Sugar Alcohols of Polyol Pathway Serve as Alarmins to Mediate Local-Systemic Innate Immune Communication in Drosophila.

Interorgan immunological communication is critical to connect the local-systemic innate immune response and orchestrate a homeostatic host defense. However, the factors and their roles in this process remain unclear. We find Drosophila IMD response in guts can sequentially trigger a systemic IMD reaction in the fat body. Sugar alcohols of the polyol pathway are essential for the spatiotemporal regulation of gut-fat body immunological communication (GFIC). IMD activation in guts causes elevated levels of sorbitol and galactitol in hemolymph. Aldose reductase (AR) in hemocytes, the rate-limiting enzyme of the polyol pathway, is necessary and sufficient for the increase of plasma sugar alcohols. Sorbitol relays GFIC by subsequent activation of Metalloprotease 2, which cleaves PGRP-LC to activate IMD response in fat bodies. Thus, this work unveils how GFIC relies on the intermediate activation of the polyol pathway in hemolymph and demonstrates that AR provides a critical metabolic checkpoint in the global inflammatory response.

Assessment of lactase activity in humans by measurement of galactitol and galactonate in serum and urine after milk intake.

Background: Lactase is an enzyme that hydrolyzes lactose into glucose and galactose in the small intestine, where they are absorbed. Hypolactasia is a common condition, primarily caused by genetic programming, that leads to lactose maldigestion and, in certain cases, lactose intolerance. Galactitol and galactonate are 2 products of hepatic galactose metabolism that are candidate markers for the intake of lactose-containing foods. Objectives: The primary objective of the study was to explore the changes in serum and urine metabolomes during postprandial dairy product tests through the association between lactase persistence genotype and the postprandial dynamics of lactose-derived metabolites. Methods: We characterized the 6-h postprandial serum kinetics and urinary excretion of lactose, galactose, galactitol, and galactonate in 14 healthy men who had consumed a single dose of acidified milk (800 g) which contained 38.8 g lactose. Genotyping of LCT-13910 C/T (rs4988235) was performed to assess primary lactase persistence. Results: There were 2 distinct postprandial responses, classified as high and low metabolite responses, observed for galactose, and its metabolites galactitol and galactonate, in serum and urine. In all but 1 subject, there was a concordance between the high metabolite responses and genetic lactase persistence and between the low metabolite responses and genetic lactase nonpersistence (accuracy 0.92), galactitol and galactonate being more discriminative than galactose. Conclusions: Postprandial galactitol and galactonate after lactose overload appear to be good proxies for genetically determined lactase activity. The development of a noninvasive lactose digestion test based on the measurement of these metabolites in urine could be clinically useful. This trial was registered at clinicaltrials.gov as NCT02230345.

Monitoring of biochemical status in children with Duarte galactosemia: utility of galactose, galactitol, galactonate, and galactose 1-phosphate.

BACKGROUND: Duarte galactosemia (DG) is frequently detected in newborn-screening programs. DG patients do not manifest the symptoms of classic galactosemia, but whether they require dietary galactose restriction is controversial. We sought to assess the relationships of selected galactose metabolites (plasma galactose, plasma galactitol, erythrocyte (RBC) galactitol, RBC galactonate, and urine galactitol and galactonate) to RBC galactose 1-phosphate (Gal-1-P), dietary galactose intake, and neurodevelopmental/clinical outcomes in DG children. METHODS: We studied 30 children 1-6 years of age who had DG galactosemia and were on a regular diet. All participants underwent a physical and ophthalmologic examination and a neurodevelopmental assessment. RBC galactitol, RBC galactonate, RBC Gal-1-P, plasma galactose, plasma galactonate, and urine galactitol and galactonate concentrations were measured. RESULTS: RBC galactitol and galactonate concentrations were about 2 and 6 times higher, respectively, than control values. Plasma galactose and galactitol concentrations were also about twice the control values. The mean values for RBC Gal-1-P and urine galactitol were within the reference interval. We found a relationship between plasma and urine galactitol concentrations but no relationship between RBC galactose metabolites and urine galactitol. There was a significant relationship between galactose intake and RBC galactose metabolites, especially RBC galactitol (P < 0.0005) and RBC galactonate (P < 0.0005). Galactose intake was not related to the urine galactitol, plasma galactose, or plasma galactitol concentration. RBC galactitol, RBC galactonate, plasma galactose, plasma galactitol, and urine galactonate concentrations showed no relationship with clinical or developmental outcomes. CONCLUSIONS: DG children on a regular diet have RBC Gal-1-P concentrations within the reference interval but increased concentrations of other galactose metabolites, including RBC galactitol and RBC galactonate. These increased concentrations correlate with galactose intake and neither cause any developmental or clinical pathology during early childhood nor oblige a lactose-restricted diet.

