Congenital Disorders of Glycosylation (CDG) are a group of some 200 genetic disorders with PMM2-CDG being the most common disease. These disorders individually remain rare with poorly understood natural history (NH) and causes of mortality. We established a NH study for CDG and collected both prospective and retrospective data on CDG outcomes. In the current data set analysis on deceased patients, we describe the clinical phenotype and causes of death for thirty-seven individuals with various genetic causes of CDG. About a third of this cohort were affected with PMM2-CDG. All of the patients presented with multisystem features with involvement of the neurological system. The majority of patients involved in this study died during the first three years of life, and only four patients lived beyond ten years. The cause of death was unavailable for two patients, and about a third died secondary to cardiopulmonary failure. Progression of neurological involvement, sepsis and respiratory infection were also among the reported causes. Pericardial effusion was the primary cause of death for three infants affected with PMM2-CDG. This study emphasizes the importance of diagnosis and supportive care following the published monitoring and management guidelines for affected patients with CDG to optimize their health and development in the early stages of the disease.

ALG6-congenital disorder of glycosylation (ALG6-CDG) is a complex of rare inherited disorders caused by mutations in the ALG6 gene, which encodes the α-1,3-glucosyltransferase enzyme required for N-glycosylation. ALG6-CDG affects multiple systems and exhibits clinical heterogeneity. Besides developmental delays and neurological signs and symptoms, behavioral and psychological symptoms are also an important group of clinical features of ALG6-CDG. Here, we present the case of a 17-year-old Chinese girl with ALG6-CDG who first visited the psychiatric department with apathy, language reduction, and substupor symptoms. The psychiatric assessments and treatment processes performed are described and discussed in this report. During diagnostic process, we found a novel mutation, c.849delT, in ALG6 by whole-exome sequencing. The patient's symptoms improved with escitalopram and risperidone treatment. However, above a certain dosage, she was sensitive to extrapyramidal side effects. This study accumulates clinical experience for diagnosing and treating ALG6-CDG and improves our understanding of this rare genetic 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.

Congenital disorders of glycosylation (CDGs) are a heterogeneous group of disorders with impaired glycosylation of proteins and lipids. These conditions have multisystemic clinical manifestations, resulting in gradually progressive complications including skeletal involvement and reduced bone mineral density. Contrary to PMM2-CDG, all remaining CDG, including ALG12-CDG, ALG3-CDG, ALG9-CDG, ALG6-CDG, PGM3-CDG, CSGALNACT1-CDG, SLC35D1-CDG and TMEM-165, are characterized by well-defined skeletal dysplasia. In some of them, prenatal-onset severe skeletal dysplasia is observed associated with early death. Osteoporosis or osteopenia are frequently observed in all CDG types and are more pronounced in adults. Hormonal dysfunction, limited mobility and inadequate diet are common risk factors for reduced bone mineral density. Skeletal involvement in CDGs is underestimated and, thus, should always be carefully investigated and managed to prevent fractures and chronic pain. With the advent of new therapeutic developments for CDGs, the severity of skeletal complications may be reduced. This review focuses on possible mechanisms of skeletal manifestations, risk factors for osteoporosis, and bone markers in reported paediatric and adult CDG patients.