Glycosylphosphatidylinositol Biosynthesis Defect 18

A number sign (#) is used with this entry because of evidence that glycosylphosphatidylinositol (GPI) biosynthesis defect-18 (GPIBD18) is caused by homozygous or compound heterozygous mutation in the PIGS gene (610271) on chromosome 17q11.

Description

GPIBD18 is a severe autosomal recessive developmental disorder characterized by severely impaired global development, hypotonia, weakness, ataxia, coarse facial features, and intractable seizures. More variable features may include abnormalities of the hands and feet, inguinal hernia, and feeding difficulties. The disorder is part of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway (summary by Nguyen et al., 2018).

For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Clinical Features

Nguyen et al. (2018) reported 4 patients from 2 unrelated families and 2 fetuses from a third family with GPIBD18. In the first family, 2 monozygotic twin brothers presented in the first year of life with hypotonia, global developmental delay, hearing loss, visual impairment with nystagmus and cortical blindness, and intractable seizures, both febrile and nonfebrile. They had coarse dysmorphic facial features, including almond-shaped palpebral fissures, arched eyebrows, long nose, deep philtrum, broad tongue, gingival hypertrophy, and thick helices. Additional features included brachydactyly, fifth finger clinodactyly, short fourth metatarsals and metacarpals, and ataxia and balance problems. Brain imaging showed cerebellar atrophy. Two brothers in the second family, of Mexican descent, had feeding difficulties, profound developmental delay, and coarse facial features similar to the first family. Additional more variable features included umbilical and inguinal hernia, cryptorchidism, pectus carinatum, single transverse palmar creases, hypoplastic distal phalanges, hepatomegaly, hip laxity, bulbous toes, and intractable seizures. They had profoundly impaired intellectual development and were unable to walk or make eye contact. Brain imaging showed diffuse cortical atrophy. In the third family, 2 fetuses showed increased nuchal translucency, decreased or absent fetal movements, and multiple joint contractures consistent with arthrogryposis. Both pregnancies were terminated.

Clinical Management

Nguyen et al. (2018) found that oral pyridoxine was effective in alleviating seizures in 1 patient with GPIBD18.

Inheritance

The transmission pattern of GPIBD18 in the families reported by Nguyen et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients, including 2 fetuses, from 3 unrelated families with GPIBD18, Nguyen et al. (2018) identified homozygous or compound heterozygous mutations in the PIGS gene (610271.0001-610271.0005). The mutations were found by exome sequencing and segregated with the disorder in the families. Patient cells showed variably decreased levels of GPI-anchored proteins compared to controls, consistent with a hypomorphic or loss-of-function effect.