Galactitol and galactonate in red blood cells of children with the Duarte/galactosemia genotype.

We measured galactitol, galactonate, and galactose-1-phosphate in the red blood cell (RBC) to elucidate the biochemical phenotype of infants with a Duarte/galactosemia (D/G) genotype by isotope dilution GC/MS. The RBC galactonate, galactitol and Gal-1-P were quantified in 14 D/G newborns on a lactose containing formula or breast milk, eight D/G newborns on a galactose-free formula, and 18 D/G children between 1 and 2 years of age that were on a regular diet. The results were compared with those of non-galactosemic subjects of comparable age. In the D/G newborns on regular formula/breast milk, the levels of RBC galactitol, galactonate, and Gal-1-P were significantly higher than those of D/G newborns on diet treatment and non-galactosemic newborns. There was no difference in the levels of RBC galactitol, galactonate, and Gal-1-P between D/G newborns on a lactose-restricted diet and the control group. There appears to be two different responses to dietary galactose intake in D/G children. The first group of D/G children placed on a regular diet after a year of lactose restriction had higher RBC galactitol, galactonate levels than those of non-galactosemic children. The mean level of RBC galactonate was higher and the mean value of RBC galactitol was as high as that of galactosemic (G/G) patients on diet treatment. The second group of D/G children on a regular diet had normal levels of RBC galactitol and galactonate. The levels of RBC Gal-1-P were normal in both groups of D/G patients. The alternative pathway products may reflect galactose intake better than RBC Gal-1-P in D/G children.

Age dependence of endogenous galactose formation in Q188R homozygous galactosemic patients.

The age dependence of endogenous galactose formation was investigated in Q188R homozygous galactosemic patients (n=18; 4-38 years) using the primed continuous infusion approach with D-[1-13C]galactose as a substrate. Studies were conducted under postabsorptive conditions (fasting >10h) and good metabolic control. In the patients, the release of galactose from endogenous sources into plasma (R(a)) decreased with age and ranged from 4.6 to 2.0 micromol/kg body weight per h. Galactitol and galactonate release rates paralleled the galactose R(a) but at a lower level. The mean relation of galactose, galactitol, and galactonate release was 10:5:1. Statistically, there was a highly significant (p<0.0001) inverse correlation between total galactose release (i.e., sum of R(a) plus galactitol and galactonate release) and age. The data (total galactose=y, age=t) were best fitted to the simple exponential model y=y(0)+axexp(-bt) by non-linear regression analysis. The parameter estimates were y(0)=3.0+/-0.2, a=6.5+/-0.4, and b=0.11+/-0.02. The value of y(0) provides an estimate of total galactose release in adult patients (i.e., approximately 13 mg/kg body weight per day), summation operator (y(0)+a) provides an estimate for galactosemic newborns (i.e., approximately 41 mg/kg body weight per day). The data show that significant amounts of endogenous galactose are formed in galactosemic patients with release rates being several fold higher in infants than in adults. The present findings can explain the persistently elevated galactose-1-phosphate levels in erythrocytes-and its age dependence-in galactosemic patients even when under strict dietary treatment.

