Severe, fatal multisystem manifestations in a patient with dolichol kinase-congenital disorder of glycosylation

• Published in: Molecular genetics and metabolism 2013-12, Vol.110 (4), p.484-489
• Main Authors: Lieu, Michelle T., Ng, Bobby G., Rush, Jeffrey S., Wood, Tim, Basehore, Monica J., Hegde, Madhuri, Chang, Richard C., Abdenur, Jose E., Freeze, Hudson H., Wang, Raymond Y.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Cardiomyopathy, Dilated - complications; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - pathology; Congenital disorder of glycosylation; Congenital Disorders of Glycosylation - complications; Congenital Disorders of Glycosylation - genetics; Congenital Disorders of Glycosylation - mortality; Congenital Disorders of Glycosylation - pathology; Dolichol - metabolism; Dolichol kinase deficiency; DOLK-CDG; Fatal Outcome; Glycosylation; Hepatic dysfunction; Homozygote; Humans; Infant, Newborn; Insulin-resistant hyperglycemia; Lipid Metabolism - genetics; Male; Mutation; Phosphotransferases (Alcohol Group Acceptor) - deficiency; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Renal failure
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2013.09.016

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 9months. 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. •We report a patient with novel traits that expand the DOLK-CDG phenotype.•The p.Q483K DOLK mutation encodes a severely impaired dolichol kinase enzyme.•The patient had dysmorphic features, refractory seizures, and insulin resistance.•Cardiomyopathy, hepatomegaly, and anuria developed prior to death at 4months.