Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots.

Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0-6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.

Multiplexed detection of DOCK8, PGM3 and STAT3 proteins for the diagnosis of Hyper-Immunoglobulin E syndrome using gold nanoparticles-based immunosensor array platform.

Multiplexed biosensors hold great promise for early diagnosis of diseases where the detection of multiple biomarkers is required. Hyper Immunoglobulin E syndromes (HIES) are rare primary immunodeficiency disorders associated with mutations either in the signal transducer and activator of transcription 3 (STAT3), dedicator of cytokinesis 8 DOCK8) or phosphoglucomutase 3 (PGM3) genes. Yet, the diagnosis of HIES is challenged by the complexity of the existing laboratory assays. Here, we report for the first time the development of a multiplexed electrochemical immunosensor for the simultaneous detection of DOCK8, STAT3 and PGM3 proteins. The immunosensor was constructed on carbon array electrodes that were first modified by electrodeposition of gold nanoparticles (AuNPs). The array electrodes were then used to immobilize specific antibodies for the three proteins after the functionalization of the electrodes with cysteamine/glutaraldehyde linkers. The simultaneous detection of the DOCK8, PGM3 and STAT3 proteins was successfully realized by the immunosensor with respective limits of detections of 3.1, 2.2 and 3.5 pg/ml. The immunosensor has shown good sensitivity as well as selectivity against other proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and Duchenne Muscular Dystrophy (DMD). Moreover, the immunosensor was successfully applied in human serum samples showing capability to distinguish the HIES from the control samples.

PGM1 deficiency diagnosed during an endocrine work-up of low IGF-1 mediated growth failure.

OBJECTIVE AND IMPORTANCE: Phosphoglucomutase 1 (PGM1) deficiency, first described as a glycogenosis (type XIV) is also a congenital disorder of glycosylation (CDG). We want to illustrate the wide clinical spectrum of PGM1 deficiency and in particular the associated disturbance in glucose metabolism and the endocrine dysfunction. Treatment with d-galactose is experimental. CASE PRESENTATION: PGM1 deficiency was diagnosed in an 8-year-old boy, who was referred because of an unexplained complex syndrome, including recurrent hypoglycaemia and low IGF-1 mediated growth failure. CONCLUSION: The timely diagnosis of this disorder is particularly important, because d-galactose treatment can improve the latter symptoms.

Phosphoglucomutase activity as a novel biomarker in patients with acute myocardial infarction.

BACKGROUND: Phosphoglucomutase (PGM), a key enzyme in cellular glucose utilization and energy homeostasis, has been reported to show a relationship with oxidative stress. However, the clinical importance of PGM activity has not been investigated in patients with ischemic heart disease (IHD). The aim of the present pilot study was to clarify whether PGM activity has potential as a cardiovascular risk predictor in patients with IHD. METHODS AND RESULTS: The levels of serum PGM activity in 237 patients with IHD (63 patients with acute myocardial infarction (AMI) and 174 patients with stable effort angina pectoris (EAP)) were evaluated. PGM activity was compared with levels of various myocardial, thrombosis, and inflammatory biomarkers on admission. PGM activity in the AMI group was significantly increased relative to that in the EAP group on admission (AMI, 55.5 µmol·min(-1)·L(-1) (U/L); EAP, 14.4 U/L (P<0.001)), and was observed to increase in parallel with well-established myocardial markers (P<0.001). Moreover, PGM activity and the lipid, thrombosis, and inflammatory biomarkers in the AMI group were higher than those in the EAP group. CONCLUSIONS: PGM activity increased with levels of myocardial, thrombosis, and inflammatory biomarkers in patients with AMI, and might be useful in diagnostic applications during the acute phase in patients with AMI.

Intelligence and genetic markers in Chilean children.

Genetic markers and total intelligence quotient (IQ) assessed by WISC (Wechsler Intelligence Scale for Children) were studied in children of both sexes from Santiago, Chile. Heterozygous boys for phosphoglucomutase 1 (PGM) and heterozygous girls for haptoglobin (Hp) had lower IQ than homozygotes. For ABO system, B girls had lower and B boys had higher IQ than children with other ABO phenotypes. These differences were highly significant with the two tailed t'-test (Student's t-test with the Welch-Satterthwaite correction for degrees of freedom), and most of them remained significant after the correction for multiple comparisons. Girls had greater variance of IQ than boys. Relationships between homozygotes and heterozygotes were found in two independent studies. Thus, the genetic relationship found here seems likely to be a true biotic effect.

[Distribution of erythrocyte EsD and PGM1 (phosphoglucomutase) phenotypes in the Han population of Changsha district].

Phenotyping of erythrocyte EsD and PGM1 enzymes was performed by a mixed agarose-starch gel electrophoresis in 165 healthy blood donors of Changsha District. The gene frequencies and cumulative discrepancy power(CDP) were calculated. The phenotype frequencies of EsD and PGM1 were compared not only with the different Chinese nationalities but also with those reported by the other countries showing a good correlation with the phenotype distributions of Han people in the other cities of China. The result showed that the gene frequencies of erythrocyte EsD1 and PGM1(1) were 0.6242 and 0.7121 in Han population of Changsha District, respectively. This method is now used routinely in our laboratory and is superior for the examination of individuality and identification of paternity.

