UNASSIGNED: Congenital disorders of glycosylation (CDG) refer to monogenetic diseases characterized by defective glycosylation of proteins or lipids causing multi-organ disorders. Here, we investigate the clinical features and genetic variants of SSR4-CDG and conduct a preliminary investigation of its pathogenesis.
UNASSIGNED: We retrospectively report the clinical data of a male infant with early life respiratory distress, congenital diaphragmatic eventration, cosmetic deformities, and moderate growth retardation. Peripheral blood was collected from the case and parents, genomic DNA was extracted and whole-exome sequencing was performed. The mRNA expression of SSR4 gene was quantified by Real-time Quantitative PCR. RNA sequencing analysis was subsequently performed on the case and a healthy child.
UNASSIGNED: Whole-exome sequencing of the case and his parents\' genomic DNA identified a hemizygous c.80_96del in SSR4, combined with the case\'s clinical features, the diagnosis of CDG was finally considered. In this case, the expression of SSR4 was downregulated. The case were present with 1,078 genes downregulated and 536 genes upregulated. SSR4 gene expression was significantly downregulated in the case. Meanwhile, gene set enrichment analysis (GSEA) revealed that SSR4-CDG may affect hemostasis, coagulation, catabolism, erythrocyte development and homeostatic regulation, and muscle contraction and regulation, etc. Improvement of growth retardation in case after high calorie formula feeding and rehabilitation training.
UNASSIGNED: Our study expanded the SSR4-CDG variant spectrum and clinical phenotype and analyzed pathways potentially affected by SSR4-CDG, which may provide further insights into the function of SSR4 and help clinicians better understand this disorder.

UNASSIGNED: Congenital disorders of glycosylation (CDG) are rare genetically inherited defects leading to enzyme deficiency or malfunction in the glycosylation pathway. Normal glycosylation is essential to the development of normal cardiac anatomy and function. Congenital disorders of glycosylation-related cardiomyopathy are often the first manifestation detected in early life and may lead to sudden cardiac death. Approximately one-fifth of CDG types are related to cardiac diseases that include cardiomyopathy, rhythm disturbances, pericardial effusions, and structural heart disease.
UNASSIGNED: We report a rare case of a 26-year-old lady with CDG-1 who presented with acute-onset dyspnoea. She had respiratory tract symptoms for the past 2 weeks. With the relevant clinical and biochemical findings, including supportive findings on echocardiogram and cardiac magnetic resonance imaging, we have managed to arrive at a diagnosis of severe pneumonia leading to acute decompensated heart failure, as well as the discovery of an underlying CDG-associated dilated cardiomyopathy (DCM) and acute myocarditis. Anti-failure medications and i.v. methylprednisolone were commenced, and she showed gradual clinical improvement with an increase of her left ventricular function. She was discharged home well with anti-failure therapy, prednisolone, and a follow-up echocardiogram with further review in the heart failure clinic.
UNASSIGNED: In conclusion, this case report highlights the need for accurate diagnosis and prompt management of CDG-associated DCM, leading to a successful recovery and discharge from hospital care. With this, we hope to add to the increasing number of reported cases of CDG-related cardiac disease in the medical literature to emphasize the importance of screening and follow-up for any underlying cardiac diseases in patients with CDG.

BACKGROUND: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoproteins. Neurocognitive dysfunctions have been documented in patients with CDDG1; however, deteriorating phenotypes of affected individuals remain elusive.
METHODS: A Japanese boy with delayed psychomotor development showed ataxic movements from age 5 years and myoclonic seizures from age 12 years. Appetite loss, motor and cognitive decline became evident at age 12 years. Electrophysiological studies identified paroxysmal discharges on myoclonic seizure and a giant somatosensory evoked potential. Perampanel was effective for controlling myoclonic seizures. Exome sequencing revealed that the patient carried compound heterozygous variants in NGLY1, NM_018297.4: c.857G > A and c.-17_12del, which were inherited from mother and father, respectively. A literature review confirmed that myoclonic seizures were observed in 28.5% of patients with epilepsy. No other patients had progressive myoclonic epilepsy or cognitive decline in association with loss-of-function variations in NGLY1.
CONCLUSIONS: Our data provides evidence that a group of patients with CDDG1 manifest slowly progressive myoclonic epilepsy and cognitive decline during the long-term clinical course.

