Congenital disorders of glycosylation presenting as epileptic encephalopathy with migrating partial seizures in infancy

Aim: Epilepsy is commonly observed in congenital disorders of glycosylation (CDG), but no distinctive electroclinical pattern has been recognized. We aimed at identifying a characteristic clinical presentation that might help targeted diagnostic work-up. Method: Based on the initial observation of an index case with CDG and migrating partial seizures, we evaluated 16 additional children with CDG and analysed their clinical course, biochemical, genetic, electrographic, and imaging findings. Results: Four of 17 consecutively observed children with CDG (three females, one male) were first referred between the first and fourth month of life, after early onset of migrating partial seizures. All four patients manifested developmental delay, microcephaly, and multi-organ involvement. Magnetic resonance imaging disclosed cerebral and cerebellar atrophy. Isoelectrofocusing of transferrin, enzymatic studies, and lipid-linked oligosaccharide analysis indicated CDG-I. Genetic testing demonstrated either homozygous or compound heterozygous variants involving the ALG3 gene in patients 1 and 3, the RFT1 gene in patient 2, and the ALG1 gene in patient 4. At last follow-up, patients 1 and 2 were 5 and 31/2 years old. Patients 3 and 4 had died due to respiratory failure during pneumonia and refractory status epilepticus respectively. Interpretation: Children with migrating partial seizures and concomitant multisystem involvement should be investigated for CDG

Challenges in molecular diagnosis of X-linked Intellectual disability

BACKGROUND: Intellectual disability (ID) affects 1-3% of the Western population and is heterogeneous in origin. Mutations in X-linked genes represent 5-10% of ID in males. Fragile X syndrome, due to the silencing of the FMR1 gene, is the most common form of ID, with a prevalence of around 1:5000 males. Females are usually non- or mildly affected carriers, and in a few rare cases, the only gender affected. Array comparative genome hybridization (aCGH) and next-generation sequencing (NGS) have dramatically changed the nature of human genome analysis leading to the identification of new X-linked intellectual disability syndromes and disease-causing genes. SOURCES OF DATA: Original papers, reviews, guidelines and experiences of the diagnostic laboratories. AREAS OF AGREEMENT: Family history and clinical examination still are essential to choose the appropriate diagnostic tests, including, a disease-specific genetic test, aCGH or FMR1 molecular analysis. If negative, NGS approaches like well-defined gene panels, whole exome, or even whole genome sequencing, are increasingly being used, improving diagnostics and leading to the identification of novel disease mechanisms. AREAS OF CONTROVERSY: The main challenge in the era of NGS is filtering and interpretation of the data generated by the analysis of a single individual. In X-linked cases, assessing pathogenicity is particularly challenging, even more when the variant is found to be inherited from a healthy carrier mother or when a heterozygous X-linked mutation is found in an impaired female. GROWING POINTS: At present, variant interpretation remains a challenging task, especially in X-linked disorders. We review the main difficulties and propose a comprehensive overview that might aid in variant interpretation. Establishing a genetic diagnosis facilitates counseling and allows better delineation of clinical phenotypes. AREAS TIMELY FOR DEVELOPING RESEARCH: To improve variant interpretation, there is need to refine in silico predictions with specific criteria for each gene, and to develop cost-effective functional tools, which can be easily transferred to diagnostics.status: publishe

Quality control of glycoproteins bearing truncated glycans in an ALG9 defective (CDG-IL) patient

We describe an ALG9 defective (Congenital Disorders of Glycosylation type IL) patient who is homozygous for the p.Y286C (c.860A>G) mutation. This patient presented with psychomotor retardation, axial hypotonia, epilepsy, failure to thrive, inverted nipples, hepatomegaly and pericardial effusion. Due to the ALG9 deficiency, the cells of this patient accumulated the lipid-linked oligosaccharides Man(6)GlcNAc(2)-PP-dolichol and Man(8)GlcNAc(2)-PP-dolichol. It is known that the oligosaccharide structure has a profound effect on protein glycosylation. Therefore we investigated the influence of these truncated oligosaccharide structures on the protein transfer efficiency, the quality control of newly synthesized glycoproteins and the eventual degradation of the truncated glycoproteins formed in this patient. We demonstrated that lipid-linked Man(6)GlcNAc(2) and Man(8)GlcNAc(2) are transferred onto proteins with the same efficiency. In addition, glycoproteins bearing these Man(6)GlcNAc(2) and Man(8)GlcNAc(2) structures efficiently entered in the glucosylation/deglucosylation cycle of the quality control system to assist in protein folding. We also showed that in comparison to control cells, patient's cells degraded misfolded glycoproteins at an increasing rate. In comparison to Man(6)GlcNAc(2), the Man(8)GlcNAc(2) isomer C on the patient's glycoproteins was found to promote the degradation of misfolded glycoproteins.status: publishe

Galactose Epimerase Deficiency: Expanding the Phenotype

Galactose epimerase deficiency is an inborn error of metabolism due to uridine diphosphate-galactose-4'-epimerase (GALE) deficiency. We report the clinical presentation, genetic and biochemical studies in two siblings with generalized GALE deficiency.Patient 1: The first child was born with a dysmorphic syndrome. Failure to thrive was noticed during the first year. Episodes of heart failure due to dilated cardiomyopathy, followed by liver failure, occurred between 12 and 42 months. The finding of a serum transferrin isoelectrofocusing (IEF) type 1 pattern led to the suspicion of a congenital disorder of glycosylation (CDG). Follow-up disclosed psychomotor disability, deafness, and nuclear cataracts.Patient 2: The sibling of patient 1 was born with short limbs and hip dysplasia. She is deceased in the neonatal period due to intraventricular hemorrhage in the context of liver failure. Investigation disclosed galactosuria and normal transferrin glycosylation.Next-generation sequence panel analysis for CDG syndrome revealed the previously reported c.280G>A (p.[V94M]) homozygous mutation in the GALE gene. Enzymatic studies in erythrocytes (patient 1) and fibroblasts (patients 1 and 2) revealed markedly reduced GALE activity confirming generalized GALE deficiency. This report describes the fourth family with generalized GALE deficiency, expanding the clinical spectrum of this disorder, since major cardiac involvement has not been reported before.status: publishe

