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PubMedDate not supplied

Galactosemia in infancy: diagnosis, management, and prognosis.

Galactosemia is an inherited metabolic disorder in which the individual is unable to metabolize lactose. In the newborn, classic galactosemia presents with symptoms of severe feeding intolerance, malnutrition, and rapid organ damage. Without immediate treatment, the infant will almost certainly succumb to rampant disease or sepsis. Through increased clinical awareness, pediatric care providers can be better prepared to detect and manage an infant with this disorder. A multidisciplinary approach is often necessary to maintain optimal health. The nurse can play an important role in coordinating specialty services and in helping the family to manage the disease and its sequelae over time.

Developmental Disabilities↗
PubMed2000

Apparent galactose appearance rate in human galactosemia based on plasma [(13)C]galactose isotopic enrichment.

Determination of endogenous galactose formation in galactosemic subjects provides important information in understanding the etiology of the long-term complications. To accomplish this task a sensitive method for measurement of isotopic enrichment of plasma galactose was developed. The aldononitrile pentaacetate derivative of galactose was utilized for gas chromatography/mass spectrometry analysis. Using a phenyl-methylsilicone capillary column, adequate separation of galactose from glucose was obtained by temperature programming of the chromatography. The specific fragmentation pattern of m/z 212, 225, 314 from d-[(12)C]galactose and m/z 213, 226, 315 from l-[(13)C]galactose was used for the galactose enrichment measurement by atom percent excess (APE). There was good correlation between expected enrichment and determined APEs at galactose concentrations of 1, 2, and 5 micromol/L with a coefficient of variation ranging from 0.22 to 7.17%. The method provides an accurate estimation of plasma [(13)C]galactose enrichment from which the galactose production rate can be calculated. The steady-state plasma l-[(13)C]galactose isotopic enrichment of three individuals with galactosemia, two males ages 33 and 13, and one female age 9, during constant infusion of l-[(13)C]galactose was 55, 41, and 55%, allowing the estimation of the apparent galactose appearance rate of 0.62, 1.09, and 0.82 mg/kg/h, respectively. The reanalysis of three previous studies by the present method found that APE values determined by the method then employed, butylboronate acetate derivatization, were systemically lower than those determined with aldononitrile pentaacetate derivatization, making for an overestimation of the apparent galactose appearance rate. The small plasma sample volumes needed make it feasible to perform these studies in infants and young children with galactosemia.

Carbon Isotopes↗
PubMed2026

Coagulopathy in Neonates With Classic Galactosemia: A Life-Threatening Yet Underrecognized Complication.

INTRODUCTION: Classic galactosemia (CG) is a rare metabolic disorder caused by galactose-1-phosphate uridylyltransferase deficiency, leading to toxic metabolite accumulation and life-threatening complications such as failure to thrive, sepsis, and acute liver failure. We hypothesize that coagulopathy is an underrecognized complication of CG and that this gap is reflected by limited documentation in the medical literature. METHODS: A PubMed literature review was conducted to identify articles describing coagulopathy in CG. We filtered for guidelines, meta-analyses, reviews, and systematic reviews. Our article screening followed PRISMA guidelines. RESULTS: Of 49 identified articles, 26/49 (53%) met inclusion criteria. Only 6/49 (12%) explicitly described coagulopathy in CG, and only 1/49 (2%) discussed management. DISCUSSION: These data supports our hypothesis that coagulopathy may be an underrecognized complication of CG by clinicians and identifies a gap in current medical literature. Improved early recognition of coagulopathy in neonates with CG could prevent delays in treatment and improve outcomes.

Humans↗
PubMed1995

Retinopathy in galactosemic dogs continues to progress after cessation of galactosemia.

BACKGROUND: Progression of diabetic retinopathy in human subjects and animal models is difficult to halt promptly by intensified insulin therapy and strict glycemic control. OBJECTIVE: To learn whether this resistance to arrest is peculiar to diabetes and insulin therapy or is a characteristic of hyperglycemia itself, we have determined the effect of intervention on diabetic-like retinopathy in a non-diabetic animal model, the galactose-fed dog. METHODS: Dogs were given a 30% galactose diet. At the end of 24 months, the dogs were divided into two groups, one of which continued to receive the galactose diet, while the second immediately began receiving the diet minus galactose. All animals were killed after 60 months of study. RESULTS: Consumption of the galactose-rich diet resulted, as expected, in galactosemia evident by elevated hemoglobin A1, plasma nonenzymatically glycated protein, and erythrocyte polyol concentrations, each of which decreased to normal levels following withdrawal of dietary galactose. Retinopathy was found to be equivocal at the end of 24 months of the galactose diet and subsequently progressed significantly despite cessation of the galactose diet. CONCLUSION: The fact that retinopathy did not halt promptly at intervention is consistent with previous data from diabetic dogs and suggests that the vascular lesions may be due to sequelae of excessive tissue aldohexose that are not promptly corrected by correction of the aldohexose level.

