Encyclopedia
Mabry syndrome is a condition characterized by intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms.
- genetic conditions
Frequency
Mabry syndrome is likely a rare condition, but its prevalence is unknown. More than 20 cases have been described in the scientific literature.
Causes
Mutations in the PIGV, PIGO, or PGAP2 gene cause Mabry syndrome. These genes are all involved in the production (synthesis) of a molecule called a glycosylphosphosphatidylinositol (GPI) anchor. This molecule is synthesized in a series of steps. It then attaches (binds) to various proteins and binds them to the outer surface of the cell membrane, ensuring that they are available when needed. Alkaline phosphatase is an example of a protein that is bound to the cell membrane by a GPI anchor.
The proteins produced from the PIGV and PIGO genes are involved in piecing together the GPI anchor. After the complete GPI anchor is attached to a protein, the protein produced from the PGAP2 gene adjusts the anchor to enhance the anchor's ability to bind to the cell membrane.
Mutations in the PIGV, PIGO, or PGAP2 gene result in the production of an incomplete GPI anchor that cannot attach to proteins or to cell membranes. Proteins lacking a functional GPI anchor cannot bind to the cell membrane and are instead released from the cell. The release of non-GPI anchored alkaline phosphatase elevates the amount of this protein in the blood, causing hyperphosphatasia in people with Mabry syndrome. It is unclear how gene mutations lead to the other features of Mabry syndrome, but these signs and symptoms are likely due to a lack of proper GPI anchoring of proteins.
PIGV gene mutations are the most frequent cause of Mabry syndrome, accounting for approximately half of all cases. Mutations in the PIGO and PGAP2 genes are responsible for a small proportion of Mabry syndrome. The remaining affected individuals do not have an identified mutation in any of these three genes; the cause of the condition in these individuals is unknown.
Inheritance
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Other Names for This Condition
- hyperphosphatasia with mental retardation syndrome
- hyperphosphatasia with seizures and neurologic deficit
This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/mabry-syndrome
References
- Hansen L, Tawamie H, Murakami Y, Mang Y, ur Rehman S, Buchert R, Schaffer S,Muhammad S, Bak M, Nöthen MM, Bennett EP, Maeda Y, Aigner M, Reis A, Kinoshita T,Tommerup N, Baig SM, Abou Jamra R. Hypomorphic mutations in PGAP2, encoding aGPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability.Am J Hum Genet. 2013 Apr 4;92(4):575-83. doi: 10.1016/j.ajhg.2013.03.008.
- Horn D, Krawitz P, Mannhardt A, Korenke GC, Meinecke P.Hyperphosphatasia-mental retardation syndrome due to PIGV mutations: expandedclinical spectrum. Am J Med Genet A. 2011 Aug;155A(8):1917-22. doi:10.1002/ajmg.a.34102.
- Horn D, Schottmann G, Meinecke P. Hyperphosphatasia with mental retardation,brachytelephalangy, and a distinct facial gestalt: Delineation of a recognizable syndrome. Eur J Med Genet. 2010 Mar-Apr;53(2):85-8. doi:10.1016/j.ejmg.2010.01.002.
- Krawitz PM, Murakami Y, Hecht J, Krüger U, Holder SE, Mortier GR, Delle ChiaieB, De Baere E, Thompson MD, Roscioli T, Kielbasa S, Kinoshita T, Mundlos S,Robinson PN, Horn D. Mutations in PIGO, a member of the GPI-anchor-synthesispathway, cause hyperphosphatasia with mental retardation. Am J Hum Genet. 2012Jul 13;91(1):146-51. doi: 10.1016/j.ajhg.2012.05.004.
- Krawitz PM, Murakami Y, Rieß A, Hietala M, Krüger U, Zhu N, Kinoshita T,Mundlos S, Hecht J, Robinson PN, Horn D. PGAP2 mutations, affecting theGPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardationsyndrome. Am J Hum Genet. 2013 Apr 4;92(4):584-9. doi:10.1016/j.ajhg.2013.03.011.
- 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, KerickM, 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. Identity-by-descent filtering of exome sequence data identifies PIGVmutations in hyperphosphatasia mental retardation syndrome. Nat Genet. 2010Oct;42(10):827-9. doi: 10.1038/ng.653.
- Murakami Y, Kanzawa N, Saito K, Krawitz PM, Mundlos S, Robinson PN,Karadimitris A, Maeda Y, Kinoshita T. Mechanism for release of alkalinephosphatase caused by glycosylphosphatidylinositol deficiency in patients withhyperphosphatasia mental retardation syndrome. J Biol Chem. 2012 Feb24;287(9):6318-25. doi: 10.1074/jbc.M111.331090.
- Thompson MD, Nezarati MM, Gillessen-Kaesbach G, Meinecke P, Mendoza-Londono R,Mornet E, Brun-Heath I, Squarcioni CP, Legeai-Mallet L, Munnich A, Cole DE.Hyperphosphatasia with seizures, neurologic deficit, and characteristic facialfeatures: Five new patients with Mabry syndrome. Am J Med Genet A. 2010Jul;152A(7):1661-9. doi: 10.1002/ajmg.a.33438. Erratum in: Am J Med Genet A. 2011May;155A(5):1215. Mendoza, Roberto [corrected to Mendoza-Londono, Roberto].
- Thompson MD, Roscioli T, Marcelis C, Nezarati MM, Stolte-Dijkstra I, SharomFJ, Lu P, Phillips JA, Sweeney E, Robinson PN, Krawitz P, Yntema HG, Andrade DM, Brunner HG, Cole DE. Phenotypic variability in hyperphosphatasia with seizuresand neurologic deficit (Mabry syndrome). Am J Med Genet A. 2012Mar;158A(3):553-8. doi: 10.1002/ajmg.a.35202.