Galactitol and galactonate in red blood cells of galactosemic patients.

The red blood cell (RBC) concentration of galactitol and galactonate was measured in 27 patients with galactose-1-phosphate uridyltransferase (GALT) deficiency galactosemia and 19 non-galactosemic subjects by a newly devised isotope dilution gas chromatography/mass spectrometry (GC/MS) method. The method utilizing UL[13C]galactitol and UL[13C]galactonate was reproducible with excellent precision and recovery of 99%. The RBC galactitol in galactosemic patients on galactose-restricted diets averaged 5.98+/-1.2 microM (M+/-SD) with a range of 3.54-8.81 microM. The mean in non-galactosemic patients was 0.73+/-0.31 microM with a range of 0.29-1.29 microM. The mean of RBC galactonate in the same galactosemic patients was 4.16+/-1.32 microM (M+/-SD) with a range of 0.68-6.47, while the mean in non-galactosemic subjects was 1.94+/-0.96 (M+/-SD) with a range of 0.69-3.84. In galactosemic RBC the galactitol was higher than galactonate while this was reversed in non-galactosemic cells. RBC galactose-1-phosphate (Gal-1-P) measured at the same time as galactitol and galactonate was 30 times the level of the other two metabolites. There was no relationship between RBC Gal-1-P and galactitol or galactonate. The ability to measure all three galactose metabolites in the same procedure offers the possibility of augmented monitoring of the galactose metabolic status of patients. The measurement of RBC galactitol and galactonate presents a new means of characterizing galactosemic patients and their levels monitored over time may provide new insight in the development of long-term complications observed in afflicted patients.

Stable-isotope dilution analysis of galactose metabolites in human erythrocytes.

An established gas chromatography/mass spectrometry (GC/MS) method, devised for stable-isotope dilution analysis of plasma galactose, was developed to allow determination of erythrocyte (red blood cell, RBC) concentrations of galactose-1-phosphate and other primary metabolites relevant in galactosaemia. Galactose-1-phosphate was enzymatically converted to galactose, and the aldononitrile pentaacetate derivative was separated by gas chromatography and determined by mass spectrometry using chemical ionisation and selected ion monitoring of the [MH-60](+) ion. U-(13)C-Labelled standard was used for quantification. Comparative measurements were conducted using established fluorimetric and radiometric enzymatic methods. The GC/MS analysis for galactose-1-phosphate was linear (range examined 0-600 micromol/L(RBC), packed cells), of acceptable repeatability at low and high concentrations (within and between run CVs <15%), with a limit of quantification of 0.01 micromol/L(RBC). With samples from patients with classical galactosaemia there was a linear correlation with conventional enzymatic assays (r(2) > 0.927). In erythrocytes from post-absorptive patients under treatment, Q188R-heterozygous parents, and healthy subjects, galactose-1-phosphate concentrations (mean +/- SD) were found to be 142 +/- 38 (n = 41), 1.4 +/- 0.2 (n = 8), and 1.9 +/- 0.5 (n = 33) micromol/L(RBC), respectively. In comparison, free galactose concentrations were 3.8 +/- 1.7, 0.49 +/- 0.19, and 0.43 +/- 0.20 mol/L(RBC), respectively. The procedure allowed simultaneous galactitol analysis and proved to be useful to trace incorporation of (13)C-label into erythrocyte galactose metabolites in a D-[1-(13)C]galactose in vivo turnover study.

Minalrestat and leukocyte migration in diabetes mellitus.