Animals↗
PubMed1997

An aldose reductase inhibitor and aminoguanidine prevent vascular endothelial growth factor expression in rats with long-term galactosemia.

OBJECTIVE: To study the effects of an aldose reductase inhibitor (ARI-509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents that have been reported to prevent or delay diabetic retinopathy, on retinal vascular abnormalities and the immunocytochemical expression in the retina of vascular endothelial growth factor (VEGF) in rats maintained for up to 2 years on a 50% galactose diet. METHODS: Albino rats were placed on a control diet, a diet containing 50% galactose, or the 50% galactose diet containing either ARI-509 or AMG. Treatment with ARI-509 or AMG was initiated at the beginning of the experiment or after 12 months of galactose feeding. After 22 to 24 months, the rats were killed and the retinal vasculature from half of one eye was isolated by trypsin-elastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immunocytochemistry and stained for the presence of VEGF, factor VIII, vimentin, and glial fibrillary acidic protein. Red blood cells, sciatic nerves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin. RESULTS: Galactose-fed animals developed a vascular retinopathy characterized by severe cellular loss in the retinal capillaries and intensification of periodic acid-Schiff staining of the vascular basement membranes. Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, but were unaffected in all of the other treatment groups. None of the rats receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivity. With the exception of the animals receiving ARI-509 from the beginning of the experiment, all of the galactose-fed animals developed dense cataracts within 6 weeks of the beginning of the galactose diet. Galactitol levels in animals receiving ARI-509 were 86% to 93% lower in red blood cells, retina, and sciatic nerve than those in the other galactose-fed groups. CONCLUSIONS: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galactosemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsible for VEGF expression in the retina, and that aldose reductase inhibitors and AMG have potential roles in preventing such expression and, thus, perhaps preventing retinal neovascularization.

Aldehyde Reductase↗
PubMed2006

Galactosemia: the good, the bad, and the unknown.

Alpha-D-galactose is metabolized in species ranging from E. coli to mammals predominantly via a series of sequential reactions collectively known as the Leloir pathway. Deficiency of any one of these enzymes in humans results in a form of the inherited metabolic disorder, galactosemia, although the symptoms and severity depend upon the enzyme impaired, and the degree of functional deficiency (Tyfield and Walter, 2002, The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill.). Studies of these enzymes, and the disorders associated with their loss, have led to a much deeper appreciation of the intricate and interwoven levels of regulation that govern their normal function. These insights have further identified likely mediators of outcome severity in patients, and have enabled a rational approach to the development of novel strategies of intervention.

Animals↗
PubMed1998

Molecular and biochemical basis of galactosemia.

Galactosemia is a clinically heterogeneous autosomal recessive inborn error of metabolism caused by deficiency of galactose-1-phosphate uridylyltransferase (GALT). Despite the numerous point mutations identified in the GALT gene, the prevalence of these mutations in different ethnic groups has not been studied. Reports on genotype/phenotype correlation are not consistent due to the small sample sizes studied and the lack of a sensitive enzyme assay. We applied multiplex PCR/ASO dot blot analysis to screen 293 galactosemic patients for 17 known point mutations in exons 5, 6, and 10. Our data demonstrate that only 7 of these mutations were detected in our patients, accounting for 65% of the GALT mutant alleles. Although Q188R is the most common mutation in Caucasian and Hispanic patients, the S135L mutation is most common in African-Americans. Another mutation, F171S, was observed only among African-American patients. An improved, sensitive, and accurate method was used to measure GALT activity in patient's red blood cells. The results indicated that patients homozygous for Q188R have no enzyme activity while those homozygous for S135L had residual enzyme activity. Interestingly, both Q188R/S135L and S135L/F171S compound heterozygotes demonstrated zero enzyme activity. Overall, 85% of Q188R compound heterozygotes also did not have any enzyme activity, whereas the remaining Q188R and the majority of S135L compound heterozygotes expressed variable amounts of GALT activity. We speculate that heterodimeric subunit interaction plays an important role in determining the overall enzymatic activity. Various genotypes thus result in biochemical and clinical heterogeneity among the patients.

