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

Abstract

Congenital disorders of glycosylation (CDGs) are a group of genetic diseases caused by mutations in genes that are necessary for the addition of oligosaccharides to acceptor proteins or lipids. An early step in this process requires dolichol kinase (DK) to catalyze the formation of dolichyl phosphate, which acts as a membrane anchor for initial attachment of sugar residues that are subsequently built up to oligosaccharides and transferred to acceptor proteins and lipids for further processing. Biallelic mutations in DOLK, the gene for DK, result in human in a CDG with variable symptoms, ranging from nonsyndromic dilated cardiomypopathy to severe multiorgan involvement. We report two female siblings with novel compound heterozygous mutations in DOLK: c.951C>A (p.Tyr317Ter) and c.1558A>G (p.Thr520Ala). Both patients presented in the neonatal period with severe ichthyosis, unusual distal digital constrictions and dilated cardiomyopathy which resulted in death. Histology of the skin showed lipid droplet accumulation in the stratum corneum and keratinocytes, which suggests defective epidermal lipid metabolism. These patients represent an earlier and more severe form of DOLK-CDG (CDG-1m) with a striking presentation at birth that expands the known phenotypic spectrum.

Toward understanding tissue‐specific symptoms in dolichol‐phosphate‐mannose synthesis disorders; insight from DPM3‐CDG

“…Phosphomannomutase 2 (PMM2)‐CDG (MIM 601785) patients show a very broad phenotype with involvement of nearly all organs. Steroid 5alpha‐reductase type 3 (SRD5A3)‐CDG (MIM 611715) patients mainly present with eye, skin, and central nervous system involvement, while dolichol kinase ( DOLK ) deficiency (MIM 610746) results in dilated cardiomyopathy without obvious skeletal muscle abnormalities . DPM3‐CDG (MIM 605951) and patients with mutations in guanosine‐diphosphate‐mannose (GDP‐mannose) pyrophosphorylase B ( GMPPB , MIM 615320) can present with muscular dystrophy, a symptom of the dystroglycanopathies .…”

“…These congenital muscular dystrophies present with deficient O‐mannosylation of alpha‐dystroglycan (αDG), which also requires DPM. Indeed, reduced O‐mannosylation of αDG has been found in skeletal muscle of DPM3‐CDG and GMPPB‐CDG patients, and in heart muscle of DOLK‐CDG patients . However, it is unclear whether O‐mannosylation is specifically affected in DPM synthesis disorders, or if N‐glycosylation and O‐mannosylation are both similarly affected, but involve tissue‐specific metabolic pathways.…”

“…10,11 Mutations in DOLK lead to abnormal serum transferrin N-glycosylation and heart αDG O-glycosylation with dilated cardiomyopathy, muscular hypotonia, neurological involvement, and/or ichthyosis. [12][13][14][15][16] The clinical phenotypes associated with mutations in the DPM synthase subunits DPM1, DPM2, or DPM3 are different: DPM1-CDG patients show multivisceral presentations characteristic for CDG-I and muscular dystrophy, [17][18][19][20][21] DPM2-CDG patients have microcephaly, seizures, developmental delay, and hypotonia, 22 and two DPM3-CDG patients have been reported with muscular dystrophy, of which one patient also presented with cardiomyopathy. 23,24 Blue boxes: abnormal serum transferrin N-glycosylation.…”

“…Steroid 5alpha-reductase type 3 (SRD5A3)-CDG (MIM 611715) patients mainly present with eye, skin, and central nervous system involvement, [3][4][5][6] while dolichol kinase (DOLK) deficiency (MIM 610746) results in dilated cardiomyopathy without obvious skeletal muscle abnormalities. 13,14,16 DPM3-CDG (MIM 605951) and patients with mutations in guanosinediphosphate-mannose (GDP-mannose) pyrophosphorylase B (GMPPB, MIM 615320) can present with muscular dystrophy, a symptom of the dystroglycanopathies. 7,8,25 These congenital muscular dystrophies present with deficient Omannosylation of alpha-dystroglycan (αDG), which also requires DPM.…”

“…Indeed, reduced O-mannosylation of αDG has been found in skeletal muscle of DPM3-CDG and GMPPB-CDG patients, and in heart muscle of DOLK-CDG patients. 14,16,23,24 However, it is unclear whether Omannosylation is specifically affected in DPM synthesis disorders, or if N-glycosylation and O-mannosylation are both similarly affected, but involve tissue-specific metabolic pathways. To increase our understanding of the pathophysiology of the tissue-specific phenotypes of the DPM synthesis disorders, we studied protein N-and O-glycosylation in muscle tissue of all three known DPM3-CDG patients.…”