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PubMed2000

Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia.

PURPOSE: To examine the relationship between early retinal capillary cell apoptosis and late histologic lesions of diabetic retinopathy and to compare the effects of aminoguanidine (AMG) on the retinopathies caused by diabetes and galactose feeding. METHODS: Rats with alloxan-induced diabetes and rats fed a 30% galactose diet (known to induce diabetic-like retinopathy) were assigned randomly to receive diet with (2.5 g/kg diet) or without AMG. After 6 to 8 months of diabetes or galactosemia, retinal trypsin digests were prepared, and capillary cell apoptosis was quantitated using the Tdt-mediated dUTP nick-end labeling (TUNEL) reaction in association with morphologic evidence of nuclear fragmentation. At 18 months duration, pericyte ghosts and acellular capillaries were quantitated in the isolated vasculature. Several advanced glycation end products (AGEs) were measured at 4 months of study and at 18 months of study by established methods to assess biochemical effects of AMG. RESULTS: As expected, both diabetic and galactosemic rats showed increased frequency of TUNEL-positive capillary cells at 6 to 8 months and vascular lesions characteristic of retinopathy at 18 months. AMG inhibited both the early apoptosis and late histopathology in the diabetic rats, but neither of these abnormalities in the galactosemic rats. In contrast to its preventative effect on retinopathy in the diabetic rats, AMG showed no inhibitory effect on levels of hemoglobin AGE, or tail collagen pentosidine, fluorescence, and thermal breaking time. Diabetes of 4 months' duration did not cause a detectable increase in retinal levels of several AGEs. CONCLUSIONS: The frequency of early apoptosis in retinal microvascular cells predicted the development of the histologic lesions of retinopathy in diabetes as well as in galactosemia. The beneficial effect of AMG on retinal lesions in diabetes is exerted on pathways that are either not operative or are less important in galactosemia and that may not relate to the accumulation of AGEs.

Animals↗

PubMed1999

Screening for galactosemia: Philippines experience. Newborn Screening Study Group.

Galactosemia is an inborn error of galactose metabolism due to a deficiency of any of the galactokinase, galactose-1-phosphate uridyl transferase (GALT), or epimerase enzymes. The Philippines, with its pilot newborn screening project, has been screening for this disorder for 2 years now. A total of 62,841 babies have been screened using the galactose and galactose-1-phosphate spot test. Confirmatory testing is done by the newborn screening laboratory of the The New Children's Hospital in Westmead, Australia. Two cases of galactosemia: 1 classical galactosemia and 1 galactokinase deficiency have so far been confirmed. Clinical review, problems encountered, and management are described. Long-term outcome of these patients, however, is yet to be determined.

Female↗

PubMed1975

[A case of atypical galactosemia(author's transl)].

The case of a male infant suffering from clinical manifest galactosemia in connexion with a disease of only about 70% in uridyltransferase activity is characterized as atypical galactosemia. As compared with the described "Indiana variant" of a galactosemic female infant showing an unstable uridyltransferase activity this case demonstrates an unchanged enzyme activity still after 72 hrs. The metabolic disease of this patient clearly demonstrated that the lack of a typical pronounced reduction of enzyme activity maybe not the leading criterion for excluding the clinical diagnosis of galactosemia. In the present case only the consistent galactose-free diet lead to the decisive improvement of the clinical picture. The investigation of the family revealed the typical pattern of an autosomal recessive mode of heredity.

Erythrocytes↗

PubMed2001

Selective screening for neonatal galactosemia: an alternative approach.

UNLABELLED: No universal consensus exists for population-based neonatal screening for galactosemia. In our institution, selective screening for classical galactosemia is carried out on infants under 2 wk of age and those with symptoms suggestive of this disorder. Eighteen cases were diagnosed from 25,099 tests done; 17 were symptomatic at the time of diagnosis. CONCLUSION: We suggest that improved clinical vigilance and selective screening would identify most infants with severe galactosemia as early as a population-based program.

Biomarkers↗

PubMedDate not supplied

Association of Escherichia coli sepsis and galactosemia in neonates.

Galactosemia in newborns and infants is associated with the following symptoms: jaundice, hepatomegaly, failure to thrive, feeding difficulties, hypoglycemia, convulsions, lethargy, amino-aciduria, cataracts, hepatic cirrhosis, ascites, and mental retardation. If the preliminary evaluation indicates galactosemia, there is high risk for E. coli sepsis and death. Strong consideration should therefore be given for early antibiotic therapy in infants with suspected galactosemia in spite of the absence of clinical signs or symptoms of sepsis.

