Effects of Sodium Lactate Infusion in Two Girls with Glucose Transporter 1 Deficiency Syndrome.

BACKGROUND: Glucose is an important fuel for the brain. In glucose transporter 1 deficiency syndrome (GLUT1DS), the transport of glucose across the blood-brain barrier is limited. Most individuals with GLUT1DS present with developmental problems, epilepsy, and (paroxysmal) movement disorders, and respond favorably to the ketogenic diet. Similar to ketones, lactate is an alternative energy source for the brain. The aim of this study is to investigate whether intravenous infusion of sodium lactate in children with GLUT1DS has beneficial effects on their epilepsy. METHODS: We performed a proof of principle study with two subjects with GLUT1DS who were not on a ketogenic diet and suffered from absence epilepsy. After overnight fasting, sodium lactate (600 mmol/L) was infused during 120 minutes, under video electroencephalographic (EEG) recording and monitoring of serum lactate, glucose, electrolytes, and pH. Furthermore, the EEGs were compared with pre-/postprandial EEGs of both subjects, obtained shortly before the study. RESULTS: Fasting EEGs of both subjects showed frequent bilateral, frontocentral polyspike and wave complexes. In one subject, no more epileptic discharges were seen postprandially and after the start of lactate infusion. The EEG of the other subject did not change, neither postprandially nor after lactate infusion. Serum pH, lactate, and sodium changed temporarily during the study. CONCLUSION: This study suggests that sodium lactate infusion is possible in individuals with GLUT1DS, and may have potential therapeutic effects. Cellular abnormalities, beyond neuronal energy failure, may contribute to the underlying disease mechanisms of GLUT1DS, explaining why not all individuals respond to the supplementation of alternative energy sources.

Modifier genes: Moving from pathogenesis to therapy.

This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms. Since one of the goals of research on modifier genes and networks is to identify novel therapeutic targets, the challenges to patient access and compliance because of the high costs of medications for rare genetic diseases must be recognized. A recent article explored protective modifiers, including plastin 3 (PLS3) and coronin 1C (CORO1C), in spinal muscular atrophy (SMA). SMA is an autosomal recessive deficit of survival motor neuron protein (SMN) caused by mutations in SMN1. However, the severity of SMA is determined primarily by the number of SMN2 copies, and this results in significant phenotypic variability. PLS3 was upregulated in siblings who were asymptomatic compared with those who had SMA2 or SMA3, but identical homozygous SMN1 deletions and equal numbers of SMN2 copies. CORO1C was identified by interrogation of the PLS3 interactome. Overexpression of these proteins rescued endocytosis in SMA models. In addition, antisense RNA for upregulation of SMN2 protein expression is being developed as another way of modifying the SMA phenotype. These investigations suggest the practical application of protective modifiers to rescue SMA phenotypes. Other examples of the potential therapeutic value of novel protective modifiers will be discussed, including in Duchenne muscular dystrophy and glycerol kinase deficiency. This work shows that while we live in an exciting era of genomic sequencing, a functional understanding of biology, the impact of its disruption, and possibilities for its repair have never been more important as we search for new therapies.

Improved Starch Digestion of Sucrase-deficient Shrews Treated With Oral Glucoamylase Enzyme Supplements.

BACKGROUND AND OBJECTIVE: Although named because of its sucrose hydrolytic activity, this mucosal enzyme plays a leading role in starch digestion because of its maltase and glucoamylase activities. Sucrase-deficient mutant shrews, Suncus murinus, were used as a model to investigate starch digestion in patients with congenital sucrase-isomaltase deficiency.Starch digestion is much more complex than sucrose digestion. Six enzyme activities, 2 α-amylases (Amy), and 4 mucosal α-glucosidases (maltases), including maltase-glucoamylase (Mgam) and sucrase-isomaltase (Si) subunit activities, are needed to digest starch to absorbable free glucose. Amy breaks down insoluble starch to soluble dextrins; mucosal Mgam and Si can either directly digest starch to glucose or convert the post-α-amylolytic dextrins to glucose. Starch digestion is reduced because of sucrase deficiency and oral glucoamylase enzyme supplement can correct the starch maldigestion. The aim of the present study was to measure glucogenesis in suc/suc shrews after feeding of starch and improvement of glucogenesis by oral glucoamylase supplements. METHODS: Sucrase mutant (suc/suc) and heterozygous (+/suc) shrews were fed with C-enriched starch diets. Glucogenesis derived from starch was measured as blood C-glucose enrichment and oral recombinant C-terminal Mgam glucoamylase (M20) was supplemented to improve starch digestion. RESULTS: After feedings, suc/suc and +/suc shrews had different starch digestions as shown by blood glucose enrichment and the suc/suc had lower total glucose concentrations. Oral supplements of glucoamylase increased suc/suc total blood glucose and quantitative starch digestion to glucose. CONCLUSIONS: Sucrase deficiency, in this model of congenital sucrase-isomaltase deficiency, reduces blood glucose response to starch feeding. Supplementing the diet with oral recombinant glucoamylase significantly improved starch digestion in the sucrase-deficient shrew.

Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis.

We report a patient from a consanguineous family who presented with transient acute liver failure and biochemical patterns suggestive of disturbed urea cycle and mitochondrial function, for whom conventional genetic and metabolic investigations for acute liver failure failed to yield a diagnosis. Whole exome sequencing revealed a homozygous 12-bp deletion in PCK1 (MIM 614168) encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK); enzymatic studies subsequently confirmed its pathogenic nature. We propose that PEPCK deficiency should be considered in the young child with unexplained liver failure, especially where there are marked, accumulations of TCA cycle metabolites on urine organic acid analysis and/or an amino acid profile with hyperammonaemia suggestive of a proximal urea cycle defect during the acute episode. If suspected, intravenous administration of dextrose should be initiated. Long-term management comprising avoidance of fasting with the provision of a glucose polymer emergency regimen for illness management may be sufficient to prevent future episodes of liver failure. This case report provides further insights into the (patho-)physiology of energy metabolism, confirming the power of genomic analysis of unexplained biochemical phenotypes.

Mechanistic and therapeutic overview of glycosaminoglycans: the unsung heroes of biomolecular signaling.

Immune regulation is a complex biological signaling pathway in which several classes of biomolecules and small molecules play a complacent role to mediate this process. Glycoimmunology is a rapidly evolving research area that deals with the structure, binding interactions and immunological functions of glycans. Great deal of information regarding proteins and nucleic acids in molecular recognition events have been established owing to their well-established structural features and straight forward replication, transcription and translation principles. However considering the complexities of template free synthesis and structural heterogeneity, role of carbohydrates in immune regulation are still unsung to a large extent. In the current review, we illuminate the canonical structural features, emerging and significant pathophysiological functions of glycosaminoglycans (GAGs), the negatively charged linear carbohydrate molecules that are primarily present on all types of cell surfaces and extra cellular matrix. A snap shot of their association with protein counterparts of diversified protein families has been updated exclusively to provide mechanistic insights into their cellular signaling functions. Eventually, this review throws light on the recent biomedical/biotechnological advances of GAG based biomarkers, nutraceuticals, therapeutics, and nanocomposites for inflammatory, immune disorders and their invaluable contribution in tissue engineering.

Exploring diazoxide and continuous glucose monitoring as treatment for Glut1 deficiency syndrome.

Glut1 deficiency syndrome is caused by SLC2A1 mutations on chromosome 1p34.2 that impairs glucose transport across the blood-brain barrier resulting in hypoglycorrhachia and decreased fuel for brain metabolism. Neuroglycopenia causes a drug-resistant metabolic epilepsy due to energy deficiency. Standard treatment for Glut1 deficiency syndrome is the ketogenic diet that decreases the demand for brain glucose by supplying ketones as alternative fuel. Treatment options are limited if patients fail the ketogenic diet. We present a case of successful diazoxide use with continuous glucose monitoring in a patient with Glut1 deficiency syndrome who did not respond to the ketogenic diet.

Effect of short-term intensive insulin therapy on α-cell function in patients with newly diagnosed type 2 diabetes.

