Congenital Disorder Of Glycosylation, Type Iu

A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Iu (CDG1U) is caused by homozygous or compound heterozygous mutation in the DPM2 gene (603564) on chromosome 9q34.

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

Clinical Features

Barone et al. (2012) reported 3 patients from 2 unrelated families with a severe multisystem and neurologic phenotype resulting in early death. Two brothers, born of consanguineous Sicilian parents, had originally been reported by Messina et al. (2009). At birth, both boys showed severe hypotonia, myopathic facies, and dysmorphic features. One had micrognathia, malocclusion, and strabismus. Both had severe congenital contractures of the joints and scoliosis. Onset of severe focal, generalized, or myoclonic seizures began between 3 and 5 months of age. Both had profoundly delayed psychomotor development without visual tracking, head control, or speech. Microcephaly was also present, and brain MRI of 1 showed cerebellar hypoplasia. The boys died of respiratory infections at ages 16 and 7 months, respectively. Skeletal muscle biopsy of 1 boy showed a dystrophic pattern, and immunohistochemical studies showed a reduction of the O-mannosyl glycans on DAG1 (128239), suggestive of a dystroglycanopathy (see, e.g., 236670). Fibroblasts showed an accumulation of Dol-PP-GlcNAc2Man5, consistent with a CDG. The third child, also of Sicilian origin, showed respiratory distress and severe hypotonia at birth. She had facial dysmorphism, including trigonocephaly, hypotelorism, small nose, high-arched palate, and micrognathia. She developed seizures at age 1 week. Over the first 2 years of life, she had lack of psychomotor development, was unaware of her surroundings, and had poor visual fixation. Brain MRI showed loss of periventricular and subcortical white matter. Laboratory studies showed increased serum transaminases and creatine kinase, and decreased antithrombin activity. Serum transferrin showed abnormal N-glycosylation, consistent with CDG type I. She died at age 36 months.

Inheritance

The transmission pattern of CDG1U in the families reported by Barone et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated Sicilian families with CDG1U, Barone et al. (2012) identified homozygous or compound heterozygous mutations in the DPM2 gene (603564.0001 and 603564.0002). DPM activity was severely decreased in patient fibroblasts.