Escherichia coli Infections↗

PubMed2004

Diagnosis and management of galactosemia: an Egyptian experience.

OBJECTIVE: To screen normal and high risk Egyptian neonates for galactosemia. SUBJECTS AND METHODS: The study included 2238 neonates classified into two groups. Group I included screening of 1794 normal newborns. Group II included 374 high risk neonates (jaundice, hepatomegaly and failure to thrive). Group III 70 prematures. Total galactose was determined by enzymatic colourimetric method in dried blood spot (Quantase). The enzymes activities (uridyltransferase and epimerase) were measured using C14. RESULTS: One case of galactosemia was found in the first group and 26 cases in the second group. 19 patients suffered from uridyltransferase deficiency, the parents of 16 (88.8%) of this classic form were consanguineous and 5 (27.7%) parents had history of a previously affected child. Mean age of diagnosis was 3.8 month with a mean total gal value of 52.9 mg/dl. 10 (55.5%) of them have cataract. The other 8 affected neonates were epimerase deficiency patients. 5 (62.5%) of them born to consanguineous parents. Parents of the epimerase deficiency neonates have no previously affected children. Mean age of diagnosis was 7.2 month with a mean total gal of 17.5 mg/dl. All eight patients have cataract. CONCLUSION: Mass screening program is not available yet in Egypt. Screening of the high risk neonates is a priority. Diagnosis of different galactosemia forms is mandatory to structure the management strategy accordingly. (Fig. 4, Ref: 26.)

Egypt↗

PubMed1989

Pitfalls in diagnosing galactosemia: false negative newborn screening following red blood cell transfusion.

Newborn galactosemia screening programs using the fluorescence spot test to detect red cell galactose-1-phosphate uridyltransferase activity are prone to inaccuracy if the screened infants have received blood transfusions. We describe an infant with galactosemia who received packed red cell transfusions in the first few days of life and was misdiagnosed after an initial positive screening test result. Although the patient was thought to have cytomegaloviral hepatitis, a percutaneous liver biopsy helped direct the evaluation toward identifying the galactosemia carrier state in both parents. This case report illustrates the need for careful consideration of the patient's history of transfusion of blood products when evaluating newborn screening results.

Blood Transfusion↗

PubMed1989

Newborn screening for galactosemia: a new method used in Manitoba.

In July 1983, the Manitoba Perinatal Screening Programme modified its existing procedure for neonatal screening for galactosemia by introducing quantitation of total galactose plus galactose-1-phosphate from dried blood spots using the Multistat centrifugal analyzer. The first 4 years of experience with this method in combination with the Beutler spot test for galactose-1-phosphate uridyl transferase activity is the subject of this report. Of 70,336 newborns screened, 142 (0.20%) met the criteria for clinical follow up. Of these, one child was confirmed to have classical galactosemia and nine children were found to be Duarte/galactosemia genetic compounds. This method of galactosemia screening has proven to be rapid, sensitive, efficient, and the method of choice for mass screening of disorders of galactose metabolism.

Galactose↗

PubMed1985

Screening of newborn infants for galactosemia in British Columbia.

With simple microbiologic and fluorescent tests, we detected two cases of classic galactosemia, confirmed by specific enzyme assays, in the first 25 000 newborn infants in British Columbia screened for this disorder. The results were equivocally abnormal for another 31 infants, and a second blood sample was requested from each, either for repeat screening or for enzyme assays. The two infants with galactosemia were in hospital with an undiagnosed acute illness and had only a trace of non-glucose reducing substances in the urine when the screening tests were done. Screening for galactosemia fits well with our established programs of screening for phenylketonuria and hypothyroidism and costs less than $1 per infant tested.

British Columbia↗

PubMed1978

Galactosemia as a result of galactose-1-phosphate uridyltransferase deficiency.

This study was designed to determine the activity of galactose-1-phosphate uridyltransferase enzyme in a family (parents and eight children): four of these with clinical diagnosis of classical galactosemia. In two of them a complete transferase deficiency was found, thus confirming diagnosis; the other two, a pair of dizygotic twins, who since birth up to 11 years of age had been on a galactose free diet, showed enzymatic activity consistent with normal heterozygotes, one of them, and with normal homozygotes, the other. The parents and four brothers had the same enzyme activity levels an those found in heterozygotes for galactosemia. Early diagnosis is of utmost importance in classical galactosemia, and we emphasize this point because patients can be treated with dietotherapy and primary prevention is possible through genetic counseling.