BACKGROUND: We recently demonstrated that aldose reductase inhibition was effective in restoring the reduced migratory capacity of leukocytes in diabetic rats. To investigate the mechanism(s) involved in the restoring effect, we used minalrestat, an aldose reductase inhibitor. METHODS: In sodium pentobarbital-anesthetized (40 mg/kg, intraperitoneally) alloxan-diabetic or galactosemic male Wistar rats, the internal spermatic fascia was exteriorized, and the number of leukocytes rolling along the venular endothelium and the number of leukocytes sticking to the vascular wall after topical application of zymosan-activated plasma or leukotriene B(4) (1 ng/ml), as well as after the application of a local irritant stimulus (carrageenan, 100 microg), were determined using intravital microscopy. Data from animals that were treated with and those that were not treated with minalrestat (10 mg/kg/d by gavage) were compared. RESULTS: The reduced number of leukocytes rolling along the venular endothelium (by about 70%) and the number of adhered and migrated leukocytes in postcapillary venules (by 60%) were significantly restored to control values after minalrestat treatment. Total or differential leukocyte counts, venular blood flow velocity or wall shear rate were not altered by minalrestat treatment. The expression of ICAM-1 and P-selectin, cell adhesion molecules involved in the interaction of leukocyte-endothelium, reduced in diabetic rats was restored by minalrestat treatment. CONCLUSION: We conclude that an enhanced flux through the polyol pathway might be involved in the reduced expression of ICAM-1 and P-selectin contributing to the impaired leukocyte-endothelial interactions in diabetes mellitus and that aldose reductase inhibition restores the defect, restoring the reduced expression.

Mutations in galactose-1-phosphate uridyltransferase gene in patients with idiopathic presenile cataract.

Impaired activity of the enzyme galactose-1-phosphate uridyltransferase (GALT) has been proposed as a risk factor for idiopathic presenile cataract. A study was undertaken to determine the prevalence of the three most common mutations in the GALT gene (Q188R, K285N and N314D, including its variant Duarte-2) in a group of Slovenian patients with idiopathic presenile cataract. GALT activity was determined in the erythrocytes of 30 cataract patients. DNA was isolated from their blood and analysed for Q188R, K285N and N314D mutations and IVS5-24G>A intronic variation by means of polymerase chain reaction and digestion with restriction enzymes. The average GALT activity of the cataract group was 19.5+/-4.9 U/g Hb, which is lower than the normal range (p = 0.034). Frequencies of Q188R, K285N, N314D and Duarte-2 alleles in the cataract group were 0.00%, 5.0%, 11.7% and 3.3%, respectively. Only the frequency of the K285N mutation was significantly higher in the patient group than in the control group (p = 0.0244). Our results support the reported association of decreased GALT activity with idiopathic presenile cataract. Molecular analysis indicates that, in the Slovenian population, this association is linked to the K285N mutation, which is neonatally benign in heterozygotes.

Identification of galactitol and galactonate in red blood cells by gas chromatography/mass spectrometry.

BACKGROUND: Because the products of alternate pathways of galactose metabolism, galactitol and galactonate are important in galactosemia, we sought to identify these compounds in red blood cells (RBC). METHODS: RBC extracts were trimethylsilylated (TMS) and analyzed by gas chromatography/mass spectrometry (GC/MS). RESULTS: The presence of both galactitol and galactonate was identified in RBC of 15 galactosemic and 13 normal subjects by their mass spectra and chromatographic comparisons with both unlabeled and 13C labeled standards. The levels in RBC of galactosemics appear to be much higher than those of normal subjects. CONCLUSION: The determination of these compounds in RBC along with galactose-1-phosphate (gal-1-P) in the same procedure provides the potential for their use in better monitoring of diet therapy in galactosemic patients.

Plasma galactose and galactitol concentration in patients with galactose-1-phosphate uridyltransferase deficiency galactosemia: determination by gas chromatography/mass spectrometry.

