Congenital Disorder Of Glycosylation, Type Im

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Im (CDG1M), also known as dolichol kinase deficiency, is caused by homozygous mutation in the DOLK gene (610746), which encodes the enzyme responsible for the final step of the de novo biosynthesis of dolichol phosphate, on chromosome 9q34.

For a general discussion of CDGs, see CDG1A (212065).

Clinical Features

Kranz et al. (2007) described 2 consanguineous families, one German and one Turkish, each with 2 infants with dolichol kinase deficiency. In the cousins from the German family, weight, body length, and head circumference were within the normal range at birth but were below the 3rd percentile a few months later. One of the cousins showed dry, thin, and parchmentlike skin. Electron microscopy of a skin biopsy sample revealed hyperkeratosis. There was minimal hair growth. Seizures started at age 7 weeks, and muscular hypotonia and tetraplegia developed rapidly. There was progressive bilateral nystagmus. The patient died at age 8.5 months. The other cousin had several episodes of hypoketotic hypoglycemia with high levels of free fatty acids and normal insulin levels recorded in the first few months of life, which necessitated continuous glucose supplementation via a gastric tube. Ichthyosis was present during the first weeks of life. Death was caused by a pulmonary infection with respiratory syncytial virus leading to massive cell lysis and cardiac failure at age 6 months. The second family reported by Kranz et al. (2007) included 2 affected sibs born of consanguineous Turkish parents. In the first sib, ichthyosis congenita with inflammation of the skin was present at birth. At age 5 months, progressive hair loss was nearly complete, with sparse eyelashes and eyebrows. Dilated cardiomyopathy was present from birth and persisted throughout life. Severe muscular hypotonia was present and death occurred at home at age 7 months, most likely from aspiration. A sister showed muscular hypotonia at birth, and progressive dilated cardiomyopathy developed shortly after birth. Dry, ichthyosiform skin occurred at the bend of the elbow, the hollow of the knee, and the scalp. The infant died at age 4 months. Kranz et al. (2007) pointed out that dilated cardiomyopathy was the life-limiting factor in 2 of the patients, and that dilated cardiomyopathy is a rare symptom of metabolic diseases in infancy, with a cumulative incidence of 4 to 5 in 100,000 children in this age group. All patients showed a remarkable loss of oligosaccharide structures on serum transferrin, as shown by isoelectric focusing and immunoprecipitation of the protein, implicating a disorder affecting N-glycosylation. Analysis of lipid-linked oligosaccharides (LLOs) showed no structural abnormalities of the N-glycans assembled on dolichol but did show a severely reduced amount of total LLOs. Therefore, Kranz et al. (2007) analyzed the biosynthetic pathway of dolichol phosphate.

Lefeber et al. (2011) studied 11 children from 4 unrelated consanguineous families with CDG, who had predominantly nonsyndromic presentations of dilated cardiomyopathy (CMD) between 5 and 13 years of age. The proband from an Israeli family of Druze origin failed to thrive, had persistently elevated transaminases during infancy, and was diagnosed with CDG1 at 10 months of age. At 6 years of age, mild asymptomatic dilatation of the left ventricle was seen on echocardiogram; at 11 years of age, he developed acute heart failure. His younger brother, who was clinically asymptomatic, was noted to have mildly elevated transaminases at 4 years of age, and echocardiography revealed mild CMD. A second Israeli Druze proband from a consanguineous family from a different village was clinically healthy until 9 years of age when he presented with acute congestive heart failure and CMD. He died suddenly due to cardiac arrhythmia. A sister was diagnosed with CMD at 7 years of age; ventricular biopsies from the explanted heart showed myocyte hypertrophy and interstitial fibrosis, more pronounced in the left ventricle than the right. Another sister, who had a history of mild hypotonia, failure to thrive, short stature, and ichthyosiform dermatitis, was diagnosed with CMD at 6 years of age. A third proband, from a consanguineous Israeli Bedouin family, presented at 9 years of age with progressive weakness and was diagnosed with 'viral myocarditis;' he died after unsuccessful resuscitation, with end-stage CMD. His 13-year-old sister was found to have asymptomatic CMD, and 2 younger brothers showed asymptomatic minimal evidence of cardiomyopathy on repeated echocardiograms. The sister and younger brothers also had ichthyosiform dermatitis. A fourth proband was an 11-year-old Indian female with a history of learning difficulties, mild hypotonia, and ichthyosis, who presented with cardiac failure due to severe CMD; she died awaiting transplant. Her younger brother was also diagnosed with CMD, but had normal cardiac function; he also had mild developmental delay. Enzyme analysis of patients' fibroblasts confirmed a dolichol kinase deficiency in all families.

