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L J Elsas

Publications and source records attributed to L J Elsas.

144 records · Page 8Linked to original sources
PubMed1970

Renal and intestinal hexose transport in familial glucose-galactose malabsorption.

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 (V(max)), but a normal affinity (K(m)) 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 transport, and that absent intestinal glucose transport is accompanied by partial impairment of renal glucose transport.

Adolescent↗
PubMed1969

Familial renal glycosuria: a genetic reappraisal of hexose transport by kidney and intestine.

Renal glucose titration studies were carried out in 10 members of two pedigrees with familial renal glycosuria to test the accepted hypothesis of autosomal dominant inheritance and to investigate the genetic significance of "type A" and "type B" renal glycosuria. In one family, a brother and sister each had a moderately reduced threshold and tubular maximum for glucose (type A), but both of their parents reabsorbed glucose normally. In the second family, two brothers had severe type A renal glycosuria, their mother and one brother had a mild type A defect, and another brother demonstrated a reduced threshold, an exaggerated splay, and a normal tubular maximum, indicative of type B glycosuria.Hexose transport by intestinal mucosa was also investigated in controls and in the three brothers with the most severe renal glycosuria. D-glucose-(14)C and 3-O-methylglucose-(14)C were accumulated by jejunal mucosa from controls by processes which were saturable and concentrative. No differences in hexose transport were observed in the patients with renal glycosuria. We conclude that familial renal glycosuria can be inherited as an autosomal recessive trait; that mild and severe type A renal glycosuria and type B renal glycosuria can occur in the same pedigree; and that defective reabsorption of glucose by the kidney need not be accompanied by abnormalities in intestinal glucose transport. These findings indicate that glucose transport in the gut and kidney are not mediated by identical mechanisms, and that several different mutations are responsible for the phenotypic variability in familial renal glycosuria.

Adult↗
PubMedDate not supplied

Structure-function analyses of a common mutation in blacks with transferase-deficiency galactosemia.

We previously identified a missense mutation at amino acid 135 of human galactose 1-phosphate uridyltransferase (hGALT) in which a leucine (TTG) was substituted for a serine (TCG), S135L. This mutation was common in black patients with galactosemia and homozygotes (S135L/S135L) had no GALT activity or protein in their erythrocytes or lymphoblasts. However, there was residual GALT activity and protein in their leukocytes, and they had near normal total body [13C]galactose oxidation to 13CO2 in breath. To evaluate the biochemical mechanism(s) producing these effects, we overexpressed hGALT proteins with site-directed mutations in this nonconserved amino acid in a GALT-minus Escherichia coli. Enzyme activities detected in bacterial lysates overexpressing either S135 (wild type), A135, C135, H135, L135, S132-H135, T135, or Y135 were 100, 4.7, 3.0, 4.0, 2.7, 0.7, 35.4, and 1.4%, respectively. Only the threonine substitution (S135T) had significant enzyme activity in these lysates. There was also decreased abundance of all mutant proteins in the lysates exposed to bacterial proteolysis during preparation and analysis. This added the variable of bio-instability to analysis of enzyme activities in lysates. To further characterize the catalytic role of serine at amino acid 135 and to differentiate bio-instability from impaired catalysis by the leucine substitution, we purified wild-type and L135-hGALT proteins to homogeneity and analyzed identical amounts of enzyme protein. We found that the apparent Vmax of the purified L135-hGALT protein was significantly reduced from 80 +/- 5.9 to 5.8 +/- 1.8 micromol glucose 1-phosphate released/min/mg hGALT protein with no increase in KM for galactose 1-phosphate for the second displacement. The first displacement reaction, although three orders of magnitude slower, was similar between the wild type and L135-hGALT. We conclude that a hydroxyl group on amino acid 135 is required for the catalysis of uridyl transfer from UDP-glucose to UDP-galactose in the presence of galactose 1-phosphate, and plays a role in the bio-stability of hGALT.

Animals↗
PubMedDate not supplied

The molecular biology of galactosemia.