The congenital disorder of glycosylation associated with ALG1 (ALG1-CDG) is a rare autosomal recessive disease. Due to the deficiency of β1,4 mannosyltransferase caused by pathogenic variants in ALG1 gene, the assembly and processing of glycans in the protein glycosylation pathway are impaired, resulting in a broad clinical spectrum with multi-organ involvement. To raise awareness of clinicians for its manifestations and genotype, we here reported a new patient with a novel variant in ALG1 gene and reviewed the literature to study the genotype-phenotype correlation.
Clinical characteristics were collected, and clinical exome sequencing was used to identify the causative variants. MutationTaster, PyMol, and FoldX were used to predict the pathogenicity, changes in 3D model molecular structure of protein, and changes of free energy caused by novel variants.
The proband was a 13-month-old Chinese Han male characterized by epileptic seizures, psychomotor development delay, muscular hypotonia, liver and cardiac involvement. Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal). The literature review found that in severe phenotypes, the incidences of clinical manifestations were significantly higher than that in mild phenotypes, including congenital nephrotic syndrome, agammaglobulinemia, and severe hydrops. Homozygous c.773C>T was a strongly pathogenic variant associated with a severe phenotype. When heterozygous for c.773C>T, patients with another variant leading to substitution in amino acids within the strongly conserved regions (c.866A>T, c.1025A>C, c.1182C>G) may cause a more severe phenotype than those within less-conserved regions (c.434G>A, c.450C>G, c.765G>A, c.1287T>A). c.1129A>G, c.1076C>T, and c.1287T>A were more likely to be associated with a mild phenotype. The assessment of disease phenotypes requires a combination of genotype and clinical manifestations.
The case reported herein adds to the mutations identified in ALG1-CDG and a review of this literature expands the study of the phenotypic and genotypic spectrum of this disorder.

ALG6-CDG is a rare, but second most common, type 1 congenital disorder of glycosylation (CDG) caused by a defect in the α-1-3-glucosyltransferase (ALG6) enzyme in the N-glycan assembly pathway. Many mutations have been identified and inherited in an autosomal recessive pattern. There are less than 100 ALG6-CDG cases reported, all sharing the phenotype of hypotonia and developmental delay. The majority (perhaps >70%) have seizures, but a minority have intractable epilepsy or epileptic encephalopathy. We report the clinical course, EEG findings, and neuroimaging of a child found to have compound heterozygous alleles c.257 + 5G > A and c.680G > A (p.G227E) who developed explosive onset of intractable epilepsy and epileptic encephalopathy. Initially, CDG was not suspected due to its rarity and lack of multi-organ system involvement, but rapid whole exam sequence (8-day turnaround) revealed the specific diagnosis quickly.

Rafiq syndrome (RAFQS) is a congenital disorder of glycosylation (CDG) that is caused by mutations in the MAN1B1 gene and characterized by impaired protein and lipid glycosylation. RAFQS is characterized by a delay in intellectual and motor development, facial and other dysmorphism, truncal obesity, behavior problems, and hypotonia. We describe a Russian patient with delayed intellectual and motor development, a lack of speech, disorientation in space and time, impaired attention and memory, and episodes of aggression. Screening for lysosomal, amino acid, organic acid, and mitochondrial disorders was normal. The patient was referred for the targeted sequencing of the “Hereditary Metabolic Disorders” panel. The genetic testing revealed two heterozygous pathogenic variants in the MAN1B1 gene: the previously reported c.1000C > T (p.Arg334Cys) and the novel c.1065 + 1 G > C. Thus, the patient’s clinical picture and genetic analysis confirmed RAFQS in the patient.

NGLY1 deficiency is a rare congenital disorder of deglycosylation with a unique constellation of symptoms that include hypo- or alacrima, movement disorder, epilepsy, and severe intellectual disability (OMIM #615273). Here we report a patient with NGLY1 deficiency whose clinical presentation lacks many of the features associated with the disease and has a much milder intellectual disability than had been previously reported, expanding the phenotypic spectrum.

