Congenital disorder of glycosylation (CDG)-Ih patient with a severe hepato-intestinal phenotype and evolving central nervous system pathology
ABSTRACT We present the clinical, molecular, and biochemical diagnosis of a patient with congenital disorder of glycosylation (CDG)-Ih. We report significant brain dysfunction in this multisystem disease, further expanding its complex clinical spectrum.
- SourceAvailable from: Conny van Ravenswaaij-Arts
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- "Cataract has been described in ALG8-CDG (CDG-Ih) and as a later presentation in PMM2-CDG. Congenital colobomas, however , are extremely rare in CDG syndromes (De Lonlay et al., 2001; Thiel et al., 2003; Eklund et al., 2005; Morava et al., 2008). Glaucoma has not yet been described in other types of CDG defects (Morava et al., 2008). "
ABSTRACT: Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.Brain 11/2010; 133(11):3210-20. DOI:10.1093/brain/awq261 · 9.20 Impact Factor
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- " , they presented with hypotonia , ataxia , and mental retardation [ Stölting et al . , in press ] . The ALG8 a - 1 , 3 glucosyltransferase is predicted to be an 11 TM domain ER protein with a size of 526 amino acids ( Fig . 11 ) . To date , 12 mutations have been described ( Supp . Table S10 ) [ Chantret et al . , 2003 ; Schollen et al . , 2004 ; Eklund et al . , 2005b ; Stölting et al . , in press ; Vesela et al . , in press ] . The p . N222S mutation is likely to represent a single nucleotide polymorphism , since the healthy father of a patient is homozygous for this mutation [ Schollen et al . , 2004 ] . The other 11 mutations segregate into four missense mutations , one nonsense mutation , three s"
ABSTRACT: Defects in the biosynthesis of the oligosaccharide precursor for N-glycosylation lead to decreased occupancy of glycosylation sites and thereby to diseases known as congenital disorders of glycosylation (CDG). In the last 20 years, approximately 1,000 CDG patients have been identified presenting with multiple organ dysfunctions. This review sets the state of the art by listing all mutations identified in the 15 genes (PMM2, MPI, DPAGT1, ALG1, ALG2, ALG3, ALG9, ALG12, ALG6, ALG8, DOLK, DPM1, DPM3, MPDU1, and RFT1) that yield a deficiency of dolichol-linked oligosaccharide biosynthesis. The present analysis shows that most mutations lead to substitutions of strongly conserved amino acid residues across eukaryotes. Furthermore, the comparison between the different forms of CDG affecting dolichol-linked oligosaccharide biosynthesis shows that the severity of the disease does not relate to the position of the mutated gene along this biosynthetic pathway.Human Mutation 12/2009; 30(12):1628-41. DOI:10.1002/humu.21126 · 5.14 Impact Factor
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- "413delC Exon 4 Frameshift, premature stop codon (PTC) and probably nonsense mediated decay (NMD, both) 396insA Exon 4 Schollen et al.  c.96-2A>G Intron 1 Aberrant splicing, probably NMD c.139A>C Exon 2 Missense mutation c.672+4A>G Intron 6 Aberrant splicing, probably NMD c.824G>A Exon 8 Missense mutation Eklund et al.  "
ABSTRACT: Congenital disorders of glycosylation (CDG) are an expanding group of inherited disorders caused by defects in the N- or O-Glycosylation of proteins and lipids. Several CDG subtypes have been described so far, including CDG type Ih which is caused by a deficiency of the dolichyl-P-Glc:Glc(1)Man(9)GlcNAc(2)-PP-dolichyl alpha1,3-glucosyltransferase (hALG8). The defect leads to an accumulation of Dol-PP-GlcNAc(2)Man(9) and Dol-PP-GlcNAc(2)Man(9)Glc(1) in the endoplasmic reticulum of patients' fibroblasts that can be detected by analyzing the lipid-linked oligosaccharyl intermediates. Five patients with CDG-Ih have been described so far. The clinical presentation of four of these patients was severe with death in early infancy. In this report, we describe two mildly affected siblings with CDG-Ih caused by two novel mutations. While one mutation (c.1434delC) causes a frame shift resulting in a premature termination codon (p.485X), the point mutation of the other allele (c.845C>T, p.A282V) causes an amino acid replacement in a highly conserved region of the hALG8 gene. The two siblings show similar symptoms, including pseudo-gynecomastia, epicanthus, muscular hypotonia, mental retardation and ataxia, expanding the genetic and clinical spectrum of CDG-Ih.Molecular Genetics and Metabolism 06/2009; 98(3):305-9. DOI:10.1016/j.ymgme.2009.06.010 · 2.63 Impact Factor