Congenital Disorder Of Glycosylation, Type Ik

A number sign (#) is used with this entry because congenital disorder of glycosylation type Ik is caused by homozygous or compound heterozygous mutation in the gene encoding beta-1,4-mannosyltransferase (ALG1; 605907) on chromosome 16p13.

Description

Congenital disorders of glycosylation (CDGs) comprise a group of multisystem diseases with mostly severe psychomotor and mental retardation. Type I CDG comprises those disorders in which there are defects that affect biosynthesis of dolichol-linked oligosaccharides in the cytosol or the endoplasmic reticulum (ER), as well as defects involving the transfer of oligosaccharides onto nascent glycoproteins. Type II CDG comprises all defects of further trimming and elongation of N-linked oligosaccharides in the ER and Golgi (Schwarz et al., 2004).

CDG1K is a type I CDG characterized by predominant neurologic involvement. Survival ranges from the second day of life to adulthood. The liver is affected in a minority of patients and shows hepatomegaly, edema, ascites, cholestatic jaundice, portal hypertension, and Budd-Chiari syndrome (summary by Marques-da-Silva et al., 2017).

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

Clinical Features

Schwarz et al. (2004) described a patient with type I CDG, which they designated CDG Ik. The patient had previously been reported by de Koning et al. (1998). Ultrasound analysis at the thirtieth week of pregnancy revealed nonimmune fetal hydrops and hepatosplenomegaly. After birth at 35 weeks, the boy showed multiple dysmorphic features, with a large fontanel, hypertelorism, micrognathia, hypogonadism, contractures, areflexia, cardiomyopathy, and multifocal epileptic activity. The patient died at 2 weeks of age. Isoelectric focusing of serum transferrin revealed a typical CDG type I pattern. Biochemical and enzymatic studies showed a severely reduced activity of beta-1,4-mannosyltransferase.

Kranz et al. (2004) reported 2 patients with CDG Ik. In early infancy, both patients developed recurrent refractory seizures, rapidly developing microcephaly, and severe coagulation abnormalities. MRI showed cerebral atrophy. One of the patients had nephrotic syndrome and a severe decrease of B cells with a complete absence of serum immunoglobulin G (IgG). The patients died at 10 months and 11 weeks of age. Kranz et al. (2004) noted that compared with other CDG types, CDG Ik has a very severe phenotype with rapid progression and early death. Functional studies showed a residual mannosyltransferase activity of approximately 10%, and the authors suggested that complete deficiency of the enzyme may be lethal in humans.

Dupre et al. (2010) reported 5 unrelated French patients with CDG Ik confirmed by genetic analysis. All patients presented in infancy or early childhood with a severe neurologic disorder characterized by psychomotor retardation and hypotonia. Two were born of pregnancies complicated by pregnancy-induced hypertension and 2 had poor fetal growth. All had at least 1 episode of seizures, which ranged in severity from 1 treatable occurrence in 1 patient to multiple intractable seizures in another. Brain imaging showed cortical atrophy in 3 patients, cerebellar atrophy in 1, and normal results in 2. Three patients had microcephaly and 4 had dysmorphic features, but there was no recognizable common pattern. Three patients had abnormal visual evoked potentials, suggesting partial blindness. One patient died of respiratory insufficiency at age 4 years, 9 months. None had hepatic or renal involvement.

Harshman et al. (2016) reported a patient with congenital nephrotic syndrome and CDG Ik confirmed by genetic analysis. At age 1 month, he had microcephaly, hypertelorism, weak gag reflex, hypotonia, clenched hands, shortened limbs, bilateral cryptorchidism, and sacral dimple. Medical history was notable for hypertension, mild generalized edema, and failure to thrive. The patient also had hypoalbuminemia, proteinuria, and microscopic hematuria, and a renal biopsy performed because of progressive renal dysfunction was suggestive of congenital nephrotic syndrome. He had progressive neurologic deterioration, with seizures that were refractory to multiple antiepileptic medications. Brain MRI showed pontocerebellar atrophy with an absent cerebellar vermis and small posterior fossa. He had sepsis with 2 different organisms. After developing worsening respiratory and renal failure, the patient died at 3 months of age.

Molecular Genetics

In a patient with CDG Ik, Schwarz et al. (2004) identified a homozygous mutation in the ALG1 gene (S258L; 605907.0001).

In 2 patients with CDG Ik, Kranz et al. (2004) identified compound heterozygous mutations in the ALG1 gene (605907.0001-605907.0002).

In a patient with CDG Ik, Grubenmann et al. (2004) identified compound heterozygosity for 2 mutations in the ALG1 gene (see 605907.0003).

In 5 unrelated French patients with CDG type Ik, Dupre et al. (2010) identified homozygous or compound heterozygous mutations in the ALG1 gene, including 7 novel mutations (see, e.g., 605907.0004-605907.0007). The phenotype was severe, with neurologic impairment in all patients and dysmorphic features in 4.

In a patient with CDG Ik and nephrotic syndrome, Harshman et al. (2016) identified homozygosity for the previously identified S258L mutation in the ALG1 gene (605907.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.