Pubertal development in ALG6 deficiency (congenital disorder of glycosylation type Ic)

Information on the hypothalamic pituitary ovarian axis in congenital disorders of glycosylation (CDG) females is scarce. Varying hormonal profiles and degrees of virilization in CDG females suggest a spectrum of yet unidentified mechanisms affected by impaired N-glycosylation. We describe an ALG6D woman who completed puberty with normal gonadotropins and testosterone levels, no virilization, and regular menses. Hormonal follow-up of CDG females is necessary to improve our understanding of the role of glycosylation in pubertal development.     

先天性糖基化病的研究进展

先天性糖基化病 (ｃｏｎｇｅｎｉｔａｌｄｉｓｏｒｄｅｒｓｏｆｇｌｙｃｏｓｙｌａ ｔｉｏｎ,ＣＤＧ) ,旧称为糖类缺陷性糖蛋白综合征 (ｃａｒｂｏ ｈｙｄｒａｔｅ-ｄｅｆｉｃｉｅｎｔｇｌｙｃｏｐｒｏｔｅｉｎｓｙｎｄｒｏｍｅｓ,ＣＤＧＳ) ,是一类由于聚糖的合成和结合到其他复合体 (蛋白质和脂质 )过程的缺陷引起的常染色体隐性遗传病[1,2 ] 。绝大多数ＣＤＧ患者有多种系统病变且均有不同程度的精神发育迟缓。迄今发现的ＣＤＧ主要是由于人体内蛋白Ｎ -糖基化途径缺陷引起的 ,不同酶的缺陷产生不同的ＣＤＧ类型。最新的命名系统将脂联寡…     

Risk assessment of acute vascular events in congenital disorder of glycosylation type Ia

The congenital disorder of glycosylation type Ia (CDG-Ia) presents a broad clinical spectrum. Some patients suffer from acute vascular events (thrombosis and bleeding) and stroke-like events. No correlations have been made between the marked hemostasis abnormalities of CDG-Ia and the occurrence of acute vascular events. We report on 6 patients with CDG-Ia presenting vascular events, then we analyze the clinical and hemostasis data of 39 CDG-Ia patients described in the literature, 17 with vascular events (E) and 21 unscathed from any event (EF), to determine the risk factors for acute vascular events in CDG-Ia. Acute vascular events occurred in patients younger than 15 years, especially with fever and prolonged immobilization. Hemostasis and liver cytolysis were statistically abnormal in patients younger than 5 years whatever the occurrence of vascular events and they normalized with time. Higher factors VIII and IX activities were statistically observed in the E cluster (p = 0.03) compared to the EF cluster. The activity/antigenicity ratio for protein C (p = 0.02) was also higher in the E group. CDG-Ia patients younger than 15 years old are at risk of acute vascular events. The paradoxical results—abnormal VIII and IX factors in EF patients and normal results in E patients, while XI, antithrombin, protein C, ASAT and ALAT are abnormal in both groups, could suggest a disequilibrium between prothrombotic and antithrombotic factors in the E group. Vascular events may also occur in patients where glycoproteins are proportionally more hypoglycosylated, particularly protein C.     

Exome sequence identified a c.320A > G ALG13 variant in a female with infantile epileptic encephalopathy with normal glycosylation and random X inactivation: Review of the literature

Congenital Disorders of Glycosylation (CDG) are new and rapidly expanding neurometabolic disorders with multisystem involvements, broad phenotypic manifestations, and variable severity. The majority results from a defect of one of the steps involved with protein or lipid N-glycosylation pathway. Almost all are inherited in autosomal recessive patterns with a few exceptions such as the X-linked ALG13. Mutations of ALG13 are reported, so far in only 10 patients, all were ascertained through exome/genome sequencing. Specifically, the ALG13 c.320A > G (p.Asn107Ser) variant was reported only in females and in all were de novo mutations. These findings may suggest an X-linked dominant inheritance of this mutation with embryonic male lethality. These patients presented with severe infantile epileptic encephalopathy, global developmental delay, and multisystem abnormalities. Only two of these females had glycosylation studies done, and both showed normal pattern of glycosylated serum transferrin isoforms, and none had their X-chromosome inactivation patterns studied.Here, we report on another female patient who is heterozygous for the same ALG13 c.320A > G (p.Asn107Ser) variant. She presented with infantile spasms, epileptic encephalopathy, hypsarrhythmia, hypotonia, developmental delay, intellectual disability, abnormal coagulation profile, feeding problems, hypotonia, and dysmorphic features. The diagnosis of CGD was suspected clinically, but glycosylation studies were done twice and showed normal patterns on both occasions. Her X-inactivation study was also done and, surprisingly, showed a random pattern of X-inactivation, with no evidence of skewness.     

Novel variants and clinical symptoms in four new ALG3‐CDG patients,review of the literature,and identification of AAGRP‐ALG3 as a novel ALG3 variant with alanine and glycine‐rich N‐terminus

ALG3‐CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER‐mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3‐CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man₅GlcNAc₂‐PP‐dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right‐descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3‐CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open‐reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP‐ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.     

一个先天性糖基化病家系的临床特征和致病变异分析

目的:探讨一个先天性糖基化病家系的临床特点及遗传学特征。方法:对该家系两例患者的临床资料进行分析,对家系成员进行全外显子组测序,并用Sanger测序对疑似致病变异进行验证。结果:先证者及其弟弟均携带 PMM2基因复合杂合突变,其中第5外显子的c.395T>C(p.I132T)为已知致病突变,第5内含子的c....     

Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip

Congenital disorders of glycosylation (CDG) comprise a clinically and biochemically heterogeneous group of monogenetic-inherited, multisystemic diseases that affect the biosynthesis of N- and/or O-glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic-orientated GDP-mannose:Man(3-4) GlcNAc(2)-PP-dolichol alpha-1,2-mannosyltransferase (ALG11), who presented an accumulation of shortened dolichol-linked oligosaccharides leading to CDG-Ip (ALG11-CDG). Here we describe an improved metabolic labeling method that allowed the identification of three new CDG-Ip cases that were missed so far in routine diagnostics. Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life.     

TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability

PurposeTRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.MethodsExome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients’ blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.ResultsAll 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.ConclusionWe identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.     

The liver in congenital disorders of glycosylation: ultrastructural features

A new group of genetic diseases characterized by defective glycoprotein biosynthesis was recently described. Transferrin isoelectric focusing enabled identification of several types of patients with congenital disorders of glycosylation (CDG). The authors report on the liver involvement in two siblings with CDG type Ix presenting with failure to thrive and hypertransaminasemia who developed cardiomyopathy. In the initially affected infant, liver biopsy at 13 months of age showed increased periportal cellularity, steatosis, and mild fibrosis. Ultrastructurally, the hepatocytes displayed numerous myelinosomes, mostly with a pericanalicular polarization. No myelinosomes were seen in the bile canaliculi, Kupffer cells, and sinusoidal lining cells. Focal large droplet steatosis was also noticed. These ultrastructural findings represent another diagnostic element in this heterogenic group of conditions. Electron microscopy can contribute to the elucidation of hypertransaminasemia and differentiate some types of CDG from other lysosomal diseases.     

Single‐center experience of N‐linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs

Congenital disorders of glycosylation (CDG) represent an expanding group of conditions that result from defects in protein and lipid glycosylation. Different subgroups of CDG display considerable clinical and genetic heterogeneity due to the highly complex nature of cellular glycosylation. This is further complicated by ethno‐geographic differences in the mutational landscape of each of these subgroups. Ten Arab CDG patients from Latifa Hospital in Dubai, United Arab Emirates, were assessed using biochemical (glycosylation status of transferrin) and molecular approaches (next‐generation sequencing [NGS] and Sanger sequencing). In silico tools including CADD and PolyPhen‐2 were used to predict the functional consequences of uncovered mutations. In our sample of patients, five novel mutations were uncovered in the genes: MPDU1, PMM2, MAN1B1, and RFT1. In total, 9 mutations were harbored by the 10 patients in 7 genes. These are missense and nonsense mutations with deleterious functional consequences. This article integrates a single‐center experience within a list of reported CDG mutations in the Arab world, accompanied by full molecular and clinical details pertaining to the studied cases. It also sheds light on potential ethnic differences that were not noted before in regards to CDG in the Arab world.     

The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy

Potassium channels in the plasma membrane of the pancreatic beta cells are critical in maintaining glucose homeostasis by responding to ATP and coupling metabolic changes to insulin secretion. These channels consist of subunits denoted the sulfonylurea receptor SUR1 and the inwardly rectifying ion channel KIR6.2, which are encoded by the genes ABCC8 and KCNJ11 , respectively. Activating mutations in the subunit genes can result in monogenic diabetes, whereas inactivating mutations are the most common cause of congenital hyperinsulinism of infancy (CHI). Twenty-six Norwegian probands with CHI were analyzed for alterations in ABCC8 and KCNJ11 . Fifteen probands (58%) had mutations in the ABCC8 gene. Nine patients were homozygous or compound heterozygous for the mutations, indicating diffuse pancreatic disease. In five patients, heterozygous and paternally inherited mutations were found, suggesting focal disease. One patient had a de novo mutation likely to cause a milder, dominant form of CHI. Altogether, 16 different ABCC8 mutations (including the novel alterations W231R, C267X, IVS6-3C>G, I462V, Q917X and T1531A) were identified. The mutations IVS10+1G>T, R1493W and V21D occurred in five, three and two families, respectively. KCNJ11 mutations were not found in any patients. Based on our mutation screening, we estimate the minimum birth prevalence of ABCC8 -CHI in Norway to 1:70,000 during the past decade. Our results considerably extend the knowledge of the molecular genetics behind CHI in Scandinavia.     

Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic

Congenital Disorder of Glycosylation (CDG) type Ic is caused by mutations in ALG6. This gene encodes an alpha1,3 glucosyltransferase used for synthesis of the lipid linked oligosaccharide (LLO) precursor of the protein N-glycosylation pathway. CDG-Ic patients have moderate to severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties. We previously identified a typical patient with a heterozygous point mutation, c.391T>C (p.Tyr131His) in ALG6. Using complementation analysis of ALG6-deficient yeast, we show that this alteration is as severe as the most common disease-causing mutation, c998C>T (p. Ala333Val), which occurs in over half of all known CDG-Ic patients. The frequency of c.391T>C (p.Tyr131His) in the US population, is 0.0214, suggesting that homozygotes would occur at a rate of& tilde;1:2,200. We identified one patient with typical CDG-Ic symptoms and a homozygous p.Tyr131His alteration in ALG6. However, in contrast to most CDG patients, her LLO and plasma transferrin glycosylation appeared normal. Thus, it is unclear whether c.391T>C causes CDG-Ic or contributes to the symptoms. Genotyping additional patients with CDG-like symptoms will be required to resolve this issue.     

Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.     

The skeletal manifestations of the congenital disorders of glycosylation

The congenital disorders of glycosylation (CDG) are a rapidly expanding disease group with protean presentations. Specific end-organ involvement leads to significant morbidity and mortality, and the skeletal manifestations are often not appreciated, apart from the common association of osteopaenia with CDG-Ia. We performed a literature review of all documented skeletal manifestations in reported CDG patients, revealing a diverse range of skeletal phenotypes. We discuss the possible underlying mechanisms of these skeletal manifestations observed in CDG that are important and frequently under-recognized.