Helander et al. (2013) reported 2 sibs, born of consanguineous Syrian Turkish parents, with CDG type Im. The patients presented at age 4 months with severe intractable seizures and hypsarrhythmia, consistent with a clinical diagnosis of West syndrome (see 308350). Both had normal early development before the onset of seizures, but thereafter showed delayed psychomotor development with lack of speech. The seizures eventually remitted later in childhood in both patients after intense therapy. Neither patient had cardiac involvement. Serum transferrin analysis showed a CDG type 1 pattern, and lipid-linked oligosaccharides were normal, suggesting an early defect in glycan assembly. Helander et al. (2013) emphasized the purely neurologic presentation in these patients.

Mapping

Lefeber et al. (2011) performed homozygosity mapping in affected sibs from 2 Israeli Druze families with dolichol kinase deficiency and CMD, and identified a 5.0-Mb overlapping region of homozygosity at chromosome 9q33.3-q34.11; 3 affected sibs from an Israeli Bedouin family were homozygous for the same region.

Molecular Genetics

In all 4 patients with dolichol kinase deficiency examined by them, Kranz et al. (2007) found homozygosity for 1 of 2 mutations in the DOLK gene (610746.0001; 610746.0002). The DOLK gene encodes dolichol kinase, the enzyme responsible for the final step in the de novo synthesis of dolichol phosphate, which is involved in several glycosylation reactions, such as N-glycosylation, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and C- and O-mannosylation.

In affected individuals from 2 consanguineous Israeli Druze families with dolichol kinase deficiency and CMD mapping to chromosome 9q33.3-q34.11, who were negative for mutations in the DOLPP1 gene (614516), Lefeber et al. (2011) identified homozygosity for a missense mutation in the DOLK gene (H408D; 610746.0003). In similarly affected individuals from an Israeli Bedouin family, homozygosity for another missense mutation in DOLK was identified (W304C; 610746.0004). In affected members of an Indian family with CDG1 and CMD, homozygosity for a third missense mutation was identified (M1I; 610746.0005). None of the mutations was found in more than 1,000 Caucasian controls or in the 1000 Genomes Project. Lefeber et al. (2011) noted that unlike the patients with DOLK mutations described previously by Kranz et al. (2007), who died in early infancy with a severe congenital multisystem phenotype, these children presented primarily with nonsyndromic dilated cardiomyopathy at 5 to 13 years of age, and additional clinical symptoms in some of the patients, including ichthyosiform dermatitis, failure to thrive, and neurologic involvement, were mild.

In 2 sibs, born of consanguineous Syrian Turkish parents, with CDG type Im and a purely neurologic phenotype, Helander et al. (2013) identified a homozygous mutation in the initiating methionine codon of the DOLK gene (610746.0006).

Nomenclature

Congenital disorders of glycosylation type I are diagnosed by demonstration of undersialylation of serum transferrins by isoelectric focusing and immunofixation. Kranz et al. (2007) suggested that since dolichol kinase deficiency can be detected by isoelectric focusing (IEF) of serum transferrin, the disorder could be included in the CDG I group with the designation CDG Im.