Adolescent↗

PubMed1995

Galactosemia: clinical features, diagnosis and management. A case report.

The case report and discussion presented here were prepared in response to legislation in Louisiana which requires that the Dept of Health and Hospitals establish a program to inform physicians and hospitals of the current medical standards for the diagnosis, clinical management, and recognition of galactosemia. Classical galactosemia is an inborn error of galactose metabolism caused by a deficiency of galactose-1-phosphate uridryl transferase. It is inherited as an autosomal recessive trait and its estimated occurrence is 1/60,000. The presenting symptoms which include vomiting, diarrhea, jaundice, and failure to thrive result from the ingestion of foods containing galactose--breast milk and formulas containing cow's milk. Although some states routinely screen all newborns for galactosemia, the results of the newborn screening are often not available before the infant presents with symptoms. Early recognition and immediate withdrawal of galactose from the diet can prevent serious morbidity and mortality. There is significant clinical variability and not all infants present with typical acute manifestations of the disease.

Diagnosis, Differential↗

PubMed2003

Galactosemia.

Despite the dramatic response of sick neonates with galactosemia to the withdrawal of galactose from the diet, over the long-term, complications, including learning disorders, verbal apraxia, and ataxia, often develop. It is clear that, although lifelong galactose restriction remains the basis of treatment for this disease, additional treatment methods are needed. The neurologist familiar with galactosemia can assist in diagnosis of neonates presenting with central nervous system symptoms. Familiarity with the long-term neurologic consequences of galactosemia can help the neurologist assist the family with prognostic information and to avoid unnecessary tests when complications occur.

Journal Article↗

PubMed2003

Galactosemia: a treatable metabolic disorder.

Galactosemia is a rare metabolic disorder. It has good prognosis, if detected in neonatal period or early infancy. Two cases of classic galactosemia are presented. One case was detected in neonatal period. Early intervention has led to normal development till now. The second case was diagnosed at 1 year of age. Elimination of milk from diet is quite simple and effective treatment modality.

Failure to Thrive↗

PubMed1996

Capillary lesions develop in retina rather than cerebral cortex in diabetes and experimental galactosemia.

OBJECTIVE: To isolate microvessels from cerebral cortex of dogs with alloxan-induced diabetes and dogs with experimental galactosemia to compare the prevalence of microvascular lesions in cerebral cortex with that in retina. METHODS: Microvessels were isolated from cerebral cortex of experimental animals using a sieving method, and compared with the retinal vasculature isolated from the same animals using the trypsin digestion method. RESULTS: Dogs with diabetes or experimental galactosemia of 5 years' duration had retinopathy that was morphologically indistinguishable from that of humans with diabetes, including microaneurysms, acellular capillaries, and pericyte ghosts. These lesions never were seen in cerebral cortical vessels of the same animals. The only morphologic abnormality observed in cerebral capillaries of dogs with diabetes and dogs fed galactose was thickening of basement membrane. CONCLUSIONS: Local influences in the eye apparently play an important role in the development of diabetic retinopathy. Current hypotheses about the pathogenesis of the retinopathy do not account adequately for such differences in the tissue distribution of vascular lesions.

Animals↗

PubMed1999

Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.

