Congenital Disorder Of Glycosylation, Type Iik

A number sign (#) is used with this entry because congenital disorder of glycosylation type IIk (CDG2K) is caused by homozygous or compound heterozygous mutation in the TMEM165 gene (614726) on chromosome 4q12.

Description

CDG2K is an autosomal recessive disorder with a variable phenotype. Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern (summary by Foulquier et al., 2012).

For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066).

Clinical Features

Foulquier et al. (2012) reported 5 patients from 4 families with CDG2K. The first family contained 2 affected sibs, born of Georgian Jewish parents. The 19-year-old boy had psychomotor retardation and severe growth retardation. He also had midface hypoplasia, muscle weakness, fat excess, joint laxity, and hepatosplenomegaly with increased serum transaminases. Laboratory studies showed increased creatine kinase and partial growth hormone deficiency. Skeletal anomalies included osteoporosis and epiphyseal, metaphyseal, and diaphyseal dysplasia. Brain MRI showed white matter abnormalities and hypoplasia of the pituitary gland. His sister, who had similar clinical features, also had recurrent, unexplained fever episodes; she died at 14 months of age from an acute infectious shock. Another Georgian Jewish child with similar features, including unexplained fever, also had transient epilepsy, dwarfism, and unexplained restrictive lung pathology. A Turkish boy had delayed psychomotor development and mild rhizomelia, but no significant skeletal anomalies. An American girl had short stature, facial dysmorphism, wrinkled skin, abnormal fat distribution, and dysplastic toenails. She had amelogenesis imperfecta and multiple skeletal abnormalities, including osteoporosis, anterior beaking of vertebrae, dysplastic vertebrae and ribs, dysplastic fourth metacarpals and metatarsals, hypoplasia of femoral heads, and kyphoscoliosis. Serum transferrin analysis of the patients showed a CDG type II pattern, and patient cells showed an N-glycosylation defect and abnormal Golgi morphology.

Zeevaert et al. (2013) provided a detailed clinical summary of the 3 Georgian Ashkenazi Jewish patients with CDG2K reported by Foulquier et al. (2012). Additional dysmorphic features noted in the Georgian Jewish boy included dense hair, long and dense eyelashes, delayed dentition, and hoarse voice. He also had a waddling gait and muscular hypotrophy. Laboratory abnormalities included a moderate decrease in certain clotting factors and low levels of certain pubertal hormones at age 16. His younger sister also had some dysmorphic features, including ptosis, strabismus, low-set ears, long philtrum, high-arched palate, short and broad neck, broad thorax, sacral dimple, and absent second toenails. The unrelated boy had macrocephaly, tongue protrusion, downslanting palpebral fissures, flat nose, and posteriorly rotated ears. All 3 patients had radiologic evidence of skeletal dysplasia, which Zeevaert et al. (2013) noted was a distinctive feature in this form of CDG.

Molecular Genetics

In 5 patients from 4 families with CDG2K, Foulquier et al. (2012) identified homozygous or compound heterozygous mutations in the TMEM165 gene (614726.0001-614726.0004). The mutations were found by autozygosity mapping followed by gene expression profiling. Silencing of the TMEM165 gene in HEK cells resulted in disturbed N-glycosylation in the terminal Golgi. The findings suggested an important role for TMEM165 in Golgi glycosylation and Golgi morphology maintenance.