Intelligence and genetic markers in Chilean children

Genetic markers and total intelligence quotient (IQ) assessed by WISC (Wechsler Intelligence Scale for Children) were studied in children of both sexes from Santiago, Chile. Heterozygous boys for phosphoglucomutase 1 (PGM) and heterozygous girls for haptoglobin (Hp) had lower IQ than homozygoytes. For ABO system, B girls had lower and B boys had higher IQ than children with other ABO phenotypes. These differences were highly significant with the two tailed t'-test (Student's t-test with the Welch-Satterthwaite correction for degrees of freedom), and most of them remained significant after the correction for multiple comparisons. Girls had greater variance of IQ than boys. Relationships between homozygotes and heterozygotes were found in two independent studies. Thus, the genetic relationship found here seems likely to be a true biotic effect.

Isoelectric focusing differences in the mobility of blood and semen PGM1 bands--the role of hemoglobin as a cause.

When using isoelectric focusing for the analysis of phosphoglucomutase isoenzymes, differences between the mobility of the first locus phosphoglucomutase (PGM1) bands have been noted in blood and semen samples from the same individual. This study was thus initiated to determine whether hemoglobin is responsible for these differences. Results revealed that the mobility of the PGM1 bands in diluted hemolysate and hemoglobin-removed hemolysate was similar to that seen in non-treated seminal plasma. Further, the mobility of PGM1 bands in hemoglobin-added seminal plasma was also similar to that seen in non-treated hemolysate. Additionally, on isoelectric focusing of the pI-markers, as well as non-treated hemolysate, hemoglobin-removed hemolysate, hemoglobin-added seminal plasma, and non-treated seminal plasma, distortions of iso-pH lines, i.e., "crank" formations were seen in the lanes of the non-treated hemolysate and hemoglobin-added seminal plasma. The above findings appear to indicate that differences in the mobility of PGM1 bands in the blood and semen result from the presence of high concentrations of hemoglobin in the analyzed samples.

Low blood protein heterozygosity in zoo-bred hamadryas baboons.

An electrophoretic study of erythrocyte allozymes and serum proteins representing 32 genetic loci in 32 hamadryas baboons (Papio H.hamadryas) from Cologne and Frankfurt zoos revealed biallelic polymorphism in phosphoglucomutase (PGM), mannose phosphate isomerase (MPI) and transferrin (Tf). Polymorphism amounted to P = 0.097 over 31 loci and observed heterozygosity to H(o) = 0.011, indicating significant reduction from the respective gene diversity parameters encountered in free-living hamadryas baboons. Polygynous mating reduced numbers of heterozygotes at the Tf and the PGM-II loci significantly below Hardy-Weinberg expectations. This results support the importance of active genetic management in programmes for captive breeding and species conservation.

Polymorphism of phosphoglucomutase 1 (PGM1) in five Han subpopulations in China.

PGM1 polymorphism in five Han subpopulations in China was investigated by polyacrylamide gel isoelectric focusing. The frequency of PGM1*1A was 0.6256 for Xi'an Han, 0.5982 for Zhengzhou Han, 0.6429 for Huhhot Han, 0.6232 for Lanzhou Han, and 0.6000 for Hakka in Guangdong Province. There was a north to south cline of PGM1*1A frequency.

Distribution of PGM1 and GC subtypes in the four Sardinian provinces.

Genetic polymorphism subtypes of PGM1 and GC were studied in four samples of the Sardinian population from the four Provinces of the island. The results show heterogeneity within the Sardinian population. The PGM1 alleles exhibiting the greatest variability were: PGM1*1S and PGM1*1F, with a range of .675-.724 (Nuoro - Sassari) and .072-.107 (Sassari - Nuoro) respectively. The observed GC allele frequency range were: GC*1F = .029-.168 (Cagliari - Sassari); GC*1S = .565-.752 (Sassari - Oristano); GC*2 = .194-.267 (Cagliari - Sassari). Sardinians showed a marked differentiation with respect to other Italian and European populations thus confirming their genetic peculiarity.

PGM1 subtypes in Cantabria (middle N Spain).

A sample of 500 unrelated individuals from Cantabria (middle north Spain) has been studied for red cell Phosphoglucomutase (PGM1) using isoelectric focusing in polyacrylamide. The allele frequencies observed were: PGM1*1 +: 0.643, PGM1*1-: 0.121, PGM1*2 +: 0.195, PGM1*2-: 0.041 and are similar to those reported for other European and Spanish populations. The theoretical exclusion rate in cases of disputed paternity is 30.24%.

Is there a genetic basis for gestational diabetes?

