Hyperphosphatasia With Mental Retardation Syndrome 6

A number sign (#) is used with this entry because of evidence that hyperphosphatasia with mental retardation syndrome-6 (HPMRS6) is caused by homozygous mutation in the PIGY gene (610662) on chromosome 4q22.

Description

Hyperphosphatasia with mental retardation syndrome-6 (HPMRS6) is an autosomal recessive multisystem disorder characterized by global developmental delay, dysmorphic features, seizures, and congenital cataracts. Severity is variable, and the disorder may show a range of phenotypic and biochemical abnormalities, including increased serum alkaline phosphatase levels (summary by Ilkovski et al., 2015). 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

Ilkovski et al. (2015) reported 2 sisters, born of possibly remotely related Australian parents, with a severe multisystem disorder resulting in early death. One patient was born at 32 weeks' gestation and had a complicated course with necrotizing enterocolitis and chronic lung disease. She developed intractable seizures at age 5 months, followed by developmental regression and death from respiratory infection at age 2 years. Her sister was born at 28 weeks' gestation due to polyhydramnios. There was dilatation of the renal collecting systems and increased echogenicity of the renal parenchyma. She developed intractable seizures at age 6 weeks followed by developmental regression and death at age 7 months secondary to aspiration. Both patients had dysmorphic features, including bitemporal narrowing, depressed nasal bridge with upturned nares, deep-set eyes, congenital cataracts, short neck, fleshy earlobes, brachytelephalangy, proximal limb shortening, flexion contractures, hip dysplasia, and osteopenia. The patients also had poor feeding and abdominal discomfort resulting in poor growth and hypotonia. Creatine kinase was increased, and muscle biopsy showed variation in fiber size with small rounded atrophic fibers and increased fibrosis. Serum alkaline phosphatase was also increased.

Clinical Variability

Ilkovski et al. (2015) reported 2 Pakistani sibs, born of consanguineous parents, with global developmental delay, poor speech, and microcephaly (-3 to -5 SD). They had mild dysmorphic features with long palpebral fissures, bulbous nasal tip, and wide mouth; 1 had strabismus. Neither patient had brachytelephalangy or seizures, and both had normal alkaline phosphatase levels. The phenotype was much less severe than that found by Ilkovski et al. (2015) in the Australian sisters.

Inheritance

The transmission pattern of HPMRS6 in the family reported by Ilkovski et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sisters, born of Australian parents, with HPMRS6, Ilkovski et al. (2015) identified a homozygous missense mutation in the PIGY gene (L46P; 610662.0001). The mutation was identified by whole-exome sequencing and segregated with the disorder in the family. Patient fibroblasts showed a 20 to 50% reduction in surface expression of GPI-anchored proteins CD55 (125240) and CD59 (107271). Transfection of the mutation into PIGY-null cells could only partially restore CD55 and CD59 expression under a strong promoter. Western blot analysis showed decreased expression of the mutant protein, consistent with reduced stability resulting in impaired PIGY function. The findings suggested that this mutation disrupts GPI biosynthesis or interferes with GPI anchoring capacity. Two sibs, born of consanguineous Pakistani parents, with a mild form of HPMRS6 had a homozygous mutation in the promoter region of the PIGY gene (610662.0002). Patient blood cells showed significantly decreased PIGY expression (6-10% of controls). Patient fibroblasts were not available for study of GPI-anchored proteins, but granulocytes showed normal CD16 surface expression (see 146740), indicating that PIGY levels in some tissues are sufficient for normal GPI synthesis. These findings were consistent with the less severe phenotype in these patients.