Amino Acid Substitution↗
PubMed2001

Functional analysis of the human galactose-1-phosphate uridyltransferase promoter in Duarte and LA variant galactosemia.

Human galactose-1-phosphate uridyltransferase (hGALT) is an evolutionarily conserved enzyme central to D-galactose metabolism. The impairment of hGALT causes galactosemia. One missense mutation, an aspartate to asparagine substitution at amino acid 314 (N314D), impairs 50% activity in the homozygous state in some patients but gives near normal activity in others. The former condition is called Duarte (D) and the latter, Los Angeles (LA). The D allele is linked to hGALT polymorphisms including a deletion 5'to the translation start site (-119 to -116delGTCA), g1391G --> A and g1105G --> C. The LA allele is linked to a g1721C --> T transition. To investigate possible mechanisms for differences in hGALT activity between the D and LA alleles, we sequenced 3951 nucleotides of genomic DNA 5' to the hGALT translation start site. Using a dual-luciferase reporter system to express deletion constructs of the hGALT promoter, we noted both positive and negative regulatory regions. Two putative positive regulatory domains overlap with the naturally occurring -119 to -116delGTCA linked to Duarte. One is an E-box motif (CACGTG) at -117 to -112 bp. The second is an AP-1 motif (TCAGTCAG) at -124 to -119 bp. The delGTCA mutation confers reduced luciferase activity to transfected cell lines derived from human ovarian and liver neoplasms. Additionally, human lymphoblasts derived from patients with the Duarte allele have reduced GALT mRNA. We conclude that the human GALT gene is regulated in the first -165 bp of its promoter region by positive regulators of GALT gene expression. The -119 to -116delGTCA reduces hGALT transcription resulting in reduced GALT activity in the Duarte allele.

Alleles↗
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↗
PubMed1994

Biochemical and molecular studies of 132 patients with galactosemia.

We evaluated 132 galactosemia patients for the Q188R (glutamine-188 to arginine) mutation in the human galactose-1-phosphate uridyltransferase (GALT) gene and for GALT activity in their hemolysates by a sensitive radioisotopic method. In those without any detectable GALT activity (GG), the Q188R mutation constituted 67% of the alleles. In patients with detectable GALT activity (GV), only 16% of the alleles were accounted for by Q188R. In all patients who were homozygous for the Q188R mutation, no erythrocyte GALT activity could be demonstrated. There was an extensive variation in the amount of detectable GALT activity ranging from 0.1% to 5% of the normal values among the GV patients. There was a difference in the frequency of Q188R mutation in the GALT alleles among patients belonging to different racial and ethnic groups. In Caucasian and Hispanic patients, the frequency was not far different (64% and 58%, respectively). On the other hand, only 12% of the GALT alleles with Q188R were found in African-American patients.

Adolescent↗
PubMed1979

Isoelectrofocusing of erythrocyte galactose 1 phospho uridyl transferase in a family with both galactosemia and Duarte variants.

A family with the presence of the genes for both galactosemia and the Duarte variant is described. Galactose 1 phospho uridyl transferase has been studied not only by electrophoresis on starch gel, but also by isoelectro-focusing on thin-layer acrylamide. Normal and variant transferases were resolved into three bands, the isoelectric point of which was between 5.40 and 5.10 for the normal subjects, and between 5.25 and 4.95 for subjects with the Duarte variant.

Adult↗
PubMed1977

The Chicago variant of clinical galactosemia.

A new variant of clinical galactosemia with two hitherto unidentified alleles on the transferase locus in one family is described. This new clinical variant of transferase has 25% of normal control activity in blood and in skin fibroblasts, and the patient accumulates galactose-1-phosphate in blood on an unrestricted galactose diet. Using starch gel electrophoresis on the hemolysate of the family members, a fast-moving transferase with mobility in between those of the normal control and of the Duarte variant is identified. This new allele is designated as GALTC1 (fast-moving Chicago variant). In addition, a second new allele was documented in this family by studying the instability of the transferase enzyme in hemolysates of family members at 50 degrees C for various time intervals. This new allele is designated as GALTC2 (heat-labile Chicago variant). On the basis of these studies, the transferase genotype of this patient is thought to be a double heterozygote compound, GALTC1/GALTG.

Alleles↗
PubMed1995

Cognitive functioning, neurologic status and brain imaging in classical galactosemia.

