ALG6‐CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies

Morava, Éva; Tiemes, Vera; Thiel, Christian; Seta, Nathalie; Lonlay, Pascale de; Klerk, H. de; Mulder, Margot F.; Rubio-Gozalbo, M. Estela; Visser, Gepke; Hasselt, Peter van; Horovitz, Dafne D.G.; Souza, Carolina Fischinger Moura de; Schwartz, Ida Vanessa Döederlein; Green, Andrew J.; Al‐Owain, Mohammed; Uziel, Graciella; Sigaudy, Sabine; Chabrol, B.; Spronsen, F. J. van; Steinert, Martin; Komini, Eleni; Wurm, Donald; Bevot, Andrea; Ayadi, Addelkarim; Huijben, Karin; Dercksen, Marli; Witters, Peter; Jaeken, Jaak; Matthijs, Gert; Lefeber, Dirk; Wevers, Ron A.

doi:10.1007/s10545-016-9945-x

Cited by 38 publications

(29 citation statements)

References 13 publications

(21 reference statements)

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“…Impaired DLO glucosylation, similar to that seen here with UGP − cells ( Figure 5A), causes protein hypoglycosylation in ALG6-CDG patients [16]. These patients present with mutations in the ALG6 gene, which encodes the glucosyltransferase that adds the first glucose residue onto the Man 9 GlcNAc 2 -PP-dolichol N-glycosylation precursor.…”

Section: Impaired Protein N-glycosylation In Ugp − Cellssupporting

confidence: 67%

“…In patients with congenital disorder of glycosylation (CDG) associated with mutations in the ALG6 gene, which encodes Man 9 GlcNAc 2 -PP-dolichol: dolichol-Glc glucosyltransferase, Man 9 GlcNAc 2 -PP-dolichol is poorly glucosylated and inefficient protein N-glycosylation ensues [16]. Accordingly, we looked at the efficiency of prion protein (PrP C ) N-glycosylation in UGP − cells.…”

Section: Ugp − Cells Are Unable To Glucosylate Dolichol-linked Oligosmentioning

confidence: 99%

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Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium

Durrant

Fuehring

Willemetz

et al. 2020

IJMS

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UDP-glucose (UDP-Glc) is synthesized by UGP2-encoded UDP-Glc pyrophosphorylase (UGP) and is required for glycoconjugate biosynthesis and galactose metabolism because it is a uridyl donor for galactose-1-P (Gal1P) uridyltransferase. Chinese hamster lung fibroblasts harboring a hypomrphic UGP(G116D) variant display reduced UDP-Glc levels and cannot grow if galactose is the sole carbon source. Here, these cells were cultivated with glucose in either the absence or presence of galactose in order to investigate glycoconjugate biosynthesis and galactose metabolism. The UGP-deficient cells display < 5% control levels of UDP-Glc/UDP-Gal and > 100-fold reduction of [6-3H]galactose incorporation into UDP-[6-3H]galactose, as well as multiple deficits in glycoconjugate biosynthesis. Cultivation of these cells in the presence of galactose leads to partial restoration of UDP-Glc levels, galactose metabolism and glycoconjugate biosynthesis. The Vmax for recombinant human UGP(G116D) with Glc1P is 2000-fold less than that of the wild-type protein, and UGP(G116D) displayed a mildly elevated Km for Glc1P, but no activity of the mutant enzyme towards Gal1P was detectable. To conclude, although the mechanism behind UDP-Glc/Gal production in the UGP-deficient cells remains to be determined, the capacity of this cell line to change its glycosylation status as a function of extracellular galactose makes it a useful, reversible model with which to study different aspects of galactose metabolism and glycoconjugate biosynthesis.

