Congenital Disorder Of Glycosylation, Type Ie

A number sign (#) is used with this entry because congenital disorder of glycosylation type Ie is caused by homozygous or compound heterozygous mutation in the DPM1 gene (603503) on chromosome 20q13.

Description

Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin.

For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579).

Clinical Features

Kim et al. (2000) reported 2 patients with phenotypic and biochemical features consistent with a congenital disorder of glycosylation. The first patient was seen at age 10 months because of developmental delay, hypotonia, seizures, and acquired microcephaly. Telangiectases on the eyelids and hemangiomas of the occiput and sacrum were observed. The second patient was born at 29 weeks of gestation, and the postnatal course was complicated by hydrops, respiratory distress, apnea, patent ductus arteriosus (see 607411), and transient hypertension. The infant later developed generalized medically intractable seizures. At 3 years of age, the child had no speech, was cortically blind, had strabismus, and swallowed poorly. Both patients had similar abnormal IEF transferrin patterns. Metabolic labeling of fibroblasts with 2-tritiated-mannose showed that the patients produced a truncated dolichol-linked precursor oligosaccharide with 5 mannose residues instead of the normal precursor with 9 mannose residues. Addition of 250 microM mannose to the culture medium corrected the size of the truncated oligosaccharide. Microsomes from fibroblasts of these patients were approximately 95% deficient in dolichol-phosphate-mannose synthase activity, with an apparent Km for GDP-mannose approximately 6-fold higher than normal.

Imbach et al. (2000) reported a brother and sister with CDG Ie who had severe developmental delay, seizures, and dysmorphic features. They were hospitalized at ages 3 years and 19 months, respectively, after repeated seizure episodes. Weight, length, and head circumference were normal at birth, but microcephaly developed in early childhood. Hypertelorism, Gothic palate, small hands with dysplastic nails, and knee contractures were observed. Notably, nipples were not inverted as is found in CDG Ia (212065). In the girl, early childhood was complicated by recurrent infections. Seizures began in the girl at the age of 5 weeks and in her brother at the age of 6 months. Both children were hypotonic and showed severe global developmental delay. There was no visual fixation, and they were unable to interact socially. Laboratory investigations showed hypoglycosylation on serum transferrin and cerebral spinal fluid beta-trace protein (176803). Mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblasts, thus precluding a possible therapeutic application of mannose in the patients.

Garcia-Silva et al. (2004) reported a 9-year-old girl, born of consanguineous parents, with CDG type Ie. She presented at birth with dysmorphic features, nystagmus, and hypotonia manifest as poor suck and weak cry. She later showed delayed psychomotor development, microcephaly, cerebellar ataxia with dysmetria, tremor, and coordination problems, seizures, and partial optic nerve atrophy. Brain imaging suggested delayed myelination, but cerebellar atrophy was not present. Dysmorphic features included trigonocephaly, prominent forehead, thick metopic suture, hypertelorism, high nasal bridge, smooth philtrum, micrognathia, Gothic palate, malocclusion, hemangiomas, and camptodactyly. She developed a deep venous thrombosis at age 8 years. At age 9 she was sociable and happy and used simple language, although her motor deficits remained. Laboratory studies showed increased serum creatine kinase, decreased levels of several coagulation proteins, and a CDG type 1 pattern of serum transferrin.

Dancourt et al. (2006) reported 2 sibs, born of consanguineous Algerian parents, with CDG Ie. The patients were 14 years and 30 months of age, respectively, at the time of the report. Both had severely delayed psychomotor development and hypotonia apparent from infancy, microcephaly (-3 to -3.5 SD), and poor growth. The older sib had mild febrile seizures in early childhood and later showed progressive neurologic deterioration with severe mental retardation (IQ less than 50), ataxic gait, intention tremor, persistent hypotonia with signs of a distal myopathy, and some pyramidal signs. He had mild pontocerebellar atrophy and abnormal signals in the dentate nucleus on brain imaging, and showed evidence of a macular retinopathy. The younger sib also had truncal ataxia. Her brain MRI showed moderate cerebral atrophy and T2-weighted hyperintensities of the dentate nucleus. Other features in both sibs included strabismus and nystagmus, but neither had dysmorphic features or severe epilepsy. Laboratory studies showed decreased levels of coagulation proteins; serum creatine kinase was normal.

Yang et al. (2013) reported a boy with CDG Ie. He was noted to have camptodactyly at birth and presented at age 2 months with nonfebrile seizures. At age 6 months, he showed motor delay, poor growth, and marked hypotonia with increased serum creatine kinase. Muscle biopsy showed a muscular dystrophy, with increased variation in fiber size, areas of necrosis, and hypoglycosylation of alpha-dystroglycan (DAG1; 128239) reminiscent of that observed in dystroglycanopathies (see, e.g., 236670). Serum transferrin analysis showed a CDG type 1 pattern. Subsequently, the patient showed delayed psychomotor development with lack of speech, recurrence of seizures, feeding difficulties, and evidence of liver dysfunction with low levels of coagulation proteins. Brain MRI later showed cerebral and hippocampal volume loss, abnormal myelination, and T2-weighted hyperintensities in several subcortical brain regions. He was severely handicapped at age 4 years.

Molecular Genetics

In 2 unrelated patients with CDG Ie, Kim et al. (2000) identified mutations in the DPM1 gene: 1 patient was homozygous (603503.0001) and the other patient was compound heterozygous (603503.0001; 603503.0002). Defects in DPM1 defined a new glycosylation disorder, CDG Ie.

In 2 affected sibs, Imbach et al. (2000) identified compound heterozygosity for 2 mutations in the DPM1 gene (603503.0001; 603503.0003).

Garcia-Silva et al. (2004) identified a homozygous missense mutation in the DPM1 gene (603503.0004) in a girl with a relatively mild form of CDG Ie.

In 2 sibs, born of consanguineous Algerian parents, with CDG Ie, Dancourt et al. (2006) identified a homozygous splice site mutation in the DPM1 gene (603503.0005). Each unaffected parent was heterozygous for the mutation. Patient cells showed only 8% residual enzyme activity and a more than 90% reduction in DPM1 transcript levels.

In a boy with CDG type Ie, Yang et al. (2013) identified compound heterozygous mutations in the DPM1 gene (603503.0006-603503.0007).