Hyperphosphatasia with mental retardation syndrome explained

Hyperphosphatasia with mental retardation syndrome
Synonyms:	Mabry syndrome

Hyperphosphatasia with mental retardation syndrome, HPMRS,^[1] also known as Mabry syndrome,^[2] has been described in patients recruited on four continents world-wide.^[3] Mabry syndrome was confirmed^[4] to represent an autosomal recessive syndrome characterized by severe mental retardation, considerably elevated serum levels of alkaline phosphatase, hypoplastic terminal phalanges, and distinct facial features that include: hypertelorism, a broad nasal bridge and a rectangular face.

Pathogenesis

While many cases of HPMRS are caused by mutations in the PIGV gene,^[5] there may be genetic heterogeneity in the spectrum of Mabry syndrome as a whole. PIGV is a member of the molecular pathway that synthesizes the glycosylphosphatidylinositol anchor.^[6] The loss in PIGV activity results in a reduced anchoring of alkaline phosphatase to the surface membrane and an elevated alkaline phosphatase activity in the serum.

Diagnosis

The clinical diagnosis can be established if the patient has repeatedly elevated levels of alkaline phosphatase activity in the blood serum and exhibits intellectual disability. Supportive for the clinical diagnosis are epilepsies, brachydactyly and a characteristic facial gestalt, which can also be assessed by means of AI.^[7] The clinical diagnosis can be confirmed by molecular testing such as exome sequencing.

Treatment

So far, no effective treatment is available for HPMRS. A mouse model that mirrors the human phenotype has been engineered by CRISPR technology and is available for compound screening.^[8]

Notes and References

1. Mabry CC, Bautista A, Kirk RF, Dubilier LD, Braunstein H, Koepke JA . Familial hyperphosphatase with mental retardation, seizures, and neurologic deficits . The Journal of Pediatrics . 77 . 1 . 74–85 . July 1970 . 5465362 . 10.1016/s0022-3476(70)80047-6 .
2. Thompson MD, Nezarati MM, Gillessen-Kaesbach G, Meinecke P, Mendoza-Londono R, Mendoza R, Mornet E, Brun-Heath I, Squarcioni CP, Legeai-Mallet L, Munnich A, Cole DE . 6 . Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: Five new patients with Mabry syndrome . American Journal of Medical Genetics. Part A . 152A . 7 . 1661–1669 . July 2010 . 20578257 . 10.1002/ajmg.a.33438 . 2806832 . free .
3. Thompson MD, Killoran A, Percy ME, Nezarati M, Cole DE, Hwang PA . Hyperphosphatasia with neurologic deficit: a pyridoxine-responsive seizure disorder? . Pediatric Neurology . 34 . 4 . 303–307 . 2006. 10.1016/j.pediatrneurol.2005.08.020 . 16638507 .
4. Horn D, Schottmann G, Meinecke P . Hyperphosphatasia with mental retardation, brachytelephalangy, and a distinct facial gestalt: Delineation of a recognizable syndrome . European Journal of Medical Genetics . 53 . 2 . 85–88. 2010. 10.1016/j.ejmg.2010.01.002 . 20080219 .
5. Krawitz PM, Schweiger MR, Rödelsperger C, Marcelis C, Kölsch U, Meisel C, Stephani F, Kinoshita T, Murakami Y, Bauer S, Isau M, Fischer A, Dahl A, Kerick M, Hecht J, Köhler S, Jäger M, Grünhagen J, de Condor BJ, Doelken S, Brunner HG, Meinecke P, Passarge E, Thompson MD, Cole DE, Horn D, Roscioli T, Mundlos S, Robinson PN . 6 . Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome . Nature Genetics . 42 . 10 . 827–829 . October 2010 . 20802478 . 10.1038/ng.653 . 205356893 .
6. Kang JY, Hong Y, Ashida H, Shishioh N, Murakami Y, Morita YS, Maeda Y, Kinoshita T . 6 . PIG-V involved in transferring the second mannose in glycosylphosphatidylinositol . The Journal of Biological Chemistry . 280 . 10 . 9489–9497 . March 2005 . 15623507 . 10.1074/jbc.M413867200 . free .
7. Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh TC, Schubach M, Gurovich Y, Fleischer N, Jäger M, Köhler S, Muhle H, Korff C, Møller RS, Bayat A, Calvas P, Chassaing N, Warren H, Skinner S, Louie R, Evers C, Bohn M, Christen HJ, van den Born M, Obersztyn E, Charzewska A, Endziniene M, Kortüm F, Brown N, Robinson PN, Schelhaas HJ, Weber Y, Helbig I, Mundlos S, Horn D, Krawitz PM . 6 . Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis . Genome Medicine . 10 . 1 . 3 . January 2018 . 29310717 . 5759841 . 10.1186/s13073-017-0510-5 . free .
8. Rodríguez de Los Santos M, Rivalan M, David FS, Stumpf A, Pitsch J, Tsortouktzidis D, Velasquez LM, Voigt A, Schilling K, Mattei D, Long M, Vogt G, Knaus A, Fischer-Zirnsak B, Wittler L, Timmermann B, Robinson PN, Horn D, Mundlos S, Kornak U, Becker AJ, Schmitz D, Winter Y, Krawitz PM . 6 . A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions . Proceedings of the National Academy of Sciences of the United States of America . 118 . 2 . January 2021 . e2014481118 . 33402532 . 10.1073/pnas.2014481118 . 7812744 . 2021PNAS..11814481R . free .