By: Heather Conneran, Mom to Bella

In honor of Rare Disease Month and the 5yr Anniversary of the passing of our sweet daughter, Isabella, I wanted to share our story.

“Bella” was the most joyful little girl greeting you from the moment she woke up with a smile that would brighten your day. She loved reading books, going for walks or bike rides and being with family and friends.

Bella had a brand new CDG type called “FUT8” that was extremely debilitating. We didn’t receive a diagnosis until she was over 2 and a half years old. It was great to finally get a diagnosis, but also scary as there was only one other child known with this CDG type. Since then, there’s been several others that have been diagnosed with this type of CDG thanks to Bella and Kati, the original two.

Shortly after losing Bella, we attended our first CDG Conference. It was supposed to be our first family trip and we were excited to meet other CDG families. It was hard to attend without Bella but I’m so glad we attended anyway. We were immediately embraced by the CDG family and it felt reassuring to be surrounded by those who “get it”. 

After that event, I knew I had to be involved with CDG CARE and became a member of the Board of Directors. It allows me to honor Bella, while helping other CDG families. In the past five years, I’ve seen tremendous growth in research and clinical trials for CDG. There is such a brighter future for CDG patients!

To say this has been a hard journey would be an understatement, but knowing we don’t travel the journey alone helps us keep going. Lots of love and gratitude to Bella and the CDG community. 

**Follow FCDGC on Twitter: @FrontierCDG**

Natural History Research Study

The natural history research study is still underway. Nearly 300 patients have been enrolled into this study and enrollment has opened at multiple sites across the country. Participation involves annual visits with a designated healthcare provider for disease follow-up, questionnaires, and optional sample collections. If you would be interested in learning more, please contact one of the clinical sites, found here: https://www.rarediseasesnetwork.org/fcdgc/sites 

The study has added a new arm to the data collection. We are now accepting enrollment of CDG Angels into our Memorial Enrollment arm, at parent’s discretion. This data will prove beneficial in the study. If you are interested in donating medical records about your CDG Angel, please contact Alexandra Miller at [email protected]. 

Publications

Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement 

Congenital disorders of glycosylation (CDG) are a large group of rare, inherited disorders that affect a complex process in the body called glycosylation. Defects in Golgi enzymes, which play a critical role in N-glycan processing and brain development, are often defined as types of CDG. However, defects in the Golgi enzyme MAN2A2 have not been known to cause defects in glycosylation. In this study, researchers investigated the effects of variants in MAN2A2. In a family of affected individuals, the team performed exome sequencing, analyzed N-glycans, and designed a cell-based complementation assay to evaluate the disease-causing effects of the variant. Findings show that variants in MAN2A2 cause a new type of CDG, which is characterized by neurological involvement and facial dysmorphism. Authors note that the cell-based complementation assay designed in this study can also help diagnose patients with potentially pathogenic variants in a very similar enzyme, MAN2A1. - Mahajan S, Ng BG, AlAbdi L, Earnest PDJ, Sosicka P, Patel N, Helaby R, Abdulwahab F, He M, Alkuraya FS, Freeze HH. Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement. J Med Genet. 2022 Nov 10:jmg-2022-108821. doi: 10.1136/jmg-2022-108821. Epub ahead of print. PMID: 36357165.

Exploring the Role of NGLY1 Deficiency in Patients with NGLY1-Congenital Disorder of Deglycosylation 

NGLY1-CDDG (congenital disorder of deglycosylation) is a multisystemic, inherited condition caused by a mutation in the NGLY1 gene. Although the NGLY1 enzyme plays an essential role in the process of deglycosylation, the effects of NGLY1 deficiency on protein glycosylation are not yet understood. In this study, researchers explored the hypothesis that NGLY1 deficiency leads to accumulation of misfolded glycoproteins. Using glycoproteomics and proteomics methods, the team analyzed fibroblasts from four patients with NGLY1 deficiency carrying different variants in NGLY1. Results showed no significant accumulation of glycoproteins in the NGLY1-deficient fibroblasts. However, researchers found distinct changes in specific glycoproteins. As the first study of its kind, authors note that these findings highlight new insights for understanding NGLY1-CDDG. - Budhraja R, Saraswat M, De Graef D, Ranatunga W, Ramarajan MG, Mousa J, Kozicz T, Pandey A, Morava E. N-glycoproteomics reveals distinct glycosylation alterations in NGLY1-deficient patient-derived dermal fibroblasts. J Inherit Metab Dis. 2022 Sep 14. doi: 10.1002/jimd.12557. Epub ahead of print. PMID: 36102038.

DDOST-CDG: Clinical and molecular characterization of a third patient with a milder and a predominantly movement disorder phenotype

DDOST-CDG is an ultra-rare type of congenital disorder of glycosylation (CDG) that is caused by mutations in the gene DDOST. The metabolic disorder was previously reported in just two patients, whose clinical features included severe developmental delay, failure to thrive, and hypotonia (low muscle tone). Both patients also had abnormal transferrin glycosylation. In this study, researchers describe a new patient with DDOST-CDG. The 18-year-old male presented with moderate developmental delay, progressive opsoclonus (involuntary, rapid eye movements), myoclonus (involuntary, sudden muscle spasms), ataxia (impaired balance or coordination), tremor, and dystonia (involuntary muscle contractions that cause repetitive or twisting movements). The team performed several tests, including biochemical studies, exome sequencing, plasma N-glycan profiling, and western blot analysis, to learn more about the patient’s clinical features. Authors state that these insights—including new findings on the clinical variability, phenotypes, and genotypes of DDOST-CDG—are essential for diagnosing and managing patients with DDOST-CDG. - https://doi.org/10.1002/jimd.12565 

Origin of Monosaccharide Determines Reactions in Glycosylation

Congenital disorders of glycosylation (CDG) are a group of inherited metabolic disorders that affect a process called glycosylation. This process uses monosaccharides (simple sugars) from multiple sources to produce nucleotide sugars (activated forms of monosaccharides). Since these sources of monosaccharides are assumed to contribute to one similar pool, their individual contributions are often overlooked. In this study, researchers explored the hypothesis that fucose (a type of monosaccharide) exists in multiple, distinct pools. The team measured the contribution of fucose from different sources. Findings show that cells identify and select from different pools of fucose for the process of glycosylation. Authors also present new perspectives on monosaccharide metabolism, which may have other applications beyond glycosylation. - Sosicka P, Ng BG, Pepi LE, Shajahan A, Wong M, Scott DA, Matsumoto K, Xia ZJ, Lebrilla CB, Haltiwanger RS, Azadi P, Freeze HH. Origin of cytoplasmic GDP-fucose determines its contribution to glycosylation reactions. J Cell Biol. 2022 Oct 3;221(10):e202205038. doi: 10.1083/jcb.202205038. Epub 2022 Sep 2. PMID: 36053214.

Other News

FCDGC has added new collaborators! Welcome to team! 

• Mount Sinai – Dr. Jaya Ganesh
• Centro Hospitalar Universitário do Porto – Portugal – Dr. Esmeralda Martins
• General University Hospital in Prague – Czech Republic – Dr. Tomas Honzik
• University Hospital Goettingen – Germany – Dr. Christin Johnsen
• University of Alberta – Canada – Dr. Saadet Andrews