The effect of intensive insulin therapy on hyperglucagonemia in newly diagnosed type 2 diabetes (T2DM), and its associations with ß-cell function, has not been elucidated. This study assessed the effect of 12 weeks of intensive insulin therapy on hyperglucagonemia in newly diagnosed T2DM and its associations with ß-cell function, with reference to the effects of 12 weeks of oral hypoglycemic agents (OHAs).One hundred eight patients with newly diagnosed T2DM were enrolled from January 2015 to December 2015. The patients were randomly divided to receive, for 12 weeks, either intensive insulin therapy or OHAs. Meal tolerance tests were conducted at baseline before treatment (0 week), at 12 weeks (end of treatment), and 12 months after the initiation of treatment. The levels of glucagon, proinsulin, C-peptide (CP), and blood glucose were measured at timepoints 0, 30, and 120 minutes during the meal tolerance test.Intensive insulin treatment was associated with a decrease in glucagon levels (at 0, 30, and 120 minutes) and proinsulin/CP, and an increase in the insulin-secretion index ΔCP30/ΔG30 and ΔCP120/ΔG120, at 12 weeks and 12 months during the follow-up, compared with the corresponding effects of OHAs. Intensive insulin therapy could reduce but failed to normalize glucagon levels at 12 weeks. There were no correlations between the change of percentages in total area under the curve of glucagon and other glycemic parameters (proinsulin/CP; ΔCP30/ΔG30; or ΔCP120/ΔG120). Patients who received intensive insulin therapy were more likely to achieve their target glycemic goal and remission, compared with those who received OHAs.Short-term intensive insulin therapy facilitates the improvement of both ß-cell and α-cell function in newly diagnosed T2DM mellitus. Decline of ß-cell secretion and concomitant α-cell dysfunction may both be involved in the pathogenesis of T2DM.

Inherited GPI deficiency: a disorder of histone hypoacetylation.

Co-operative interaction of transcription factors (TF) with epigenetic processes, such as chromatin remodeling and modification (acetylation or methylation), as well as DNA methylation, determine transcriptional activity, activation or repression of a given gene. Mutations disrupting binding of TF to their cognate DNA motifs would be expected to alter the epigenetic landscape of the promoter and selectively affect transcription of the given gene. We review here the transcriptional, epigenetic, biochemical, and clinical consequences of a constitutional mutation in the promoter of PIGM, a housekeeping gene that disrupts binding of the general TF, SP1, thus causing the autosomal recessive disease, inherited glycosylphosphatidylinositol (GPI) deficiency. We suggest that detailed dissection of the function of the mutated PIGM promoter provides important lessons pertinent to the transcriptional and epigenetic control of housekeeping genes as a whole and might have wider therapeutic implications.

Sanfilippo disease type B: enzyme replacement and metabolic correction in cultured fibroblasts.

alpha-Acetylglucosaminidase, purified from human placent, corrected the defect in mucopolysaccharide degradation when added to culture fibroblasts from patients with Sanfilippo disease type B. A small cellular concentration of enzyme gave a large corrective effect. The half-life of disappearance of enzyme activity was 4 to 7 days.

13C-breath tests for sucrose digestion in congenital sucrase isomaltase-deficient and sacrosidase-supplemented patients.

BACKGROUND: Congenital sucrase-isomaltase deficiency (CSID) is characterized by absence or deficiency of the mucosal sucrase-isomaltase enzyme. Specific diagnosis requires upper gastrointestinal biopsy with evidence of low to absent sucrase enzyme activity and normal histology. The hydrogen breath test (BT) is useful, but is not specific for confirmation of CSID. We investigated a more specific 13C-sucrose labeled BT. OBJECTIVES: Determine whether CSID can be detected with the 13C-sucrose BT without duodenal biopsy sucrase assay, and if the 13C-sucrose BT can document restoration of sucrose digestion by CSID patients after oral supplementation with sacrosidase (Sucraid). METHODS: Ten CSID patients were diagnosed by low biopsy sucrase activity. Ten controls were children who underwent endoscopy and biopsy because of dyspepsia or chronic diarrhea with normal mucosal enzymes activity and histology. Uniformly labeled 13C-glucose and 13C-sucrose loads were orally administered. 13CO2 breath enrichments were assayed using an infrared spectrophotometer. In CSID patients, the 13C-sucrose load was repeated adding Sucraid. Sucrose digestion and oxidation were calculated as a mean percent coefficient of glucose oxidation averaged between 30 and 90 minutes. RESULTS: Classification of patients by 13C-sucrose BT percent coefficient of glucose oxidation agreed with biopsy sucrase activity. The breath test also documented the return to normal of sucrose digestion and oxidation after supplementation of CSID patients with Sucraid. CONCLUSIONS: 13C-sucrose BT is an accurate and specific noninvasive confirmatory test for CSID and for enzyme replacement management.

Nutrition management of congenital glucose-galactose malabsorption: Case report of a Chinese infant.

