Mental Retardation, Autosomal Recessive 53

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-53 (MRT53) is caused by homozygous or compound heterozygous mutation in the PIGG gene (616918) on chromosome 4p16.

Description

Autosomal recessive mental retardation-53 is a neurodevelopmental disorder characterized by severely delayed psychomotor development, hypotonia apparent since infancy, and early-onset seizures in most patients. Some patients may have additional features, such as cerebellar hypoplasia and ataxia. MRT53 is one of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway (summary by Makrythanasis et al., 2016).

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

Clinical Features

Makrythanasis et al. (2016) reported 5 patients from 3 unrelated families with intellectual disability, hypotonia, and early-onset seizures. In the first family, 2 sibs presented at birth with severe hypotonia and hyporeflexia and later developed resistant seizures at age 4 months. They had severely delayed psychomotor development with profound intellectual disability. Each had some dysmorphic features, but a common pattern was not apparent. Brain imaging showed thin corpus callosum and asymmetry of the lateral ventricles. In the second family, an affected girl had poor overall growth, delayed psychomotor development with hypotonia, lack of speech development, and autistic features. She had onset of seizures at age 10 months. In the third family, 2 sibs had delayed psychomotor development with severe ataxia. Only 1 had a single episode of seizures. Brain imaging showed cerebellar hypoplasia and mild cerebral atrophy. Serum alkaline phosphatase was not increased in any of these patients. The families were of various ethnic origins, including Egyptian, Japanese, and Pakistani; 2 of the families were consanguineous.

Inheritance

The transmission pattern of MRT53 in the families reported by Makrythanasis et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated consanguineous families with MRT53, Makrythanasis et al. (2016) identified 2 different homozygous mutations in the PIGG gene (616918.0001 and 616918.0003). A patient from a third family was compound heterozygous for a missense mutation (616918.0002) and a large deletion encompassing the PIGG gene. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Studies of patients cells from 2 of the families showed abnormal accumulation of the H7 and H7' GPI precursors and absence of H8, consistent with a loss of PIGG function. These defects were restored after transfection with wildtype PIGG. However, patient cells showed normal GPI-anchored proteins, indicating that loss of PIGG does not affect cell-surface levels of these proteins; overall GPI structure was also normal.