Hyperphosphatasia with mental retardation syndrome (HPMRS), also called "Mabry syndrome", is a rare autosomal recessive form of intellectual disability, with facial dysmorphism, seizures, brachytelephalangy, and consistently elevated serum alkaline phosphatase (ALP).

(OMIM phenotype number #239300)

Hyperphosphatasia with mental retardation syndrome (HPMRS), also called "Mabry syndrome", is a rare autosomal recessive form of intellectual disability, with facial dysmorphism, seizures, brachytelephalangy, and consistently elevated serum alkaline phosphatase (ALP).
HPMRS type 1 is caused by homozygous or compound heterozygous mutation in the PIGV gene, which is a member of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. PIGV mutations leads to a defect in GPI anchor synthesis with a consequent reduction in the level of GPI-anchored substrates such as ALP localized at the cell surface. PIGV mutations have been reported in eight families affected by HPMRS1 so far.

Gene

PIGV gene, 1p36.11 (OMIM gene/locus number #610274)

Phenotype

Mental retardation, various neurologic abnormalities such as seizures and hypotonia, facial dysmorphism, variable degrees of hypoplastic terminal phalanges (brachytelephalangy). Midface hypoplasia, prognathism, hypertelorism, long palpebral fissures, arched eyebrows, broad nasal bridge and tip, cleft palate (rare), short philtrum, downturned corners of the mouth, tented mouth, ventral septal defect (rare), feeding problems necessitating tube feeding (in some patients), anteriorly displaced anus (in some patients), anovestibular fistula (in some patients), anorectal anomalies (in some patients), plagiocephaly, tapered fingers, hypoplastic toes (in some patients), bilateral adducted forefoot (rare), hypoplastic nails (in some patients), curved nails (in some patients), severe athetoid and dystonic hand movements (in some patients), moderate cortical atrophy (in some patients), delayed myelinization (in some patients), speech delay (in some patients), and no speech development (in most patients).

Main biochemical alterations:

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

Images

 Fig. 1) Hand anomalies of patients with PIGV mutations. (a) Brachytelephalangy with missing and hypoplastic nails of fingers. (b) Hand radiograph showing hypoplastic distal phalanges. (c) Broad hallux and hypoplastic toenails. Reproduced by permission from Macmillan Publishers Ltd: Eur J Hum Genet 22(6):762-7, copyright 2014.

Fig. 2) (d, e, f) The distinct pattern of facial anomalies present in a patient with PIGV mutation consisted of wide-set eyes, often with a large appearance, a short nose with a broad nasal bridge and tip, and a tented upper lip.

Reproduced by permission from Macmillan Publishers Ltd: Eur J Hum Genet 22(6):762-7, copyright 2014

Hyperphosphatasia with mental retardation syndrome 2 (HPRMS2) is a rare autosomal recessive form of HPRMS (see also HPMRS1) , and it is caused by compound heterozygous mutation in the PIGO gene.

(OMIM phenotype number #614749)

Hyperphosphatasia with mental retardation syndrome 2 (HPRMS2) is a rare autosomal recessive form of HPRMS  (see also HPMRS1) , and it is caused by compound heterozygous mutation in the PIGO gene. PIGO gene, such as PIGV gene,  is coinvolved in the glycosylphosphatidylinositol (GPI) anchor synthesis pathway, and PIGO mutations lead to a defect in GPI anchor synthesis with a consequent reduction in the level of GPI-anchored substrates such as serum alkaline phosphatase (ALP) localized at the cell surface. PIGO mutations have been identified in two families with HPMRS2 so far.

Gene

PIGO gene, 9p13.3 (OMIM gene/locus number #614730)

Phenotype

Moderately to severely delayed psychomotor development, mental retardation, various neurologic abnormalities such as seizures and hypotonia, hypoplastic or absent nails, long palpebral fissures, facial dysmorphism, and variable degrees of brachytelephalangy. Poor growth, microcephaly (1 patient), moderate to severe delayed speech and language development,  plagiocephaly (1 patient), coronal synostosis (1 patient), hypertelorism, short nose, broad nasal bridge and tip, tented mouth, atrial septal defect (1 patient), anal stenosis and atresia, vesicoureteral reflux (1 patient), broad halluces, and enlarged ventricles (1 patient).

Main biochemical alterations:

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

Image

Fig. (a) Facial appearance of a patient affected by HPRMS2 at the age of 15 years, and (b) an other patient (sister) at the age of 12 years. (c) Nail hypoplasia of the second and fourth digits and absent nail of the fifth digit. (d) Broad hallux, small nails of the second and third toes, and aplasia of the nails of the fourth and fifth digits 

Reproduced from Am J Hum Genet, Vol 91, Krawitz PM, Murakami Y, Hecht J, et al., Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation, Pages 146-51, Copyright 2012, with permission from Elsevier.

Hyperphosphatasia with mental retardation syndrome 3 (HPRMS3) is a rare autosomal recessive form of HPRMS (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP2 gene. PGAP2 encodes a protein involved in fatty-acid glycosylphosphatidylinositol (GPI)-anchor remodeling, which occurs in the Golgi apparatus.

(OMIM phenotype number #614207)

Hyperphosphatasia with mental retardation syndrome 3 (HPRMS3) is a rare autosomal recessive form of HPRMS  (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP2 gene. PGAP2 encodes a protein involved in fatty-acid glycosylphosphatidylinositol (GPI)-anchor remodeling, which occurs in the Golgi apparatus. It is required for stable association between GPI-anchored proteins (GPI-APs) and the cell-surface membrane rafts. Patients with PGAP2 mutations have secondary reduced GPI-AP surface levels also as a result of increased secretion into the extracellular space, resulting in high serum alkaline phosphatase (ALP). Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been described. All these mutations are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and high levels of ALP.

Gene

PGAP2 gene, 11p15.4 (OMIM gene/locus number #615187)

Phenotype

Delayed psychomotor development, severe mental retardation, intellectual disability mild (in some patients), hypotonia, seizures, disorder in sleep pattern (in some patients), cerebral atrophy (in some patients), microcephaly (in some patients), and cerebral atrophy (in some patients).

Main biochemical alterations

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

Images

 Fig. Phenotypic features of HPMRS3 (a and b). Face of a patient at the ages of 3 (a) and 28 years (b). (c) Normal-appearing fingernails of a patient. (d and e) Facial dysmorphism of a patient with HPMRS3 at the age of 2 years includes wide palpebral fissures, a short nose with a broad nasal bridge, a tented upper lip, and a small jaw. (f) Distal tapering of fingers and mild nail hypoplasia of the fifth digit of a patient with HPMRS3

Reproduced from Am J Hum Genet, Vol 92, Krawitz PM, Murakami Y, Rieß A, et al. PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome, Pages 584-9, Copyright 2013, with permission from Elsevier

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.

(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

 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).