RATIONALE: Congenital glucose-galactose malabsorption (CGGM) is a rare, autosomal recessive, hereditary disease that usuallypresents in newborns. CGGM manifests as severe diarrhea, hyperosmolar dehydration, and malnutrition. It does not respond to routine treatment and often is life-threatening. PATIENT CONCERNS: We described a Chinese infant girl with refractory diarrhea, who suffered from severe dehydration and malnutrition even if with fluid replacement therapy and fed with several special formulas. DIAGNOSES: The genetic analysis identified CGGM with SLC5A1 mutations. c.1436G > C (p.R479T) was a novel mutation. INTERVENTIONS: The patient was managed by free-glucose and galactose formula, and then special low-carbohydrate dietary therapy. OUTCOMES: The patient improved immediately after starting a free-glucose and galactose formula, and kept healthy with special low-carbohydrate diet. She had been followed up with nutritional management for 20 months. LESSONS: This report highlights the importance of differential diagnosis of congenital diarrhea and enteropathies. For CGGM, free-glucose and galactose milk powder was the most effective treatment. Low-carbohydrate diet gradually introduced was still a great challenge that requires continuing guidance from child nutritionists and dietitians. Long-term nutrition management was extremely important to ensure the normal growth and development of children.

Therapeutic strategies for glucose transporter 1 deficiency syndrome.

Proper development and function of the mammalian brain is critically dependent on a steady supply of its chief energy source, glucose. Such supply is mediated by the glucose transporter 1 (Glut1) protein. Paucity of the protein stemming from mutations in the associated SLC2A1 gene deprives the brain of glucose and triggers the infantile-onset neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). Considering the monogenic nature of Glut1 DS, the disease is relatively straightforward to model and thus study. Accordingly, Glut1 DS serves as a convenient paradigm to investigate the more general cellular and molecular consequences of brain energy failure. Here, we review how Glut1 DS models have informed the biology of a prototypical brain energy failure syndrome, how these models are facilitating the development of promising new treatments for the human disease, and how important insights might emerge from the study of Glut1 DS to illuminate the myriad conditions involving the Glut1 protein.

Medical and Veterinary Importance of the Moonlighting Functions of Triosephosphate Isomerase.

Triosephosphate isomerase is the fifth enzyme in glycolysis and its canonical function is the reversible isomerization of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Within the last decade multiple other functions, that may not necessarily always involve catalysis, have been described. These include variations in the degree of its expression in many types of cancer and participation in the regulation of the cell cycle. Triosephosphate isomerase may function as an auto-antigen and in the evasion of the immune response, as a factor of virulence of some organisms, and also as an important allergen, mainly in a variety of seafoods. It is an important factor to consider in the cryopreservation of semen and seems to play a major role in some aspects of the development of Alzheimer's disease. It also seems to be responsible for neurodegenerative alterations in a few cases of human triosephosphate isomerase deficiency. Thus, triosephosphate isomerase is an excellent example of a moonlighting protein.

Confirmation of a Rare Genetic Leukoencephalopathy due to a Novel Bi-allelic Variant in RPIA.

Ribose 5-phosphate isomerase deficiency is a rare genetic leukoencephalopathy caused by pathogenic sequence variants in RPIA, that encodes ribose 5-phosphate isomerase, an enzyme in the pentose phosphate pathway. Till date, only three individuals with ribose 5-phosphate isomerase deficiency have been described in literature. We report on a subject with RPIA associated progressive leukoencephalopathy with elevated urine arabitol and ribitol levels and a novel missense variant c.770T > C p.(Ile257Thr) in exon 8 of RPIA. We also compare the phenotypes of all the four subjects. Our report confirms the phenotype and the genetic cause of this condition.

Perioperative Management of a Child With Glucose Transporter Type 1 Deficiency Syndrome: A Case Report.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) causes central nervous system dysfunction including intractable epilepsy caused by impaired glucose transport to the brain. To prevent convulsions and maintain an energy source for the brain in patients with GLUT1DS, the maintenance of adequate ketone body concentrations, compensation of metabolic acidosis, and reduction of surgical stress are essential. We here report the perioperative management of a child with GLUT1DS.

Relationships among Dietary Intakes and Persistent Gastrointestinal Symptoms in Patients Receiving Enzyme Treatment for Genetic Sucrase-Isomaltase Deficiency.

