Hyperphosphatasia With Mental Retardation Syndrome 1

A number sign (#) is used with this entry because hyperphosphatasia with mental retardation syndrome-1 (HPMRS1) is caused by homozygous or compound heterozygous mutation in the PIGV gene (610274) on chromosome 1p36.

Description

Hyperphosphatasia with mental retardation syndrome-1 is an autosomal recessive disorder characterized by mental retardation, various neurologic abnormalities such as seizures and hypotonia, and hyperphosphatasia. Other features include facial dysmorphism and variable degrees of brachytelephalangy (summary by Krawitz et al., 2010). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293).

Genetic Heterogeneity of Hyperphosphatasia with Mental Retardation Syndrome

See also HPMRS2 (614749), caused by mutation in the PIGO gene (614730) on chromosome 9p13; HPMRS3 (614207), caused by mutation in the PGAP2 gene (615187) on chromosome 11p15; HPMRS4 (615716), caused by mutation in the PGAP3 gene (611801) on chromosome 17q12; HPMRS5 (616025), caused by mutation in the PIGW gene (610275) on chromosome 17q12; and HPMRS6 (616809), caused by mutation in the PIGY gene (610662) on chromosome 4q22.

Knaus et al. (2018) provided a review of the main clinical features of the different types of HPMRS, noting that some patients have a distinct pattern of facial anomalies that can be detected by computer-assisted comparison, particularly those with mutations in the PIGV and PGAP3 genes. Individuals with HPMRS have variable increased in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between HPMRS and MCAHS (see, e.g., 614080), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified under the more encompassing term of 'GPI biosynthesis defects' (GPIBD).

Clinical Features

Mabry et al. (1970) reported 3 sibs and a first cousin with severe mental retardation, seizures, various neurologic abnormalities, and greatly elevated alkaline phosphatase. Both pairs of parents were consanguineous. The alkaline phosphatase present in excess seemed to be of hepatic origin.

Kruse et al. (1988) reported that over a 10-year period they had observed 9 children (6 females) from 6 families who had unexplained persistent hyperphosphatasia and mental retardation. Six of the patients had moderately delayed motor and speech development and 3 of these patients had seizures. The other 3 patients, including male identical twins, had severe primary delayed development and generalized muscular hypotonia since early infancy, with decreased tendon jerk. They also had severe seizures that were resistant to anticonvulsant drugs. One of the twins died at age 1.9 years of an unknown cause; autopsy revealed no evidence of macroscopic or microscopic brain lesions. Even at the age of 8 and 4 years, respectively, the other 2 patients were unable to sit, speak, or make emotional contact.

Marcelis et al. (2007) reported 2 sisters, born to consanguineous Moroccan parents, with a syndrome of mental retardation, epilepsy, anteriorly displaced anus, hypoplastic terminal phalanges, hypoplastic nails, hypotonia, delayed myelinization in the brain, arched eyebrows, hypertelorism, and downturned corners of the mouth. The elder sister also had anovestibular fistula, and her nail hypoplasia was associated with hypoplasia of the distal phalanx of the fifth finger. The younger sister also had clefting of the hard and soft palates, and a small ventricular septal defect. Both sisters had elevated levels of alkaline phosphatase. Marcelis et al. (2007) noted similarities to Coffin-Siris syndrome (135900) but considered the disorder in the sibs to be distinct because neither sib had the coarse face and sparse scalp hair characteristic of Coffin-Siris syndrome.

Horn et al. (2010) reported 3 sibs, a 4-year-old girl and dizygotic twin brothers, with a syndrome consisting of severe mental retardation, considerably elevated levels of alkaline phosphatase, hypoplastic terminal phalanges, and distinct facial features. Shortness of the distal phalanges was demonstrated both clinically and radiologically in all. The girl had Hirschsprung disease, both boys had hearing impairment, and 1 boy had macrocephaly and cleft lip/palate. Horn et al. (2010) suggested that their patients and those reported by Marcelis et al. (2007) and Rabe et al. (1991) had the same syndrome originally described by Mabry et al. (1970). Rabe et al. (1991) had suggested the diagnosis of Coffin-Siris syndrome in 2 sisters with hyperphosphatasia, severe mental retardation, brachytelephalangy, and facial features characterized by hypertelorism, long palpebral fissures, broad nasal bridge or tip, and a tented mouth. Horn et al. (2010) stated that all 7 patients had hyperphosphatasia, severe psychomotor retardation, the same facial gestalt, and brachytelephalangy. Five patients learned to walk, 2 were still not walking at 2 years and 9 years, and none had developed speech. Five patients had documented hypotonia and 3 of the 5 had seizures. Four patients had anorectal anomalies.