Rh E-PGM1 (phosphoglucomutase locus 1) joint genotype frequencies (chromosome 1) have been determined in 90 women with gestational diabetes mellitus (GDM) and in 140 pregnant women with preexisting insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). The pattern of Rh E-PGM1 association differs among types of diabetes. The distortion of the pattern tends to assume opposite values in GDM and NIDDM and this is particularly evident in PGM1*2,2 subjects. The proportion of PGM1*2,2 subjects homozygous for the Rh e allele is higher in GDM than in IDDM and NIDDM. IDDM women show an intermediate proportion and NIDDM women show the lowest proportion of this genotype. The opposite pattern is observed among PGM1*2,2 subjects carrying the Rh E allele. Genotype frequencies of the hypervariable region flanking the insulin gene (chromosome 11) have been determined in 77 women with GDM, in 52 pregnant women with preexisting diabetes (IDDM and NIDDM), and in 62 normal adults. In GDM and NIDDM subjects the frequencies are similar. In IDDM women the frequency of homozygotes for the class 1 allele is higher than the frequency found in GDM and NIDDM women. The data suggest a possible genetic basis for the differentiation of a subclass of GDM from both IDDM and NIDDM.

Breeding of the gad-mdx mouse: influence of genetically induced denervation on dystrophic muscle fibers.

A new double mutant mouse strain, gad-mdx, was established. The transmission of mdx and gad genes was monitored by determining their chemical markers, creative kinase activity and phosphoglucomutase-1 isoenzyme, respectively, in blood samples. This new strain was characterized by high creatine kinase activity in the plasma, lack of dystrophin in the muscle, and the presence of axonal swellings in the neural tissue. Although the body weight and the limb muscle size of the mutant mice were significantly lower than those of either gad or mdx mice, the clinical signs were not evident until the animals were 80 days old. After that time, the disease followed the course seen in the gad strain, and muscle weakness was exhibited in the advanced stages. Histologic examination revealed that the prevalence of muscle fiber necrosis, a deleterious consequence of the mdx gene, was significantly lower in the double mutant strain than in the mdx strain. These results supported the idea that small-caliber muscle fibers, which are induced by gad gene expression, are resistant to dystrophic necrosis. We believe that this double mutant strain will be valuable for the analysis of neural influence on diseased muscle fibers, and that it will also provide an opportunity for the testing of new therapeutic strategies for human Duchenne muscular dystrophy.

Fetal growth, gestation length and phosphoglucomutase-1 phenotype.

This study investigates reports that phosphoglucomutase-1 (PGM1) phenotype is associated with fetal growth and gestation length. A total of 350 women were studied, 234 having uncomplicated pregnancies and 114 with a baby weighing greater than 90th centile, corrected for parity, gestation and fetal sex. All women had gestation confirmed by early ultrasound. Conventional cellulose acetate electrophoresis was used to distinguish the three common PGM1 phenotypes and polyacrylamide gel isoelectric focusing to distinguish the ten PGM1 subtypes. Neither PGM1 phenotype nor subtype were found to be associated with gestation length or standardised birth weight. Logistic regression, where maternal age, parity, fetal sex, maternal weight, gestation and smoking were introduced as explanatory variables in addition to PGM1 phenotype testing against the dependent variables birth weight, standardised birth weight and gestation length, did not show differences related to PGM1 phenotype. Two possible reasons for the discrepancy with previously published data are discussed. We conclude that the study provides no support for the belief that PGM1 phenotype is related to fetal growth or gestation length and that the original observations could have arisen as a result of statistical artefact due to multiple testing.

ABO, phosphoglucomutase and erythrocyte acid phosphatase typing of blood samples containing added fluoride.

Blood samples containing approximately 2% and 4% sodium fluoride have been stored at 4 degrees C for up to 5 months and 4 weeks respectively. ABO typing by absorption-elution was successful on stains made from almost all of the samples. PGM subtyping by isoelectric focusing was successful on most samples, with clearer results from whole blood than from stains. Failure to type appears to be slightly more common at the higher preservative level and yields no result rather than an erroneous one. Apparent phenotypic changes in the 1+ and 1- bands have been seen after 5 months storage. EAP typing by isoelectric focusing was successful on most samples, again with clearer results from whole bloods than from stains. Possible errors can occur in samples containing C bands, but it is not clear whether they are caused by the presence of preservative. The results obtained are illustrated by two casework examples.

Typing of human red cell and serum mixtures in three electrophoretic systems.

The isoenzymes erythrocyte acid phosphatase and phosphoglucomutase were typed in mixed red cell samples which had been derived from two individuals; the protein group specific component was typed in mixed serum samples. Typing was performed by isoelectric focusing on ultrathin polyacrylamide gels. Depending upon the mixture, from 2 to 20% (but typically 5-10%) by volume of a second blood or serum needed to be present in a mixture before it could be detected. In the majority of cases when there was significant mixing, samples were readily identified as a mixture when the results consisted of unusual band patterns or unusual band intensities. There would be a few instances when blood or serum could not be identified as a mixture when masking effects occurred or when the mixture produced a combined, apparently normal, pattern.