Hyperphosphatasia With Mental Retardation Syndrome 4

A number sign (#) is used with this entry because hyperphosphatasia with mental retardation syndrome-4 (HPMRS4) is caused by homozygous or compound heterozygous mutation in the PGAP3 gene (611801) on chromosome 17q12.

Description

Hyperphosphatasia with mental retardation syndrome-4 is an autosomal recessive neurologic disorder characterized by severely delayed psychomotor development, mental retardation, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies show increased serum alkaline phosphatase (summary by Howard et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.

For a discussion of genetic heterogeneity of HPMRS, see HPMRS1 (239300).

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

Clinical Features

Howard et al. (2014) reported 5 patients from 3 families with HPMRS4. One of the patients had previously been reported by Thompson et al. (2012). All patients had severely delayed psychomotor development since early infancy, with hypotonia and inability to speak or walk independently. Four patients developed seizures between ages 18 months and 12 years; 3 had generalized seizures and 1 had myoclonic seizures. Dysmorphic facial features included hypertelorism, upslanting palpebral fissures, broad nasal bridge, short nose, long philtrum, tented upper lip, full cheeks, and large fleshy earlobes. Three sibs in 1 family had postnatal microcephaly (-2 to -3 SD). Two patients had cleft palate, and brain MRI of 1 patient showed thin corpus callosum and dilated lateral ventricles. Laboratory studies showed increased serum alkaline phosphatase. Brachytelephalangy was not present.

Inheritance

The transmission pattern of HPMRS4 in the families reported by Howard et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 3 families with HPMRS4, Howard et al. (2014) identified homozygous or compound heterozygous mutations in the PGAP3 gene (611801.0001-611801.0004). The mutation in the first family was found by exome sequencing. Transfection of wildtype PGAP3 into CHO cells that lack both PGAP3 and PGAP2 (615187) restored the first step in fatty acid remodeling, but the second step remained defective, leading to a reduction in surface levels of GPI-anchored proteins. In vitro functional expression studies in CHO cells showed that the mutant PGAP3 proteins had either no or only residual enzymatic activity.