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Section: Impaired Protein N-glycosylation In Ugp − Cellssupporting

confidence: 67%

Section: Ugp − Cells Are Unable To Glucosylate Dolichol-linked Oligosmentioning

confidence: 99%

Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium

Durrant

Fuehring

Willemetz

et al. 2020

IJMS

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“…There are several different inborn errors of metabolism, where the associated ASD has been hypothesized to correlate with a neurodevelopmental defects and congenital brain anomalies, like congenital disorders of glycosylation (CDG) or Smith Lemli Opitz syndrome [9,10]. However, no similar brain abnormalities have been observed in our patients with PA. Basal ganglia involvement is also associated with higher frequency of autistic features, but we didn't find correlation between basal ganglia abnormalities and ASD in our small cohort [16].…”

Section: Discussionmentioning

confidence: 61%

“…Several inborn errors of metabolism have been described as increasing a patient's risk for ASD, including lysosomal storage diseases, disorders of the creatine synthesis, disorders of purine and pyrimidine metabolism or dysfunction of the urea cycle, but autistic features are not frequently reported in organic acidemias [5,8,9,10,11]. With the growing frequency of patients being diagnosed with ASD, sometimes it is difficult exclude a coincidental diagnosis of autism in certain metabolic conditions from comorbidity, especially in case of intellectual disability.…”

Section: Introductionmentioning

confidence: 99%

Autism in patients with propionic acidemia

Witters

Debbold

Crivelly

et al. 2016

Molecular Genetics and Metabolism

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Certain inborn errors of metabolism have been suggested to increase the risk of autistic behavior. In an animal model, propionic acid ingestion triggered abnormal behavior resembling autism. So far only a few cases were reported with propionic acidemia and autistic features. From a series of twelve consecutively diagnosed cases with propionic acidemia, we report on eight patients with autistic features. The patients were followed 2-4 times a year and underwent regular clinical, dietary and laboratory investigations. Psychological evaluation was performed every second to fourth year. All patients were compliant with the standard diet and carnitine supplementation. None of the patients had frequent metabolic decompensations. From the metabolic factors known to impact neuropsychological outcome we detected chronically decreased valine levels and altered valine to leucine ratios in five out of the eight patients. Recurrent lactic acid elevations were present in six out of the eight patients. Five of the eight patients were diagnosed with Autism Spectrum Disorder, four of them had pathogenic variants in PCCB. Disorder according to DSM-IV and/or DSM-5 criteria. One of the patients diagnosed with propionic acidemia by newborn screening had the most significant behavioral features and another was diagnosed with Autism Spectrum Disorder prior to propionic acidemia. We hypothesize that chronic suboptimal intracellular metabolic balance may be responsible for the increased risk for autistic features in propionic acidemia. We propose that patients diagnosed with propionic acidemia should be screened for Autism Spectrum Disorder.

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“…The α-1,3-glucosyltransferase (ALG6)-CDG (previously called CDG Ic) is a defect in N-glycan assembly in the endoplasmic reticulum and is, after PMM2-CDG, the second most common type of CDG [41,42]. Analysis of the serum of an ALG6-CDG patient revealed a CZE pattern that is essentially identical to that of PMM2 (Figure 2A).…”

Section: Diversity Of Tf Patterns Of Type I Patientsmentioning

confidence: 99%

High‐resolution capillary zone electrophoresis for transferrin glycoform analysis associated with congenital disorders of glycosylation

Tobler

Caslavska

Burda

et al. 2018

J of Separation Science

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High-resolution capillary zone electrophoresis is used to assess the transferrin profile in serum of patients with eight different congenital disorders of glycosylation that represent type I, type II, and mixed type I/II disorders. Capillary zone electrophoresis data are compared to patterns obtained by gel isoelectric focusing. The high-resolution capillary zone electrophoresis method is shown to represent an effective tool to assess the diversity of transferrin patterns. Hypoglycosylated disialo-, monosialo-, and asialo-transferrin in type I cases can be distinguished from the corresponding underdesialylated transferrin glycoforms present in type II disorders. The latter can be separated from and detected ahead of their corresponding hypoglycosylated forms of type I patients. Both types of glycoforms are detected in sera of mixed type I/II patients. The assay has the potential to be used as screening method for congenital disorders of glycosylation. It can be run with a few microliters of serum when microvials are used.

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ALG6‐CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies

Cited by 38 publications

References 13 publications

Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium

Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium

Autism in patients with propionic acidemia

High‐resolution capillary zone electrophoresis for transferrin glycoform analysis associated with congenital disorders of glycosylation

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