Thompson et al. (2010) reported 5 patients, 2 sibs, 1 child of consanguineous patients, and 2 sporadic patients, with hyperphosphatasia, mental retardation, and seizures; one of the patients had previously been reported by Thompson et al. (2006). All had similar facial dysmorphism characterized by hypertelorism, broad nasal bridge, and a tented mouth. All had some degree of brachytelephalangy, but the phalangeal shortening varied in position and degree. In all there was a persistent elevation of alkaline phosphatase activity with no evidence of active bone or liver disease. The degree of hyperphosphatasia varied considerably between patients (1.3 to 20 times the upper age-adjusted reference limit), but was relatively constant over time. All 5 patients were products of a normal pregnancy and birth history. None of the patients had growth delay, 2 had macrocephaly, 2 had normocephaly, and 1 had microcephaly. All had moderate to severe psychomotor retardation, hypotonia in the first year of life, and seizures with age of onset ranging from less than 1 month to 7 years. Of 2 patients tested, seizures were pyridoxine-responsive in one but not in the other. One patient had autistic behavior. Thompson et al. (2010) commented that at least 1 member of the family reported by Mabry et al. (1970) was found to have intracellular inclusions on biopsy of some but not all tissues; inclusions were found in a rectal biopsy, tooth, and liver. Thompson et al. (2010) found similar inclusions in only some tissues of 3 of their patients; patients 1 and 5 had inclusions in fibroblasts, and patient 2 had inclusions in osteoblasts and fibroblasts. The intracellular storage material was not identified. Thompson et al. (2010) stated that hyperphosphatasia and the presence of intracellular inclusions distinguish this disorder and suggested the designation Mabry syndrome.

Krawitz et al. (2010) reported a family in which 3 sibs, including a pair of dizygotic twin boys, had the hyperphosphatasia mental retardation syndrome. They were born of nonconsanguineous German parents. All had severe global developmental delay without any speech development, and characteristic facies, including hypertelorism, large appearing eyes, short nose with broad nasal bridge and tip, and thin upper lip with downturned corners of the mouth. Several distal phalanges, particularly digits II and V, were shortened. One patient had seizures. Alkaline phosphatase was persistently elevated in all 3 patients.

Horn et al. (2011) reported 2 unrelated patients with hyperphosphatasia mental retardation syndrome confirmed by genetic analysis. One was of German and Dutch/Polish origin and the other was of Polish origin. Both patients had developmental delay, brachytelephalangy, hyperphosphatasia, and a facial gestalt, including hypertelorism, long palpebral fissures, broad nasal bridge and tip, and tented mouth. One patient had a more severe phenotype with hypotonia, seizures, lack of speech, inability to walk, hearing impairment, Hirschsprung disease, and cleft palate. The other patient had anal atresia and a small atrial septal defect.

Thompson et al. (2012) reported a sister and brother, born of unrelated English parents, with HPMRS1. They had hypotonia, early-onset seizures, and dysmorphic features including hypertelorism with long palpebral fissures, broad nasal bridge, tented upper lip with downturned corners of the mouth, simple cupped ears with thickened helices, and brachytelephalangy. Both had profound global developmental delay with no speech. Other features included unilateral hydronephrosis in both, an anteriorly placed anus in 1 patient, and short-segment Hirschsprung disease in the other. An unrelated Dutch girl with the disorder, born of consanguineous parents, showed similar features, including brachytelephalangy and hydronephrosis. Fibroblasts of the Dutch girl contained abundant cytoplasmic vacuoles, reminiscent of a lysosomal storage disease.

Inheritance

Marcelis et al. (2007) suggested autosomal recessive inheritance for this disorder because of parental consanguinity and affected sibs.

Mapping

Marcelis et al. (2007) carried out a 10-cM whole-genome linkage scan and found that both affected sibs reported by them were homozygous with respect to 4 consecutive markers on chromosome 1p; however, the authors erroneously cited the 1p markers as D142697, D14S255, D14S199 and D14S234. On chromosome 14 the homozygous region encompassed at least the region from D14S70 to D14S280, spanning a minimum region of 65 Mb.

Molecular Genetics

Using whole-exome capture and sequencing in combination with a Hidden Markov Model algorithm to detect regions of the genome that are identical by descent, Krawitz et al. (2010) identified a homozygous mutation in the PIGV gene (A341E; 610274.0001) in 3 German sibs with the hyperphosphatasia mental retardation syndrome. Further study of this gene identified homozygous or compound heterozygous mutations (610274.0001-610274.0004) in affected individuals from 3 additional families, including those reported by Rabe et al. (1991) and Marcelis et al. (2007), as well as in 1 patient reported by Thompson et al. (2010).

In 3 patients, including 2 sibs, with HPMRS1, Thompson et al. (2012) identified compound heterozygous mutations in the PIGV gene (see, e.g., 610274.0001 and 610274.0006).

Pathogenesis

Murakami et al. (2012) stated that hyperphosphatasia in HPMRS1 results from secretion of liver alkaline phosphatase (LAPL; 171760), which is normally attached to the cell surface via a glycosylphosphatidylinositol (GPI) anchor, due to deficiency of PIGV, a mannosyltransferase essential for GPI biosynthesis. Using Chinese hamster ovary cells deficient in select GPI synthesis proteins, they found that GPI-anchored proteins were released to the medium following deletion of proteins active in intermediate steps of GPI synthesis, including Pigv, which attaches the second mannosyl to the immature GPI anchor. Deletion of proteins active earlier in GPI synthesis or of the GPI transamidase, which functions late in the process and exchanges the GPI signal sequence for the completed GPI anchor, resulted in degradation of substrate proteins. Substrate proteins released following knockdown of Pigv were cleaved following the GPI signal sequence, but they lacked the GPI anchor. Murakami et al. (2012) concluded that the GPI transamidase can cleave GPI signal sequences on substrate proteins in the presence of an immature GPI anchor with at least 1 mannosyl residue, resulting in secretion of substrate proteins, including LAPL. They noted that these findings explain the molecular mechanism of hyperphosphatasia in HPMR1.