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

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.

Dolichol kinase deficiency (DOLK‐CDG): Two new cases and expansion of phenotype

“…The most recent case of DK deficiency reported more severe multisystem manifestations (Lieu et al, ). This patient was a born to nonconsanguineous parents of Palestinian origin.…”

Fatal hyperkeratosis syndrome in four siblings due to dolichol kinase deficiency

“…Pathogenic variants in DOLK can cause lethal outcomes, particularly when the heart is involved (Kranz et al, 2007). Most deaths occur after the first week of life (Kranz et al, 2007; Lefeber et al, 2011; Lieu et al, 2013).…”

Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

“…Several case reports in the literature suggest that CDGs should be considered in infants with cardiomyopathy and multisystem disorders. Infants with CDG Ⅰa (phosphomannomutase 2 deficiency) are have been most often been reported to have hypertrophic cardiomyopathy [12][13][14][15][16] and infants with dolichol kinase deficiency have been reported to have dilated cardiomyopathy [17,18] . Case reports exist for cardiomyopa- Byers SL et al .…”

“…Additional metabolic evaluations were unremarkable, including acylcarnitine profile, urine and plasma amino acids, ammonia, cholesterol, urine and plasma carnitine and creatine kinase. Although the lactate level was normal, pyruvate was slightly low, which caused the lactate/pyruvate ratio to be elevated at 53 (normal [10][11][12][13][14][15][16][17][18][19][20]. Pompe disease was ruled out based on normal enzyme activity.…”