Congenital Disorders of Glycosylation (CDG) are a complex family of rare metabolic diseases. Robust clinical data collection faces many hurdles, preventing full CDG biological and clinical comprehension. Web-based platforms offer privileged opportunities for biomedical data gathering, and participant recruitment, particularly in rare diseases. The immunology and CDG electronic (e-) questionnaire (ImmunoCDGQ) explores this paradigm, proposing a people-centric framework to advance health research and participant empowerment.
The objectives of this study were to: (1) Describe and characterize the ImmunoCDGQ development, engagement, recruitment, participation, and result dissemination strategies; (2) To critically compare this framework with published literature and making recommendations.
An international, multistakeholder people-centric approach was initiated to develop and distribute the ImmunoCDGQ, a multi-lingual e-questionnaire able to collect immune-related data directly from patients and family caregivers. An adapted version was produced and distributed among the general \"healthy\" population (ImmunoHealthyQ), serving as the control group. Literature screening was performed to identify and analyze comparable studies.
The ImmunoCDGQ attained high participation and inclusion rates (94.6%, 209 out of 221). Comparatively to the control, CDG participants also showed higher and more variable questionnaire completion times as well as increased English version representativeness. Additionally, 20% of the CDG group (42 out of 209) chose not to complete the entire questionnaire in one go. Conditional logic structuring guided participant data provision and accurate data analysis assignment. Multi-channel recruitment created sustained engagement with Facebook emerging as the most followed social media outlet. Still, most included ImmunoCDGQ questionnaires (50.7%, 106 out of 209) were submitted within the first month of the project\'s launch. Literature search and analysis showed that most e-questionnaire-based studies in rare diseases are author-built (56.8%, 25 out of 44), simultaneously addressing medical and health-related quality of life (HRQoL) and/or information needs (79.5%, 35 out of 44). Also, over 68% of the studies adopt multi-platform recruitment (30 out of 44) actively supported by patient organizations (52.3%, 23 out of 44).
The ImmunoCDGQ, its methodology and the CDG Community served as models for health research, hence paving a successful and reproducible road to people-centricity in biomedical research.

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, characterized by a defect in the protein glycosylation process. Enzymes involved in this metabolic mechanism have ubiquitous distribution; thus, their alteration can cause systemic involvement and considerable phenotypic variability. Nephrotic syndrome (NS) is a clinical condition characterized by edema, hypoalbuminemia, hyperlipidemia, and proteinuria. We hereby report the case of a girl with central hypotonia, epilepsy, and severe psychomotor delay diagnosed with phosphomannomutase 2 deficiency (PMM2-CDG) after presenting with nephrotic syndrome at age 4 years.

Congenital disorders of glycosylation (CDG) are a group of metabolic diseases with clinical and genetic heterogeneity, and CDG-IIg is one of the rare reported types of CDG. The aim of this study is to report the clinical manifestations and gene-phenotype characteristics of a rare case of CDG caused by a COG1 gene mutation and review literatures of CDG disease.
The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg. We treated the patient with glucose infusion and he was recovered from hypoglycemia. Genetic analysis showed that the patient carried the heterozygous intron mutation c.1070 + 3A > G (splicing) in the coding region of the COG1 gene that was inherited from the mother, and the heterozygous mutation c.2492G > A (p. Arg831Gln) in exon 10 of the COG1 gene that was inherited from the father. The genes interacting with COG1 were mainly involved in the transport and composition of the Golgi. The clinical data and laboratory results from a patient diagnosed with CDG-IIg were analyzed, and the causative gene mutation was identified by high-throughput sequencing. The genes and signal pathways related to COG1 were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.
The c.2492G > A (p. Arg831Gln) mutation in exon 10 of the COG1 gene may be a potential pathogenetic variant for CDG-IIg. Because of the various manifestations of CDG in clinical practice, multidisciplinary collaboration is important for the diagnosis and treatment of this disease.