 min incubation period. Both of her parents and a half No direct parent to child transmission has been reported sister demonstrated impaired glucose transport. Their and both sexes have been affected. Several cases demon- values fell between normal and those of the proband. strated glycosuria (12). These previous observations Influx of glucose was impaired but efflux of glucose suggested that the glucose-galactose malabsorption syn- from the mucosa of these three heterozygotes was iden- drome was inherited as an autosomal recessive trait in tical with that in three normal controls. A kinetic analy- which both the kidney and intestine expressed an ab- sis indicated a reduced capacity (Vmax), but a normal normality in glucose transport. However, no systematic affinity (K.) for glucose transport by their intestinal studies of the mutant glucose transport processes have mucosa. All subjects accumulated fructose similarly. been undertaken in families affected with this disorder Renal glucose transport was investigated using renal to test this genetic hypothesis. glucose titration techniques. A partial defect in renal In the' present study, jejunal biopsy specimens were glucose reabsorption was found in the proband. Her obtained and studied in vitro. To define the mode of brother's titration curve was similar to that of seven inheritance of glucose-galactose malabsorption, several normal volunteers. parameters of glucose tarnsport were studied in a 3 yr We conclude that familial glucose-galactose malab- old girl, her parents, brother, and half sister. Glucose sorption is inherited as an autosomal recessive trait, transport by normal human intestinal mucosa was that heterozygotes for this disorder are detectable and characterized and compared to that in the patient and demonstrate a reduced capacity for' glucose transport, her family. and that absent intestinal glucose transport is accom- Like the jejunal epithelial cell, proximal renal tubular panied by partial impairment of renal glucose transport. epithelium is differentiated histologically and function- This work was presented in part at the Annual Meeting ally for the transport process. Three previously reported of the American Federation for Clinical Research, 4 May inherited! diseases of amino acid transport have associ- 1969. ated defects in the kidney and intestine (16-18). There- Dr. Patterson is Professor of Pediatrics, Emory Uni- fore, in vivo renal glucose transport was also investi- versity School of Medicine, Eggleston Hospital, Atlanta, Ga. gated by using renal glucose titration techniques to Received for publication 6 August 1969 and in revised determine whether an intestinal defect was accompanied form 29 October 1969. by impaired renal glucose transport. 576 The Journal of Clinical Investigation Volume 49 1970 METHODS 1 ~~~~23 Patients studied. The proband, patient II-9 (Fig. 1) was I 38 the subject of a previous clinical report (13). Her clinical history included the onset of refractory diarrhea at 3 days of age which remitted only on a diet free of glucose and galactose. Carbohydrate was supplied as D-fructose, a mono- saccharide transported by a different mechanism. Subsequent Itt)7t)Sttl)30)ll618 i;; ;* oral hexose tolerance tests confirmed that D-glucose and D-galactose were malabsorbed, but that D-xylose and D-fruc- tose were absorbed normally. She was 3 yr old at the time -e 3b . = Severe diarrhea of the present study. Although growth and development were 2 /6 /6 D = Female, male (asymptomftic) proceeding normally on the glucose-free, fructose-supple- 0 mented diet, dietary glucose challenges continued to produce / Proband profuse watery diarrhea. The family history revealed that a 1 Position in pedigree sister, subject II-7, had died 2 yr earlier at 17 days of age q Age of refractory diarrhea. The mother bore six normal children t = Deceased by a previous marriage, but her present marriage resulted in three children, two of whom were clinically affected. FIGURE 1 Pedigree of family affected with glucose-galactose Intestinal and renal glucose transport was investigated in malabsorption. the proband (II-9), her asymptomatic 5 yr old brother (II-8), her parents (I-2, I-3), and her half sister (II-2). allowed accurate glucose determinations from 2.5 to 25 ug A total of 16 normal volunteers were also admitted to the per sample. Tissue extracts, media, and standards were Pediatric or Adult Clinical Research Center of the Yale- lyophilized and analyzed for purity by radiochromatography New Haven Hospital for intestinal or renal transport stud- using a descending paper chromatographic system of iso- ies. Each patient was informed in detail of the investigative propanol: water (160: 40) or phenol: water (160: 40). nature of the study and the procedures to be performed. In Sugars were identified calorimetrically by a diphenylamine: the proband (II-9) an oral glucose tolerance test (1.75 aniline reagent (21). g/kg) resulted in watery diarrhea containing large amounts D-glucose-'4C uptake by biopsy specimens of jejunal of glucose and an absent rise in blood glucose. Her intra- mucosa was subjected to Michaelis-Menten analysis. At least venous glucose tolerance test and an oral D-xylose test were 10 biopsy specimens per subject were incubated for 10 min in normal (19). Normal oral hexose tolerance tests were found D-glucose-U-'4C ranging in concentration from 0.1 to 40.0 in other family members. mm. The velocity of uptake was calculated from the distri- Transport of glucose by human jejunal mucosa. A normal bution ratio, apparent diffusion constant (KD), and medium hematocrit, prothrombin time, partial thromboplastin time, concentration (Af) using previously described techniques and platelet count were obtained before accepting volunteers (22). The mean velocity of uptake from at least six observa- or patients for intestinal biopsy. In adults the Quinton 7 mm tions at each substrate concentration was plotted for controls hydraulic intestinal multibiopsy apparatus 1 was used (20). and compared to the mean velocities obtained in the parents The tube was swallowed and its tip placed at the ligament *(I-2, I-3) and half sister (11-2) of the proband. Using the of Treitz under fluoroscopic control. 20 2-3 mg specimens of double reciprocal plot of Lineweaver and Burk, the affinity jejunal mucosa were obtained and placed in chilled Krebs- (Km) and capacity (Vm..) in each group were observed Ringer bicarbonate buffer for no more than 45 min before directly from the extrapolated abscissa intercept and ordinate initiating transport studies. A Rubin tube was used in the intercept (23). proband and her brother, and four to eight jejunal specimens D-glucose-'4C efflux from jejunal biopsy specimens was were obtained. Single biopsy specimens were placed in 2.0 studied in the parents, half sister, and three normal volun- ml of fresh buffer (pH 7.4) containing 2.0 mM D-glU- teers. Two biopsy specimens were preincubated in one flask cose-U-'4C.
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