The plasma concentration of galactose and galactitol was measured in 27 patients with galactose-1-phosphate uridyltransferase (GALT) deficiency galactosemia on a lactose-restricted diet, 17 infants on lactose-free formula, and 21 infants and children on a normal diet, by a newly devised isotope dilution gas chromatograph/mass spectrometry (GC/MS) method. The method was linear in the range of 0.1 to 10 micromol/L for galactose and 1 to 20 micromol/L for galactitol with good reproducibility and a coefficient of variation less than 3%. The mean plasma galactose in 15 patients who were homozygous for the most common Q188R mutation of the GALT gene was 2.72 +/- 0.70 micromol/L (mean +/- SE) with a range of 0.58 to 3.98 in specimens obtained at regular clinic visits. In 12 patients with other GALT mutations, it was 2.45 +/- 0.75 micromol/L. The mean value in nongalactosemic subjects on lactose-free formula was 0.52 +/- 0.08 micromol/L, with a range of 0.12 to 1.25. The range in 21 normal subjects without diet restriction was 0.11 to 6.33 micromol/L, with a mean of 1.48 +/- 0.32. The plasma galactitol level was 11.63 +/- 0.46 and 10.85 +/- 1.38 micromol/L in the 2 galactosemic groups. There was no relationship between plasma galactose and galactitol levels, with variable ratios of the two substances in the galactosemic patients. Galactitol was not detectable in the plasma of normal subjects. The red blood cell galactose-1-phosphate level was also measured in the galactosemic patients, and no relationship between plasma galactose and red blood cell galactose-1-phosphate was found. The galactose-1-phosphate concentration was 28 to 54 times higher than the ambient galactose. The low galactose concentration in the plasma of galactosemics on galactose-restricted diets in relation to the higher plasma galactitol and red blood cell galactose-1-phosphate is a metabolic enigma. The ability to measure plasma galactose accurately presents a new way of characterizing the galactosemic patient and the levels monitored over time may provide insight into the development of long-term complications associated with the disorder.

[Familial cataract in plasma galactitol increase without known enzyme defect]. / Familiäre Katarakt bei Galaktitol-Erhöhung im Plasma ohne bekannten Enzymdefekt.

BACKGROUND: Several enzyme defects of the galactose pathway may lead to cataract formation. We report on a family with familiar cataract. PATIENTS: A 2-year-old Turkish girl (daughter of first cousins) presented with dense cortical and subcapsular opacifications and mature cataract respectively. Bilateral phacectomy, planned posterior capsulotomy, transpapillary vitrectomy and implantation of a posterior chamber lens were performed. The child was otherwise healthy and the pregnancy had been unremarkable. The 25-year-old mother showed circumscribed drop-like opacities of the lens cortex bilaterally, the 5-year-old sister a diffuse opacification of the lens cortex in both eyes, the 27-year-old father and the 13-year-old uncle clear lenses. RESULTS: The girl's level of galactitol was elevated to 2.8 nmol/ml in the plasma (normal values 0.25-1.13 nmol/ml) and to 3.1 nmol/mg protein in the lens (normal values 0.5-1.7 nmol/mg protein). The levels of galactose-1-phosphate in RBC and sorbitol in plasma were in the normal range. The enzyme activities of galactokinase, galactose-1-phosphate uridyl transferase, UDP-galactose epimerase and sorbitol dehydrogenase in RBC, as well as the sorbitol dehydrogenase activity in the lens were in the normal range. The sister and the uncle both had slightly elevated plasma galactitol levels. CONCLUSIONS: Cataract-formation in this family is most likely due to a defect in the galactitol pathway, e.g. cataract in galactosemia without known enzyme defect (Shin-Jakobs disease). In patients with unexplained congenital or infantile cataracts, disorders of the polyol pathway should be thoroughly checked for to ensure a therapeutic diet if necessary.

Urine and plasma galactitol in patients with galactose-1-phosphate uridyltransferase deficiency galactosemia.