Classical galactosemia is caused by a deficiency in activity of the enzyme galactose-1-phosphate uridyl transferase (GALT), which, in turn, is caused by mutations at the GALT gene. The disorder exhibits considerable allelic heterogeneity and, at the end of 1998, more than 150 different base changes were recorded in 24 different populations and ethnic groups in 15 countries worldwide. The mutations most frequently cited are Q188R, K285N, S135L, and N314D. Q188R is the most common mutation in European populations or in those predominantly of European descent. Overall, it accounts for 60-70% of mutant chromosomes, but there are significant differences in its relative frequency in individual populations. Individuals homoallelic for Q188R tend to have a severe phenotype and this is in keeping with the virtually complete loss of enzyme activity observed in in vitro expression systems. Globally, K285N is rarer, but in many European populations it can be found on 25-40% of mutant chromosomes. It is invariably associated with a severe phenotype. S135L is found almost exclusively in African Americans. In vitro expression results are discrepant, but some individuals carrying S135L appear to exhibit GALT activity in some tissues. Duarte 1 (or Los Angeles) and Duarte 2 (or Duarte) variants carry the same amino acid substitution, N314D, even though D1 is associated with increased erythrocyte GALT activity and D2 with reduced activity. N314D is in linkage disequilibrium with other base changes that differ on the D1 and D2 alleles. N314D does not impair GALT activity in in vitro expression systems. However, there are differences in the abundance of GALT protein in lymphoblastoid cells lines from D2 and D1 individuals. It is unclear whether the specific molecular changes that distinguish the D1 and D2 alleles account for the different activities. The considerable genetic heterogeneity documented to date undoubtedly contributes to the phenotypic heterogeneity that is observed in galactosemia. The additional effects of nonallelic variation and other constitutional factors on phenotypic variability remain to be elucidated.

Alleles↗

PubMed2001

Proton magnetic resonance spectroscopy of brain metabolites in galactosemia.

Brain edema may occur in infants with galactosemia and has been associated with accumulation of galactitol. Proton magnetic resonance spectra were obtained from 12 patients (four newly diagnosed neonates and eight patients on galactose-restricted diets, age range 1.7-47 years) and control subjects to measure brain galactitol levels in vivo and correlate them with urinary galactitol excretion. The results demonstrate that a markedly elevated brain galactitol level may be present only in newborn infants with galactosemia who exhibit massive urinary galactitol excretion.

Adolescent↗

PubMed2002

Molecular analysis in newborns from Texas affected with galactosemia.

The spectrum of mutations in the Galactose-1-phosphate uridyl transferase (GALT) gene is described in 11 cases of classic galactosemia and 38 of Duarte-2 type identified by the Texas Newborn Screening Program. Blinded studies were done by automated DNA sequencing of all the 11 exons and the exon-intron boundaries of the GALT gene using genomic DNA isolated from dry blood spots. Fourteen different mutations (11 missense mutations, 2 nonsense mutations and 1 splicing mutation) were detected in 94 of the 98 mutant alleles (diagnostic efficiency of 96%). The prevalent mutations were N314D (41%), Q188R (37%) and K285N (4%). The other less frequent mutations were IVS2-2A>G and S135L (3% each), T138M (2%) and T23A, H184Q, Y251S, L195P, Q207X, L264X, Q344K, and A345D (1% each). Three novel mutations, T23A, Q207X, and A345D, were identified. Our study supports previous findings that N314D and Q188R are prevalent in Hispanics and Whites and K285N was only observed in Whites. The IVS2-2A->G mutation is probably ethnic specific because it was identified exclusively in Hispanics. S135L, a prevalent mutation in Blacks, was also present in 3 Hispanics. Two unusual genotypes were observed in 2 patients homozygous for the Duarte-2 N314D allele and heterozygous for a novel mutation (Q207X- N314D/N314D in a classic galactosemia and T23A- N314D/N314D in a Duarte-2 case). The detection of GALT gene mutations in newborns from Texas should focus first on N314D, Q188R, K285N, IVS2-2A>G, S135L and T138M. Other exons and exon-intron boundaries would have to be studied if either one or no mutations are found in the primary screening.

DNA Mutational Analysis↗

PubMed1995

In vivo study of brain metabolism in galactosemia by 1H and 31P magnetic resonance spectroscopy.

In order to further evaluate different hypotheses concerning brain metabolism in galactosemia, six adult patients aged 18-29 years with classical galactosemia under dietary treatment underwent localized 1H and 31P magnetic resonance spectroscopy (MRS) in addition to conventional T1- and T2-weighted MRI. Galactose-1-phosphate levels in erythrocytes were 1.1-3.7 mg/dl, plasma concentrations of galactitol ranged from 8.4-14.2 mumol/l. Imaging revealed abnormal peripheral myelination in five and enlargement of lateral ventricles in two patients. Brain galactitol in parieto-occipital white matter was below detectability of 1H MRS leading to the assumption that brain concentrations of the free metabolite was well below 1 mmol/kg. Signal intensities of free myo-inositol, which was postulated to be indicative of changes in the second messenger pathway, were within the normal range. MRS data revealed a normal energy status of the brain. In summary 1H and 31P MRS indicated normal metabolite concentrations as compared to healthy controls.

Adolescent↗