BACKGROUND: Sucrose-isomaltase deficiency (SID) remains underdiagnosed. Absent or reduced enzyme activity promotes diarrhea, abdominal bloating, and flatulence from undigested and malabsorbed disaccharides. Frequency and severity of gastrointestinal symptoms may be associated with the type of carbohydrates consumed. OBJECTIVE: To characterize the dietary intakes of patients treated with sacrosidase (Sucraid; QOL Medical) for SID and determine relationships between type of carbohydrates, sacrosidase dose, and gastrointestinal symptoms. DESIGN: A prospective 30-day observational study. PARTICIPANTS/SETTING: Forty-nine patients treated with sacrosidase for ≥3 months were recruited from the enzyme manufacturer's nationwide clinical database between November 2014 and August 2015. MAIN OUTCOME MEASURES: Dietary energy and nutrient intakes reported during 24-hour diet recall interviews, frequency and severity of gastrointestinal (GI) symptoms, and sacrosidase dose. STATISTICAL ANALYSES PERFORMED: Relationships between nutrient intakes, sacrosidase dose, and GI symptoms were evaluated using Spearman ρ correlation coefficients. RESULTS: Sacrosidase dose averaged 5.2±3.1 mL/day. Participants reported 1.3±0.9 bowel movements daily. Having less frequent GI symptoms was associated with higher sacrosidase intake. Energy intakes averaged 1,562.5±411.5 kcal/day in children, 1,964.7±823.6 kcal/day in adolescents, and 1,952.6±546.5 kcal/day in adults. Macronutrient composition averaged 44% carbohydrate, 39% fat, and 17% protein. Average carbohydrate composition was 35% starch, 8% fiber, and 59% sugars. Sucrose and fructose intakes were not associated with GI symptoms. Lactose intake was associated with diarrhea. Maltose intake was associated with nausea, distension, and reflux. CONCLUSIONS: Intakes were lower in carbohydrates and higher in fat compared with the Acceptable Macronutrient Distribution Ranges. Sucrose and fructose intakes were not associated with GI symptoms. Higher maltose and lactose intakes were associated with GI symptom frequency and severity. These findings provide evidence to guide nutrition counseling for patients treated for SID.

Mutant holocarboxylase synthetase: evidence for the enzyme defect in early infantile biotin-responsive multiple carboxylase deficiency.

Biotin-responsive multiple carboxylase deficiency is an inherited disorder of organic acid metabolism in man in which there are deficiencies of propionyl-coenzyme A (CoA), 3-methylcrotonyl-CoA, and pyruvate carboxylases that can be corrected with large doses of biotin. It has been proposed that the basic defect in patients with the early infantile form of the disease is in holocarboxylase synthetase, the enzyme that covalently attaches biotin to the inactive apocarboxylases to form active holocarboxylases. We have developed an assay for holocarboxylase synthetase in extracts of human fibroblasts using as substrate apopropionyl-CoA carboxylase partially purified from livers of biotin-deficient rats. Fibroblasts from the initial patient with the infantile form of biotin-responsive multiple carboxylase deficiency were shown to have abnormal holocarboxylase synthetase activity with a maximum velocity about 30-40% of normal, a Km for ATP of 0.3 mM similar to the normal Km of 0.2 mM, and a highly elevated Km for biotin of 126 ng/ml, about 60 times the normal Km of 2 ng/ml. These results show that the primary defect in this patient is a mutation affecting holocarboxylase synthetase activity, and thus a genetic defect of the metabolism of biotin.

Cholestasis and Hepatic Iron Deposition in an Infant With Complex Glycerol Kinase Deficiency.

We present a 6-week-old male infant with persistent hyperbilirubinemia, hypertriglyceridemia, elevated creatine kinase levels, and transaminitis since the second week of life. When he developed hyperkalemia, clinical suspicion was raised for adrenal insufficiency despite hemodynamic stability. A full endocrine workup revealed nearly absent adrenocorticotropic hormone. Coupled with his persistent hypertriglyceridemia (peak of 811 mg/dL) and elevated creatine kinase levels (>20 000 U/L), his corticotropin level lead to a clinical diagnosis of complex glycerol kinase deficiency (GKD), also known as Xp21 deletion syndrome. This complex disorder encompasses the phenotype of Duchenne muscular dystrophy, GKD, and congenital adrenal hypoplasia due to the deletion of 3 contiguous genetic loci on the X chromosome. Our case exemplifies the presentation of this disorder and highlights the important lesson of distinguishing between adrenal hypoplasia congenita and congenital adrenal hyperplasia, as well as the sometimes subtle presentation of adrenal insufficiency. To our knowledge, it is also the first reported case of complex GKD deficiency with the additional finding of hepatic iron deposition, which may indicate a potential area for exploration regarding the pathogenesis of liver injury and cholestasis seen in cortisol-related endocrinopathies.