Classic galactosemia is an autosomal recessive disorder caused by the deficiency of galactose 1-phosphate uridyltransferase (GALT). Although the potentially lethal, neonatal hepatotoxic syndrome is prevented by newborn screening and galactose restriction, long-term outcome for older patients with galactosemia remains problematic. After the cloning and sequencing of the GALT gene, more than 130 mutations in the GALT gene have been associated with GALT deficiency; this review relates them to function and clinical outcome. Two common mutations, Q188R and K285N, account for more than 70% of G alleles in the white population and are associated with classic galactosemia and impaired GALT function. In the black population, S135L accounts for 62% of the alleles causing galactosemia and is associated with good outcomes. A large 5 kb deletion in the GALT gene is found in Ashkenazim Jews. The Duarte galactosemia variant is caused by N314D. Homozygosity for N314D reduces GALT activity to 50%. When either E203K or a 1721C-->T transition (Los Angeles variant) are present in cis with N314D, GALT activity reverts to normal. In this review, we discuss the structural biology of these mutations as they affect both the GALT enzyme and patient outcome.

Ethnicity↗
PubMedDate not supplied

Outcomes analysis of verbal dyspraxia in classic galactosemia.

PURPOSE: This study evaluates a genotype/phenotype relationship between developmental verbal dyspraxia (DVD) and the common, missense mutation of the galactose-1-phosphate uridyltransferase gene, Q188R, in patients with classic galactosemia (G/G). METHODS: As part of this study, we devised a questionnaire for "speech problems" to be completed by the patient\'s clinician. To validate the questionnaire and determine its accuracy in detecting DVD, we analyzed questionnaire responses for 21 patients by testing them independently and directly for DVD through a speech pathologist blinded to the patients' genotype. RESULTS: We found that the questionnaire had a sensitivity of 0.56 and a specificity of 0.75. We then calculated the prevalence of DVD for a larger set of 113 patients with G/G galactosemia whose biochemical phenotype, molecular genotypes, and clinical status were known. The prevalence of "speech problems" from raw data were 50 of 113 (44.2%). After adjusting for misclassification, 43 (38.1%) were classified as cases of DVD. Using multivariate, logistic, regression analyses we found a significant interaction between genotype and mean red blood cell (RBC) galactose-1-phosphate (Gal-1-P). When corrected, using mean RBC Gal-1-P < h 3.28 mg%, the Q188R/Q188R genotype was the best predictor of DVD. There was a significant risk (odds ratio = 9.6, p = 0.0504) of having DVD associated with homozygosity for Q188R compared with other genotypes. CONCLUSIONS: We conclude that homozygosity for Q188R mutations in the GALT gene is a significant risk factor for DVD. However, poor metabolic control obviates this relationship as indicated by RBC Gal-1-P greater than 3.28 mg%.

Apraxias↗
PubMedDate not supplied

Gender verification of female athletes.

The International Olympic Committee (IOC) officially mandated gender verification for female athletes beginning in 1968 and continuing through 1998. The rationale was to prevent masquerading males and women with "unfair, male-like" physical advantage from competing in female-only events. Visual observation and gynecological examination had been tried on a trial basis for two years at some competitions leading up to the 1968 Olympic Games, but these invasive and demeaning processes were jettisoned in favor of laboratory-based genetic tests. Sex chromatin and more recently DNA analyses for Y-specific male material were then required of all female athletes immediately preceding IOC-sanctioned sporting events, and many other international and national competitions following the IOC model. On-site gender verification has since been found to be highly discriminatory, and the cause of emotional trauma and social stigmatization for many females with problems of intersex who have been screened out from competition. Despite compelling evidence for the lack of scientific merit for chromosome-based screening for gender, as well as its functional and ethical inconsistencies, the IOC persisted in its policy for 30 years. The coauthors of this manuscript have worked with some success to rescind this policy through educating athletes and sports governors regarding the psychological and physical nature of sexual differentiation, and the inequities of genetic sex testing. In 1990, the International Amateur Athletics Federation (IAAF) called for abandonment of required genetic screening of women athletes, and by 1992 had adopted a fairer, medically justifiable model for preventing only male "impostors" in international track and field. At the recent recommendation of the IOC Athletes Commission, the Executive Board of the IOC has finally recognized the medical and functional inconsistencies and undue costs of chromosome-based methods. In 1999, the IOC ratified the abandonment of on-site genetic screening of females at the next Olympic Games in Australia. This article reviews the history and rationales for fairness in female-only sports that have led to the rise and fall of on-site, chromosome-based gender verification at international sporting events.

