Hyperphosphatasia with mental retardation syndrome

Pathogenesis

While many cases of HPMRS are caused by mutations in the PIGV gene, 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. 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. 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.

References

References

1. (July 1970). "Familial hyperphosphatase with mental retardation, seizures, and neurologic deficits". The Journal of Pediatrics.
2. (July 2010). "Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: Five new patients with Mabry syndrome". American Journal of Medical Genetics. Part A.
3. (2006). "Hyperphosphatasia with neurologic deficit: a pyridoxine-responsive seizure disorder?". Pediatric Neurology.
4. (2010). "Hyperphosphatasia with mental retardation, brachytelephalangy, and a distinct facial gestalt: Delineation of a recognizable syndrome". European Journal of Medical Genetics.
5. (October 2010). "Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome". Nature Genetics.
6. (March 2005). "PIG-V involved in transferring the second mannose in glycosylphosphatidylinositol". The Journal of Biological Chemistry.
7. (January 2018). "Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis". Genome Medicine.
8. (January 2021). "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.