Urinary excretion of galactitol was determined in 95 normals (N/N), 67 galactosemic (G/G), and 39 compound heterozygotes for the Duarte and galactosemia genotype (D/G). Galactitol excretion is age-dependent in both normal individuals and patients with classic galactosemia on lactose-restricted diets. In galactosemic patients who are homozygous for the Q188R mutation, urinary galactitol levels were fivefold to 10-fold higher than those of normal subjects of comparable age. All but a few patients with classic galactosemia with the Q188R mutation and another mutant G allele had urinary excretion comparable to the Q188R homozygous patients. African-American galactosemic patients with the S135L mutation of the galactose-1-phosphate uridyltransferase (GALT) gene also excreted abnormal quantities of galactitol. Most subjects with a Duarte allele and a G allele excrete normal amounts of the sugar alcohol. There is a correlation between galactitol excretion and red blood cell (RBC) galactose-1-phosphate (gal-1-P). Plasma galactitol was also elevated in galactosemic patients (3.4 to 23.2 micromol/L; undetectable in normal individuals). In contrast to the decrease in urinary galactitol with age, plasma levels remain in a narrow concentration range with no significant difference with age. Urine and plasma galactitol distinguish galactosemic patients from normals. In addition, urinary galactitol excretion may be an important parameter for the assessment of steady-state galactose metabolism in galactosemia.

Subnormal retinal oxygenation response precedes diabetic-like retinopathy.

PURPOSE: Determining which patients are at risk for the development of diabetic retinopathy is expected to greatly improve existing prevention and treatment options. In this study, using an animal model of diabetic retinopathy, the hypothesis was tested that magnetic resonance imaging (MRI) and a carbogen inhalation challenge provides important diagnostic information regarding the risk of developing diabetic retinopathy. METHODS: MRI was used to measure noninvasively the change in oxygen tension along the entire inner retina (i.e., from superior ora serrata to inferior ora serrata) during a carbogen (95% O2/5% CO2) inhalation challenge (IOVS 1996;37:2089). Two animal groups were examined by this MRI method at two time points: (1) rats fed either normal rat chow (n = 20) or a 50% galactose diet (n = 20) for 3.5 months (i.e., before the appearance of extensive retinal lesions) or (2) rats fed either normal rat chow (n = 3) for 15 months or a 30% galactose diet (n = 4) for 15 to 18 months (i.e., when lesions are present). Retinal biochemical and morphometric measurements were also obtained. RESULTS: After 3.5 months of galactosemia, before the appearance of extensive retinal morphologic lesions, a significant (P < 0.05) reduction in the panretinal oxygenation response was observed in the galactosemic group compared with its age-matched control. These galactose-fed animals also displayed a significantly (P < 0.05) larger oxygenation response in the inferior hemiretina than in the superior hemiretina. After 15 to 18 months of galactosemia, during the period when lesions are present, the panretinal oxygenation response remained significantly (P < 0.05) lower in the galactose-fed animals than in their age-matched controls. In contrast to the 3.5-month results, the oxygenation response in galactosemic animals at 15 to 18 months was significantly (P < 0.05) larger in the superior than in the inferior hemiretina. Hemiretinal oxygenation responses were not different in normal controls at either duration. CONCLUSIONS: MRI measurement of the retinal oxygenation response to a carbogen challenge appears to be a powerful new and noninvasive approach that may be useful for assessing aspects of pathophysiology underlying the development of diabetic retinopathy in galactosemic rats. These results support our working hypothesis and suggest that further research into the diagnostic potential of this MRI approach for predicting the development of diabetic retinopathy is warranted.

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs.

AIMS/HYPOTHESIS: Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalities similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied. METHODS: Dogs received either normal chow or chow containing 30% galactose with or without epalrestat given orally (20 or 50 mg x kg(-1)). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured. RESULTS: The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactose-fed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat. CONCLUSION/INTERPRETATION: This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition.

Effects of 1-(3-bromobenzofuran-2-ylsulfonyl)hydantoin on human aldose reductase examined by a new application of HPLC system for measuring tissue polyol.

