Glycosylphosphatidylinositol Biosynthesis Defect 15

A number sign (#) is used with this entry because of evidence that glycosylphosphatidylinositol biosynthesis defect-15 (GPIBD15) is caused by homozygous or compound heterozygous mutation in the GPAA1 gene (603048) on chromosome 8q24.

Description

GPIBD15 is an autosomal recessive disorder characterized by delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most patients, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Nguyen et al., 2017).

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

Clinical Features

Nguyen et al. (2017) reported 10 patients from 5 unrelated families with GPIBD15. The families were ascertained from several research studies and were of various origins, including Caucasian, Hispanic, Egyptian, Pakistani, and Finnish. The patients ranged in age from 3.8 to 30 years. All patients showed global developmental delay with mild to moderate intellectual disability, hypotonia, delayed sitting, severely delayed speech, and cerebellar atrophy. The patients had very poor speech with dysarthria and all except 2 were unable to walk or could only walk with support due to ataxic gait and gait instability; the 2 who could walk achieved the skill around age 3 years. Two older sibs in their thirties were wheelchair-bound. Three patients from a Pakistani family were noted to have frank spasticity, whereas others had brisk reflexes. Cerebellar signs included dysarthria, dysmetria, uncoordinated eye movements with ocular ataxia and apraxia, nystagmus, and tremor. Intellectual disability varied; a few patients had moderate cognitive impairment (e.g., IQ of 50 in 1 patient) and could only say a few words, whereas some patients were able to play on a computer and understand most conversation. Three children from a Pakistani family (family 4) could attend normal school with help; these children did not have seizures. The older sibs in their thirties (family 5, Finnish) lived in a sheltered housing with daily assistance, although they were able to eat and dress independently. One patient had cortical visual impairment, 3 had myopia, and 1 had optic atrophy. Seven patients from 4 families had onset of generalized seizures within the first 2 years of life that were only partially or not well controlled by medication and associated with generalized polyspike discharges on EEG. One patient had a history of status epilepticus. Brain imaging showed cerebellar atrophy or hypoplasia, which was progressive in some patients. Common dysmorphic features, seen in one-third to one-half of the patients, included bitemporal narrowing, prominent forehead, widely spaced eyes, broad nasal root, and anteverted nares. Eight patients had osteopenia or osteoporosis, and a ninth had hip dysplasia; however, plasma alkaline phosphatase was normal.

Inheritance

The transmission pattern of GPIBD15 in the family reported by Nguyen et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 10 patients from 5 unrelated families with GPIBD15, Nguyen et al. (2017) identified homozygous or compound heterozygous mutations in the GPAA1 gene (see, e.g., 603048.0001-603048.0007). The mutations, which were found by exome sequencing, segregated with the disorder in all families. There were 6 missense mutations, 2 frameshift mutations, and 1 splicing mutation, but none of the patients carried 2 frameshift or spicing mutations. Cells derived from several of the patients showed variably decreased amounts of GPI-anchored proteins at the cell surface, including CD16 (FCGR3A; 146740), CD24 (600074), CD109 (608859), and CD73 (129190). These defects could be partially rescued by expression of wildtype GPAA1. Transfection of plasmids containing the mutations into GPAA1-deficient HEK293 cells showed that some of the missense variants had decreased activity, whereas others had residual activity. The findings indicated that the mutations caused a defect in the biosynthesis of GPI-anchored proteins, and highlighted the role of this transamidase complex in the development and function of the cerebellum and the skeletal system.