A historical group of 45 children (4-18 years) and adults (18-39 years) with classical galactosemia had deficits of cognitive function that were variable and not related to the age at diagnosis or to severity of illness at presentation. There was a trend for patients to score highest on visual processing tasks. The standardized tests of speech and memory skills fell within the same range as the Broad Cognitive Ability score, indicating that the speech and language deficits may be part of a more global set of cognitive impairments. Scores on the Beery Visual Motor Integration and Block Design Tests fell in approximately the same range as other cognitive abilities. In addition, there was a high incidence of abnormality detected on MRI and 12 patients had neurologic symptoms that included ataxia, tremor and dysmetria. These abnormalities did not correlate with the age at diagnosis, severity of illness at presentation or scores on cognitive testing. The pathophysiology of neurologic and neuropsychologic impairments remains unknown. Since these appear to be unrelated to the duration of galactose exposure, other factors impacting on outcome need to be understood so that strategies can be developed to improve what appears to be a global impairment of cognitive function.

Adolescent↗
PubMed1995

Prenatal diagnosis of galactosemia.

The experience from three different European centres with the prenatal diagnosis of galactose-1-phosphate-uridyltransferase (GALT) deficiency is presented and the question whether or not there is a need for prenatal diagnosis of this disorder is discussed. Most prenatal diagnoses (n = 50) have been performed by assay of GALT activity in cultured amniotic fluid cells. The assay used is reliable and clearly distinguishes homozygous affected fetuses (n = 11; 0%-2.3% of mean control enzyme activity) from non-(homozygous)-affected fetuses. The GALT assay for cultured amniocytes was adapted to assay the enzyme directly in chorionic villi. The experience with chorionic villi comprises 23 cases with 5 affected fetuses (0%-4.2% of mean control enzyme activity). In 36 cases galactitol was determined in amniotic fluid supernatant by gas chromatography-mass spectrometry. This method also differentiated affected (n = 11; galactitol 5.9-10.6 mumol/l) and unaffected pregnancies (galactitol 0.23-1.6 mumol/l) clearly and has the advantage of providing a result within a day or two after amniocentesis. Prenatal diagnosis of galactosemia is undertaken rarely and sometimes for the wrong reasons, but it should perhaps be considered more seriously until better methods of treatment are established.

Amniocentesis↗
PubMed1995

Galactosemia unsolved.

Classic galactosemia is an enigmatic disorder that presents the challenge of unraveling the basis of the long-term complications of mental disability, speech defects, ovarian failure and neurologic syndromes which occur despite a galactose-restricted diet. A complete understanding of the pathobiochemistry and molecular genetics, and evaluation of the present theories for the poor long-term outcome, continuous intoxication, critical metabolite depletion and in utero damage is needed in order to design new therapeutic strategies. Answering this urgent question of how to treat galactosemic patients mandates enhanced clinical and basic research efforts.

Galactosemias↗
PubMed2004

Galactokinase: structure, function and role in type II galactosemia.

The conversion of beta- D-galactose to glucose 1-phosphate is accomplished by the action of four enzymes that constitute the Leloir pathway. Galactokinase catalyzes the second step in this pathway, namely the conversion of alpha- D-galactose to galactose 1-phosphate. The enzyme has attracted significant research attention because of its important metabolic role, the fact that defects in the human enzyme can result in the diseased state referred to as galactosemia, and most recently for its utilization via 'directed evolution' to create new natural and unnatural sugar 1-phosphates. Additionally, galactokinase-like molecules have been shown to act as sensors for the intracellular concentration of galactose and, under suitable conditions, to function as transcriptional regulators. This review focuses on the recent X-ray crystallographic analyses of galactokinase and places the molecular architecture of this protein in context with the extensive biochemical data that have accumulated over the last 40 years regarding this fascinating small molecule kinase.

Animals↗
PubMed1983

Transferase-deficiency galactosemia: evidence for the lack of a transferase protein in galactosemic red cells.

Red blood cell lysates from normal individuals, a homozygous Duarte variant, and a patient with transferase-deficiency galactosemia were challenged with rabbit antibody to pure human placental galactose-1-phosphate uridylyltransferase. Although the antibody quantitatively precipitated the enzymatically active proteins in the normal and Duarte hemolysates, the Duarte sample absorbed only about one-half as much antibody as did the normal. In contrast, the antibody did not react with the galactosemic hemolysate.

Adult↗