COG5-CDG: expanding the clinical spectrum

ABSTRACT: BACKGROUND: The Conserved Oligomeric Golgi (COG) complex is involved in the retrograde trafficking of Golgi components, thereby affecting the localization of Golgi glycosyltransferases. Deficiency of a COG-subunit leads to defective protein glycosylation, and thus Congenital Disorders of Glycosylation (CDG). Mutations in subunits 1, 4, 5, 6, 7 and 8 have been associated with CDG-II. The first patient with COG5-CDG was recently described (Paesold-Burda et al. Hum Mol Genet 2009; 18:4350--6). Contrary to most other COG-CDG cases, the patient presented a mild/moderate phenotype, i.e. moderate psychomotor retardation with language delay, truncal ataxia and slight hypotonia. METHODS: CDG-IIx patients from our database were screened for mutations in COG5. Clinical data were compared. Brefeldin A treatment of fibroblasts and immunoblotting experiments were performed to support the diagnosis.Results and conclusion: We identified five new patients with proven COG5 deficiency. We conclude that the clinical picture is not always as mild as previously described. It rather comprises a broad spectrum with phenotypes ranging from mild to very severe. Interestingly, on a clinical basis some of the patients present a significant overlap with COG7-CDG, a finding which can probably be explained by subunit interactions at the protein level.status: publishe

COG5-CDG: Expanding the clinical spectrum

Background: The Conserved Oligomeric Golgi (COG) complex is involved in the retrograde trafficking of Golgi components, thereby affecting the localization of Golgi glycosyltransferases. Deficiency of a COG-subunit leads to defective protein glycosylation, and thus Congenital Disorders of Glycosylation (CDG). Mutations in subunits 1, 4, 5, 6, 7 and 8 have been associated with CDG-II. The first patient with COG5-CDG was recently described (Paesold-Burda et al. Hum Mol Genet 2009; 18:4350-6). Contrary to most other COG-CDG cases, the patient presented a mild/moderate phenotype, i.e. moderate psychomotor retardation with language delay, truncal ataxia and slight hypotonia. Methods. CDG-IIx patients from our database were screened for mutations in COG5. Clinical data were compared. Brefeldin A treatment of fibroblasts and immunoblotting experiments were performed to support the diagnosis. Results and conclusion. We identified five new patients with proven COG5 deficiency. We conclude that the clinical picture is not always as mild as previously described. It rather comprises a broad spectrum with phenotypes ranging from mild to very severe. Interestingly, on a clinical basis some of the patients present a significant overlap with COG7-CDG, a finding which can probably be explained by subunit interactions at the protein level. © 2012 Rymen et al. licensee BioMed Central Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Erratum: COG5-CDG: Expanding the clinical spectrum (Orphanet Journal of Rare Diseases (2013) 8 (120))

SCOPUS: er.jinfo:eu-repo/semantics/publishe

SLC37A4-CDG: Second patient.

Recently, a disorder caused by the heterozygous de novo c.1267C>T (p.R423*) substitution in has been described. This causes mislocalization of the glucose-6-phosphate transporter to the Golgi leading to a congenital disorder of glycosylation type II (SLC37A4-CDG). Only one patient has been reported showing liver disease that improved with age and mild dysmorphism. Here we report the second patient with a type II CDG caused by the same heterozygous de novo c.1267C>T (p.R423*) mutation thereby confirming the pathogenicity of this variant and expanding the clinical picture with type 1 diabetes, severe scoliosis, and membranoproliferative glomerulonephritis. Additional clinical and biochemical data provide further insight into the mechanism and prognosis of SLC37A4-CDG

CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking

International audienceThe transmembrane domain recognition complex (TRC) pathway is required for the insertion of C-terminal tail-anchored (TA) proteins into the lipid bilayer of specific intracellular organelles such as the endoplasmic reticulum (ER) membrane. In order to facilitate correct insertion, the recognition complex (consisting of BAG6, GET4 and UBL4A) must first bind to TA proteins and then to GET3 (TRC40, ASNA1), which chaperones the protein to the ER membrane. Subsequently, GET1 (WRB) and CAML form a receptor that enables integration of the TA protein within the lipid bilayer. We report an individual with the homozygous c.633 + 4A>G splice variant in CAMLG, encoding CAML. This variant leads to aberrant splicing and lack of functional protein in patient-derived fibroblasts. The patient displays a predominantly neurological phenotype with psychomotor disability, hypotonia, epilepsy and structural brain abnormalities. Biochemically, a combined O-linked and type II N-linked glycosylation defect was found. Mislocalization of syntaxin-5 in patient fibroblasts and in siCAMLG deleted Hela cells confirms this as a consistent cellular marker of TRC dysfunction. Interestingly, the level of the v-SNARE Bet1L is also drastically reduced in both of these models, indicating a fundamental role of the TRC complex in the assembly of Golgi SNARE complexes. It also points towards a possible mechanism behind the hyposialylation of N and O-glycans. This is the first reported patient with pathogenic variants in CAMLG. CAMLG-CDG is the third disorder, after GET4 and GET3 deficiencies, caused by pathogenic variants in a member of the TRC pathway, further expanding this novel group of disorders

Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype

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