Galactose metabolism and health Coelho, Ana I; Berry, Gerard T; Rubio-Gozalbo, M Estela
Current opinion in clinical nutrition and metabolic care,
2015-July, 2015-Jul, 2015-07-00, 20150701, Letnik:
18, Številka:
4
Journal Article
Recenzirano
PURPOSE OF REVIEWGalactose – a key source of energy and a crucial structural element in complex molecules – is particularly important for early human development. However, galactose metabolism might ...be important not only for fetal and neonatal development but also for adulthood, as evidenced by the inherited disorders of galactose metabolism. The purpose of this review is to summarize the current evidence of galactose metabolism in health and disease.
RECENT FINDINGSThe biological importance of galactose goes beyond its importance as a nutrient and a metabolite. Galactose has been selected by evolutionary pressure to exert also a crucial structural role in macromolecules. Additionally, galactose has recently been reported as beneficial in a number of diseases, particularly in those affecting the brain.
SUMMARYGalactose is crucial for human metabolism, with an established role in energy delivery and galactosylation of complex molecules, and evidence for other roles is emerging.
Despite many decades of research involving both human subjects and model systems, the underlying pathophysiology of long-term complications in classic galactosemia (CG) remains poorly understood. In ...this review, intended for those already familiar with galactosemia, we focus on the big questions relating to outcomes, mechanism, and markers, drawing on relevant literature where available, attempting to navigate inconsistencies where they appear, and acknowledging gaps in knowledge where they persist.
Hereditary galactosemia Demirbas, Didem; Coelho, Ana I.; Rubio-Gozalbo, M. Estela ...
Metabolism, clinical and experimental,
June 2018, 2018-06-00, 20180601, Letnik:
83
Journal Article
Recenzirano
Hereditary galactosemia is an inborn error of carbohydrate metabolism. Galactose is metabolized by Leloir pathway enzymes; galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT) and ...UDP-galactose 4-epimerase (GALE). The defects in these enzymes cause galactosemia in an autosomal recessive manner. The severe GALT deficiency, or classic galactosemia, is life-threatening in the newborn period. The treatment for classic galactosemia is dietary restriction of lactose. Although implementation of lactose restricted diet is efficient in resolving the acute complications, it is not sufficient to prevent long-term complications affecting the brain and female gonads, the two main target organs of damage. Implementation of molecular genetics diagnostic tools and GALT enzyme assays are instrumental in distinguishing classic galactosemia from clinical and biochemical variant forms of GALT deficiency. Better understanding of mechanisms responsible for the phenotypic variation even within the same genotype is essential to provide appropriate counseling for families. Utilization of a lactose restricted diet is also recommended for GALK deficiency and some rare forms of GALE deficiency. Novel modes of therapies are being explored; they may be beneficial if access issues to the affected tissues are circumvented and optimum use of therapeutic window is achieved.
•Galactose is metabolized through Leloir pathway enzymes.•Defects in this pathway cause galactosemia.•The absence of GALT enzyme activity causes classic galactosemia.•Current therapy for classic galactosemia is dietary restriction of lactose.
Classic galactosemia is an autosomal recessive disorder of carbohydrate metabolism, due to a severe deficiency of the enzyme, galactose-1-phosphate uridyltransferase (GALT), that catalyzes the ...conversion of galactose-1-phosphate and uridine diphosphate glucose (UDPglucose) to uridine diphosphate galactose (UDPgalactose) and glucose-1-phosphate. Upon consumption of lactose in the neonatal period, the affected infants develop a potentially lethal disease process with multiorgan involvement. Since the advent of newborn screening (NBS) for galactosemia, we rarely encounter such overwhelmingly ill newborns. After ascertainment that the positive NBS indicates the possibility of galactosemia due to GALT deficiency, the critical question for the physician is whether the infant has the classic or a variant form of GALT deficiency, as classic galactosemia is a medical emergency. However, there are over 230 GALT gene mutations that have been detected around the world. Yet, most positive NBS tests are due to the Duarte biochemical variant condition or a simple false positive. In order to make the correct decision as well as provide informative counseling to parents of infants with a positive NBS, I utilize a relatively simple classification scheme for GALT deficiency. There are three basic forms of GALT deficiency: 1) classic galactosemia; 2) clinical variant galactosemia; and 3) biochemical variant galactosemia. The classic genotype is typified by Q188R/Q188R, the clinical variant by S135L/S135L and the biochemical variant by N314D/Q188R. In classic galactosemia, the erythrocyte GALT enzyme activity is absent or markedly reduced, the blood galactose and erythrocyte galactose-1-phosphate levels are markedly elevated, and the patient is at risk to develop potentially lethal E. coli sepsis, as well as the long-term diet-independent complications of galactosemia. Patients with the clinical variant form require treatment but do not die from E. coli sepsis in the neonatal period. If the clinician suspects galactosemia, even if based on clinical findings alone, then the infant should be immediately placed on a lactose-restricted diet. The purpose of this review is to help the clinician make the correct therapeutic decision after an NBS test has returned positive for galactosemia.
► A useful classification scheme for the galactosemias. ► What to do when NBS is positive for galactosemia. ► Identify when galactosemia is a true medical emergency in the newborn period.
Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case–control study evaluated 40 cases ...who progressed to ESRD during 8–12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion than cases. Plasma metabolites at baseline were measured by mass spectrometry–based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid–derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR, or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.
