Hyperphosphatasia with mental retardation syndrome 4 (HPMRS4)

(OMIM phenotype number #615716)

Hyperphosphatasia with mental retardation syndrome 4 (HPRMS4) is a rare autosomal recessive form of HPRMS (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP3 gene, encoding a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor maturation. PGAP2 and PGAP3 mutations suggest the importance of the later GPI-anchor remodelling steps for normal neuronal development (see also HPRMS3). HPRMS4 is characterized by severely delayed psychomotor development, mental retardation, lack of speech acquisition, seizures, and dysmorphic facial features.

Gene

PGAP3 gene, 17q12 (OMIM gene/locus number #611801)

Phenotype

Severely delayed psychomotor development with mental retardation, hypotonia, inability to walk, lack of speech development, generalized seizures, myoclonic seizures, involuntary movements and dysmorphic facial features. Poor growth (1 patient), microcephaly (-2 to -3 SD) (in some patients), large fleshy earlobes, hypertelorism, upslanting palpebral fissures, broad nasal bridge and tip, tented upper lip, thin upper lip, cleft palate (in some patients), and bruxism.

Main biochemical alterations

High ALP, high Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid.

Images

Hyperphosphatasia with mental retardation syndrome 4 (HPMRS4)

Fig. Photographs of individuals with HPMRS4. Facial features of three patients (a,b,c) at the ages of 4, 10, and 2 years, respectively. These individuals bear a striking resemblance with a broad nasal bridge, long-appearing palpebral fissures, a broad nasal tip, a short nose, a long philtrum, a thin and wide upper lip, full cheeks, and large fleshy ear lobes.

Reproduced from Am J Hum Genet 2014;94:278-87 under the terms of the Creative Commons Attribution License (CC BY).


References
  1. Howard MF, Murakami Y, Pagnamenta AT, et al. Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation. Am J Hum Genet. 2014 Feb 6;94(2):278-87.
  2. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  3. http://www.omim.org