Congenital disorders of glycosylation are a group of metabolic disorders with an expansive and highly variable clinical presentation caused by abnormal glycosylation of proteins and lipids. Dolichol kinase (DOLK) catalyzes the final step in biosynthesis of dolichol phosphate (Dol-P), which is the oligosaccharide carrier required for protein N-glycosylation. Human DOLK deficiency, also known as DOLK-CDG or CDG-Im, results in a syndrome that has been reported to manifest with dilated cardiomyopathy of variable severity. A male neonate born to non-consanguineous parents of Palestinian origin presented with dysmorphic features, genital abnormalities, talipes equinovarus, and severe, refractory generalized seizures. Additional multi-systemic manifestations developed including dilated cardiomyopathy, hepatomegaly, severe insulin-resistant hyperglycemia, and renal failure, which were ultimately fatal at age 9. months. Electrospray ionization mass spectrometric (ESI-MS) analysis of transferrin identified a type I congenital disorder of glycosylation; next-generation sequencing demonstrated homozygous p.Q483K DOLK mutations that were confirmed in patient fibroblasts to result in severely reduced substrate binding and catalytic activity. This patient expands the phenotype of DOLK-CDG to include anatomic malformations and multi-systemic dysfunction.
|Number of pages||6|
|Journal||Molecular Genetics and Metabolism|
|State||Published - Dec 2013|
Bibliographical noteFunding Information:
This work was supported by The Rocket Fund and by R01 DK55615 (HHF). The authors would like to thank Dr. Laura Pollard and Stephen McGee at the Greenwood Genetic Center for their help with the NGS analysis.
- Congenital disorder of glycosylation
- Dolichol kinase deficiency
- Hepatic dysfunction
- Insulin-resistant hyperglycemia
- Renal failure
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Molecular Biology