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

• Authors: Michelle T Lieu, University of California Los Angeles; Bobby G Ng, Sanford Burnham Medical Research Institute; Jeffrey S Rush, University of Kentucky; Tim Wood, Greenwood Genetic Center; Monica J Basehore, Greenwood Genetic Center; Madhuri Hegde, Emory University; Richard C Chang, CHOC Childrens Specialists; Jose E Abdenur, CHOC Childrens Specialists; Hudson H Freeze, Sanford Burnham Medical Research Institute; Raymond Y Wang, CHOC Childrens Specialists
• Journal Title: Molecular Genetics and Metabolism
• Volume: Volume 110, Number 4
• Publisher: Elsevier: 12 months | 2013-12-01, Pages 484-489
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.ymgme.2013.09.016
• Subjects: Chemistry, Biochemistry; Health Sciences, Medicine and Surgery; Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental; Research & Experimental Medicine; Congenital disorder of glycosylation; DOLK-CDG; Dolichol kinase deficiency; Renal failure; Hepatic dysfunction; Insulin-resistant hyperglycemia; MUSCULAR-DYSTROPHY; MUTATIONS; BRAIN

Abstract

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.