PHGDH – PHGDH Deficiency

Phosphoglycerate dehydrogenase (PHGDH) deficiency (MONDO:0011152) is a rare autosomal recessive disorder of L-serine biosynthesis characterized by congenital microcephaly, psychomotor developmental delay, and seizures. Onset is typically in infancy with progressive neurological impairment and low cerebrospinal fluid and serum serine and glycine levels.

Genetic evidence includes 17 unrelated probands across five studies with biallelic PHGDH variants ([PMID:11055895], [PMID:11751922], [PMID:28440900], [PMID:36308023], [PMID:19235232]). Segregation of homozygous or compound heterozygous variants in six affected sibling pairs confirms autosomal recessive inheritance. The variant spectrum comprises missense, frameshift, and splice defects distributed throughout the enzyme.

A novel missense variant, c.1211T>A (p.Val404Asp), was identified in two Chinese siblings presenting with microcephaly, developmental delay, and juvenile-onset epilepsy, expanding the phenotypic range to milder presentations ([PMID:36308023]). Other recurrent founder alleles include p.Val490Met in Ashkenazi Jewish families and several private missense mutations in diverse populations.

Functional assays demonstrate that variants such as p.Val425Leu and p.Val490Met reduce PHGDH enzymatic activity to ≤35% of wild type in vitro ([PMID:11055895], [PMID:11751922]). Phgdh knockout mice exhibit severe microcephaly, impaired neurogenesis, and embryonic lethality, recapitulating human pathology ([PMID:18228065]). L-serine supplementation ameliorates biochemical deficits and is under investigation as a targeted therapy.

Mechanistically, loss of PHGDH disrupts de novo L-serine biosynthesis leading to deficient neuronal proliferation and survival. There are no conflicting studies disputing PHGDH’s role in this disease.

In summary, multi-family segregation, a consistent variant spectrum, concordant in vitro and animal model data, and actionable serine supplementation support a Strong gene–disease association. Key Take-home: Biallelic PHGDH variants cause an autosomal recessive serine-deficiency disorder with neurodevelopmental impairment; early genetic diagnosis enables targeted L-serine therapy.

References

• American journal of human genetics • 2000 • Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis. PMID:11055895
• The Journal of biological chemistry • 2002 • V490M, a common mutation in 3-phosphoglycerate dehydrogenase deficiency, causes enzyme deficiency by decreasing the yield of mature enzyme. PMID:11751922
• American journal of medical genetics. Part A • 2017 • Phosphoglycerate dehydrogenase (PHGDH) deficiency without epilepsy mimicking primary microcephaly. PMID:28440900
• International journal of developmental neuroscience • 2023 • Mild phenotypes of phosphoglycerate dehydrogenase deficiency by a novel mutation of PHGDH gene: Case report and literature review. PMID:36308023
• Human mutation • 2009 • Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. PMID:19235232
• Functional & integrative genomics • 2008 • Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: changes in gene expression and associated regulatory networks resulting from serine deficiency. PMID:18228065

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