Classic Galactosemia due to galactose-1-phosphate uridyltransferase (GALT) deficiency is associated with apparent diet-independent complications including cognitive impairment, learning problems and ...speech defects. As both galactose-1-phosphate and galactitol may be elevated in cord blood erythrocytes and amniotic fluid despite a maternal lactose-free diet, endogenous production of galactose may be responsible for the elevated fetal galactose metabolites, as well as postnatal CNS complications. A prenatal deficiency of myo-inositol due to an accumulation of both galactose-1- phosphate and galactitol may play a role in the production of the postnatal CNS dysfunction. Two independent mechanisms may result in fetal myo-inositol deficiency: competitive inhibition of the inositol monophosphatase1 (IMPA1)-mediated hydrolysis of inositol monophosphate by high galactose-1- phosphate levels leading to a sequestration of cellular myo-inositol as inositol monophosphate and galactitol-induced reduction in SMIT1-mediated myo-inositol transport. The subsequent reduction of myo-inositol within fetal brain cells could lead to inositide deficiencies with resultant perturbations in calcium and protein kinase C signaling, the AKT/mTOR/ cell growth and development pathway, cell migration, insulin sensitivity, vescular trafficking, endocytosis and exocytosis, actin cytoskeletal remodeling, nuclear metabolism, mRNA export and nuclear pore complex regulation, phosphatidylinositol-anchored proteins, protein phosphorylation and/or endogenous iron “chelation”. Using a knockout animal model we have shown that a marked deficiency of myo-inositol in utero is lethal but the phenotype can be rescued by supplementing the drinking water of the pregnant mouse. If myo-inositol deficiency is found to exist in the GALT-deficient fetal brain, then the use of myo-inositol to treat the fetus via oral supplementation of the pregnant female may warrant consideration.
This open-label, uncontrolled, 25-year study of treatment with sodium phenylacetate and sodium benzoate documents overall survival of 84% in historically lethal urea-cycle disorders characterized by ...acute hyperammonemic episodes. When episodes are promptly recognized and treated with this therapy, together with intravenous arginine hydrochloride and adequate calories to prevent catabolism, plus dialysis when necessary, plasma ammonium levels fall, markedly improving survival.
This 25-year study of treatment with sodium phenylacetate and sodium benzoate documents overall survival of 84% in historically lethal urea-cycle disorders characterized by acute hyperammonemic episodes.
Urea-cycle disorders are inborn errors of metabolism that are characterized by episodic, life-threatening hyperammonemia resulting from partial or complete inactivity of enzymes responsible for eliminating nitrogenous waste. Historically, mortality and morbidity have been very high, and survivors commonly have had devastating neurologic sequelae.
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Initial efforts to remove accumulated ammonium in patients with hyperammonemic encephalopathy included lactulose therapy,
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exchange transfusion,
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,
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peritoneal dialysis,
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hemodialysis,
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and supplementation with nitrogen-free analogues of essential amino acids.
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These treatments prolonged survival in some patients, but the overall efficacy was disappointing — and mortality and morbidity remained high.
Current therapeutic strategies include reducing the production of . . .
High serum serotonin in sudden infant death syndrome Haynes, Robin L.; Frelinger, Andrew L.; Giles, Emma K. ...
Proceedings of the National Academy of Sciences - PNAS,
07/2017, Letnik:
114, Številka:
29
Journal Article
Recenzirano
Odprti dostop
Sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality, likely comprises heterogeneous disorders with the common phenotype of sudden death without explanation upon ...postmortem investigation. Previously, we reported that ∼40% of SIDS deaths are associated with abnormalities in serotonin (5-hydroxytryptamine, 5-HT) in regions of the brainstem critical in homeostatic regulation. Here we tested the hypothesis that SIDS is associated with an alteration in serum 5-HT levels. Serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15) SIDS, 177.2 ± 15.1 (mean ± SE) ng/mL versus controls, 91.1 ± 30.6 ng/mL (P = 0.014), as determined by ELISA. This increase was validated using high-performance liquid chromatography. Thirty-one percent (19/61) of SIDS cases had 5-HT levels greater than 2 SDs above the mean of the controls, thus defining a subset of SIDS cases with elevated 5-HT. There was no association between genotypes of the serotonin transporter promoter region polymorphism and serum5-HT level. This study demonstrates that SIDS is associated with peripheral abnormalities in the 5-HT pathway. High serum 5-HT may serve as a potential forensic biomarker in autopsied infants with SIDS with serotonergic defects.
Pathogenic variants in the SRCAP (SNF2-related CREBBP activator protein) gene, which encodes a chromatin-remodeling ATPase, cause neurodevelopmental disorders including Floating Harbor syndrome ...(FLHS). Here, we report the discovery of a de novo transposon insertion in SRCAP exon 13 from trio genome sequencing in a 28-year-old female with failure to thrive, developmental delay, mood disorder and seizure disorder. The insertion was a full-length (~2.8 kb), antisense-oriented SVA insertion relative to the SRCAP transcript, bearing a 5' transduction and hallmarks of target-primed reverse transcription. The 20-bp 5' transduction allowed us to trace the source SVA element to an intron of a long non-coding RNA on chromosome 12, which is highly expressed in testis. RNA sequencing and qRT-PCR confirmed significant depletion of SRCAP expression and low-level exon skipping in the proband. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.