Hyperphosphatasia With Mental Retardation Syndrome 3

A number sign (#) is used with this entry because hyperphosphatasia with mental retardation syndrome-3 (HPMRS3) is caused by homozygous or compound heterozygous mutation in the PGAP2 gene (615187) gene on chromosome 11p15.

Description

Hyperphosphatasia with mental retardation syndrome-3 is an autosomal recessive disorder usually characterized by severe mental retardation, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase (summary by Hansen et al., 2013). However, the severity of the disorder can also vary to include milder intellectual disability (Krawitz et al., 2013). 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

Rehman et al. (2011) reported a large 5-generation Pakistani family (MR5) with autosomal recessive nonsyndromic severe mental retardation.

Abou Jamra et al. (2011) reported a consanguineous Syrian family (MR043) in which 3 individuals had nonsyndromic severe mental retardation. Symptoms included severe motor delay with no walking or sitting, severe intellectual disability with very poor speech, and mild microcephaly. One patient had absence seizures. Hansen et al. (2013) provided follow-up of the family reported by Abou Jamra et al. (2011). Additional features included severe hypotonia, disordered sleep pattern, and increased serum alkaline phosphatase. Brain imaging showed brain atrophy in all 3 patients, increased gyration in 2, and Dandy-Walker malformation in 1.

Krawitz et al. (2013) reported 2 unrelated patients with variable severity of HPMRS3. One was a Turkish boy, born of consanguineous parents, with severely delayed psychomotor development, lack of ability to walk, sensorineural hearing loss, seizures, atrial septal defect, Hirschsprung disease, hypotonia, cleft palate, and microcephaly. The other was a 28-year-old Finnish woman who had mild intellectual disability and worked in supported employment. She had normal early development with slightly delayed walking, febrile and rare tonic-clonic seizures, and broad nasal bridge. Both patients had increased serum alkaline phosphatase.

Mapping

By autozygosity mapping using microarray SNP analysis in a Pakistani family segregating autosomal recessive nonsyndromic mental retardation, Rehman et al. (2011) identified a homozygous 6-Mb telomeric region on chromosome 11p15 between SNPs rs10769544 and rs11040272. Linkage analysis yielded a maximum lod score of 3.31. The locus was designated MRT17.

By homozygosity mapping of a consanguineous Syrian family with mental retardation, Abou Jamra et al. (2011) found linkage to a 6.4-Mb region on chromosome 11p between SNPs rs3802985 and rs7126612 (lod score of 3.55). Abou Jamra et al. (2011) referred to this locus as 'MRT21.'

Inheritance

The transmission pattern of HPMRS3 in the families reported by Hansen et al. (2013) and Krawitz et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of the families with mental retardation reported by Abou Jamra et al. (2011) and Rehman et al. (2011), Hansen et al. (2013) identified 2 different homozygous missense mutations in the PGAP2 gene (615187.0001 and 615187.0002, respectively). In vitro functional expression studies showed that the mutant alleles were hypomorphic and caused decreased enzyme activity. Hansen et al. (2013) commented that the disorder due to PGAP2 can be viewed as part of a disease family representing a spectrum of disorders due to mutations in genes involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. Mutations in genes earlier in the pathway appear to cause a more severe phenotype, including dysmorphic features (e.g., MCAHS1, 614080), than mutations in genes that act later in the pathway.

Among 13 individuals with intellectual disability and increased serum alkaline phosphatase who were screened for mutations in genes encoding proteins in the GPI-anchor biosynthesis pathway, Krawitz et al. (2013) found that 2 unrelated patients carried biallelic missense mutations in the PGAP2 gene (615187.0003-615187.0005). In vitro studies showed that the mutations caused decreased enzyme activity.