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Within the group of GPI anchor defects, six present with the clinical phenotype of Hyperphosphatasia with Mental Retardation Syndrome (HPMRS, Mabry Syndrome) characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures and persistent hyperphosphatasia. We report the case of a 5\u2010year\u2010old female with global developmental delay associated with precocious puberty and persistently raised plasma alkaline phosphatase. Targeted next generation sequencing analysis of the HPMRS genes identified novel compound heterozygous variants in the <jats:italic>PGAP2<\/jats:italic> gene (c.103del p.(Leu35Serfs*90)and c.134A\u2009&gt;\u2009Gp.(His45Arg)) consistent with the diagnosis of HPMRS type 3. Cerebrospinal fluid (CSF) neurotransmitter analysis showed low levels of pyridoxal phosphate and 5\u2010methyltetrahydrofolate and raised homovanillic acid. Supplementation with pyridoxine and folinic acid led to normalization of biochemical abnormalities. The patient continues to make developmental progress with significant improvement in speech and fine motor skills. Our reported case expands the clinical spectrum of HPMRS3 in which multisystem involvement is being increasingly recognized. Furthermore, it shows that miss\u2010targeting GPI\u2010APs and the effect on normal cellular function could provide a physiopathologic explanation for the CSF biochemical abnormalities with management implications for a group of disorders that currently has no treatment that can lead possibly to improved clinical outcomes.<\/jats:p>","DOI":"10.1002\/jmd2.12347","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T02:33:17Z","timestamp":1669170797000},"page":"42-52","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid"],"prefix":"10.1002","volume":"64","author":[{"given":"Martina","family":"Messina","sequence":"first","affiliation":[{"name":"Metabolic Medicine Department Great Ormond Street Hospital for Children  London 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