Chromatin↗
PubMedDate not supplied

Zinc and copper status of treated children with phenylketonuria.

Children with phenylketonuria (PKU) are treated with semi-synthetic diets restricted in phenylalanine. Low or phenylalanine-free formulae provide the majority of protein and energy in the diet while phenylalanine requirements are met by low-protein natural foods. Because of the restriction of natural protein sources in this diet, the study assessed the zinc and copper nutriture of treated children with PKU and correlated linear growth with zinc status. The plasma zinc of the PKU population was 66.6 +/- 3.3 micrograms/dl (mean +/- SEM). The hair zinc was 70.2 +/- 11.5 micrograms/g (mean +/- SEM). The mean plasma and hair zinc of the PKU population were significantly different (p less than 0.05) when compared to normal values of 84.2 +/- 2.9 micrograms/dl and 130.7 +/- 8.3 micrograms/g (mean +/- SEM), respectively. The dietary zinc intake of 10 PKU patients was 8.56 +/- 2.68 mg/day (mean +/- SD). No significant differences (p less than 0.123) were found when the mean zinc intake was compared with recommended dietary allowances for age of 10 mg/day. No significant correlations were found when plasma and hair zinc were plotted with height percentiles. Plasma copper of the PKU subjects (87.6 +/- 6.6 micrograms/dl, mean +/- SEM) was significantly less than that of normal young children (121.5 +/- 3.1 micrograms/dl, mean +/- SEM) despite a copper intake a 1.45 +/- 0.35 mg/day (mean +/- SD).

Child↗
PubMedDate not supplied

The Polyclinic at the 1996 Atlanta Olympic Village.

The Polyclinic, staffed mainly by volunteers, successfully provided primary health care during 16,519 patient encounters, 64% involving athletes. However, the profile of patient needs held some surprises.

Ambulatory Care↗
PubMedDate not supplied

Molecular genetics of severe insulin resistance.

Leprechaunism and type A diabetes represent inborn errors of insulin resistance whose phenotypes suggested causation by mutations in the insulin receptor gene. Cells cultured from patients with leprechaunism specifically lacked high-affinity insulin binding. Partial but different degrees of impairment were observed in cells cultured from first-degree relatives. Different mutations in the insulin receptor's alpha subunit were proposed in different families (Ark-1, Atl, Minn, Mount Sinai) based on phenotype, cellular insulin binding, and insulin receptor structure. Molecular cloning and sequencing of mutant insulin receptor cDNA from family Ark-1 confirmed that the proband inherited a maternal missense and a paternal nonsense mutation in the alpha subunit and was a compound heterozygote. The insulin receptor was immunologically present on the plasma membrane of fibroblasts cultured from patients Ark-1 and Atl but was markedly reduced in cells from patients Minn and Mount Sinai. In cells from patient Minn, but not from patient Mount Sinai, the decreased number of insulin receptors was associated with reduced insulin receptor mRNA. In two families with the less severe form of insulin resistance, type A diabetes, mutations altered post-translational processing of the insulin receptor molecule. At a cellular level, these mutations of the alpha subunit of the insulin receptor shared defective binding and impaired stimulation of sugar transport by insulin. In family Atl, however, glucose uptake was constitutively increased. Thus, genetic variation in the insulin receptor gene causes a spectrum of inherited insulin-resistant syndromes and altered cellular signaling.

Humans↗