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The association between DOLK and congenital disorder of glycosylation is supported by multiple independent case reports and multi‐patient studies that document a range of phenotypes, from isolated neurological impairment to multisystem involvement. In several families, affected individuals, including siblings, have been identified with homozygous or compound heterozygous mutations in DOLK, providing robust genetic segregation evidence (PMID:23890587). These studies document clinical presentations such as intellectual disability, epileptic seizures, and atypical organ involvement, underscoring the variable expressivity of the disorder. Detailed metabolic investigations and biochemical assays have further linked the enzyme deficiency to abnormal glycosylation profiles. The data from both isolated case reports and broader cohort analyses reinforce the validity of this gene–disease association. Overall, the genetic evidence is bolstered by consistent clinical findings across unrelated probands.
Multiple case reports have identified pathogenic variants in DOLK that result in loss of enzyme function. For instance, one study identified a homozygous missense change, reported as c.2T>C (p.Met1Thr), in siblings presenting with neurological features such as West syndrome and intellectual disability (PMID:23890587). Additional reports describe compound heterozygous mutations that expand the phenotypic spectrum to include severe multisystem involvement, cardiomyopathy, and dermatological abnormalities. Such findings illustrate both the allelic heterogeneity and the broad clinical spectrum associated with DOLK mutations. Segregation data, where multiple affected family members share rare pathogenic variants, further substantiates the causative nature of these changes. This convergence of evidence from several independent reports emphasizes a strong genetic basis for the disorder.
The inheritance pattern of DOLK‐related congenital disorder of glycosylation is autosomal recessive. Family studies have reported segregation of the mutant alleles among affected siblings, with one study detailing at least two siblings in one family and similar occurrences in other reports (PMID:24144945). This consistent pattern of biallelic mutations across diverse families strengthens the proposition that a loss of DOLK function is central to disease pathogenesis. Moreover, the presence of both missense and truncating mutations among patients supports a mutational mechanism acting through reduced or abolished protein activity. In several cases, the clinical manifestations correlate with the predicted severity of the mutations. As a result, clinicians are encouraged to consider autosomal recessive inheritance in families with relevant phenotypes.
Functional studies provide additional support for the role of DOLK in the pathogenesis of congenital disorder of glycosylation. In vitro assays and experimental models have demonstrated that mutations in DOLK lead to defective dolichol phosphate synthesis, an essential precursor in N‐glycosylation pathways. Several investigations have reported decreased substrate binding and catalytic activity in patient-derived fibroblasts, which correlates with the biochemical abnormalities observed in serum studies (PMID:28816422). Furthermore, experimental evidence from yeast and deoxyribozyme studies has helped delineate the structural elements critical for DOLK function (PMID:15751953; PMID:8108435). Although functional evidence is less extensive compared to genetic data, its concordance with clinical findings reinforces the role of DOLK in disease. Together, these functional studies contribute moderate but significant support for the observed gene–disease relationship.
Notably, while most studies consistently support the pathogenicity of DOLK variants, some reports highlight phenotypic variability, including cases with predominant cardiac involvement and others with isolated skin abnormalities. These discrepancies underscore the complexity of congenital disorders of glycosylation and suggest that additional genetic or environmental modifiers may influence the clinical outcome. However, the core biochemical defect—impaired glycosylation due to DOLK dysfunction—remains common across studies. This heterogeneity does not undermine the gene–disease association but rather expands the recognized spectrum of clinical presentations. It is imperative that clinicians integrate both the genetic and biochemical findings when evaluating patients suspected of having DOLK‐CDG. Such an integrated approach enhances diagnostic accuracy and informs therapeutic decision‑making.
In summary, the convergence of robust genetic evidence, including multiple segregating pathogenic variants such as c.2T>C (p.Met1Thr), with supportive functional data from biochemical assays, firmly establishes the association between DOLK and congenital disorder of glycosylation. Although clinical presentations may vary from neurological impairment to multisystem involvement, the underlying defect in protein glycosylation is consistent. This clinical and molecular synthesis not only aids in patient diagnosis but also guides future research and potential therapeutic strategies. Key take‑home: Integrating detailed genetic screening with biochemical assessments is essential for accurate diagnosis and management of patients with suspected DOLK‐CDG.
Gene–Disease AssociationStrongMultiple independent case reports, segregation in sibling pairs (PMID:23890587) and multi‑patient studies support the association between DOLK mutations and congenital disorder of glycosylation. Genetic EvidenceStrongConfirmed homozygous and compound heterozygous mutations in several unrelated probands, with documented segregation and a spectrum of variant types including the observed c.2T>C (p.Met1Thr) (PMID:24144945). Functional EvidenceModerateFunctional assays demonstrate reduced dolichol kinase activity and impaired glycosylation consistent with the clinical phenotype (PMID:15751953; PMID:8108435). |