M16209 (1-(3-bromobenzofuran-2-ylsulfonyl)hydantoin, CAS 128851-36-5) displayed potent inhibitory effects upon recombinant human aldose reductase (rhAR, IC50 = 0.051 mumol/l). The inhibition of rhAR by M16209 was uncompetitive with respect to both glyceraldehyde and NADPH. The effects of M16209 on human AR were investigated using a new application of HPLC system developed for analysis of tissue polyol. M16209 and epalrestat suppressed galactitol accumulation in human erythrocytes cultured in 25 mmol/l galactose with IC50 values of 1.2 and 2.6 mumol/l, respectively. The new application of HPLC system equipped with an electrochemical detector did not require any derivatization procedure for polyols and enabled simultaneous determination of glucose, galactose, fructose, myo-inositol, galactitol and sorbitol.

Galactitol in galactosemia.

Urinary galactose and galactitol excretion in controls is age-dependent with the highest concentrations at a younger age. Untreated patients with classical galactosemia excreted highly elevated amounts of galactitol (8000-69,000 mmol/mol creatinine; controls 3-81) which did not correlate with galactose excretion. After treatment, galactose excretion returned to normal in all patients whereas galactitol excretion (45-900 mmol/mol creatinine) remained above the age-matched control range. The excretion of galactitol (96-170 mmol/mol creatinine) in untreated compound heterozygotes was much lower although still above the age-matched control levels, and it returned to normal after treatment. In untreated classical galactosemia patients the galactitol in plasma (120-500 mumol/l) was markedly elevated (controls 0.08-0.86 mumol/l); under treatment, the galactitol concentrations (4.7-20 mumol/l) remained above the control range in all. There was no correlation with age nor with galactose-1-phosphate and UDP-galactose levels. Two untreated compound heterozygotes had elevated plasma galactitol (6.0 and 63 mumol/l) which, when treated, returned to normal.

Long-term outcome in 134 patients with galactosaemia.

In a retrospective study 134 galactosaemic patients, born between 1955 and 1989 in the Federal Republic of Germany were traced and their long-term outcome evaluated. We investigated 83 galactosaemic patients (78 homozygotes, 5 compound heterozygotes) by clinical, psychometric and laboratory testing; 31 patients were evaluated by medical history, the remaining 20 patients had died due to sequelae of the underlying disease. In 48 out of 78 classical galactosaemia patients galactose-free therapy had been started before the 15th day, in 19 between days 15 and 56 and in 11 patients after the 56th day. Physical findings revealed that puberty was delayed in 1 out of 18 males and 6 out of 11 females. Neurological abnormalities included ataxia (n = 6), intention tremor (n = 11) and microcephaly (n = 10). Speech abnormalities were found in 43 out of 66 patients over 3 years of age and disturbance of visual perception and/or arithmetic deficits in 29. Intelligence declined with age, i.e., a DQ or IQ less than 85 was found in 4 out of 34 patients less than 6 years of age (12%), in 10 out of 18 between 7 and 12 years (56%) and in 20 out of 24 older than 12 years (83%). Metabolite patterns (RBC galactose-1-phosphate and UDP-galactose, plasma and urinary galactitol) did not correlate with DQ or IQ. Dietary compliance was good in almost all patients. Compound heterozygotes (n = 5) had normal mental and growth development and all laboratory parameters were in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

[Galactosemia and galactitolemia--ignored pathologies?]. / Galactozemia si galactitolemia patologiei ignorate?

The regular or common appearance of galactose into the sangvin medium because of the great consumption of galactose for the common subjects and especially for the alcoholics, and the temperate consumption for the persons having enzymatic deficiencies into their metabolism for lactose and galactose, too; they both might become dangerous. It is discussed about the methods that must be taken early to forestalling the appearance of the cataract and other complicated affection of galactosemia and galactitolemia.