PHGDH – Neurometabolic Disorder due to Serine Deficiency

Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step of de novo L-serine biosynthesis. Biallelic loss-of-function variants in PHGDH underlie a neurometabolic disorder due to serine deficiency (Neurometabolic disorder due to serine deficiency), characterized by congenital microcephaly, psychomotor retardation, seizures, and spasticity.

In a cohort of two new patients, one individual with PHGDH deficiency presented with microcephaly (<3rd centile), encephalopathy, spasticity, and intractable seizures; plasma and CSF serine levels were markedly reduced. Oral l-serine supplementation at ages 4.5 and 0.25 years led to a rapid reduction in seizure frequency and improved spasticity, although head growth and neurocognitive outcomes remained suboptimal ([PMID:26610677]).

A familial case report described two affected siblings carrying a novel missense variant, c.1211T>A (p.Val404Asp), demonstrating variable expressivity within the same genotype and further expanding the allelic spectrum of PHGDH deficiency ([PMID:36308023]).

Six additional patients from four unrelated families were homozygous for recurrent variants p.Val490Met (five patients) or p.Val425Met (one patient), supporting founder and pan-ethnic recurrence of these alleles ([PMID:11055895]; [PMID:11055895]).

The variant spectrum includes missense (e.g., c.1468G>A (p.Val490Met)), frameshift (p.Pro479_Thr480insTer), and splice variants distributed throughout the coding sequence, all leading to markedly reduced enzymatic activity.

Functional studies demonstrate that p.Val490Met yields <35% of wild-type PHGDH activity in vitro, primarily due to impaired folding and increased degradation, while Phgdh knockout mice recapitulate severe microcephaly, CNS growth retardation, and lethality; transcriptomic profiling in knockout embryos reveals dysregulated cell-cycle and neurogenesis pathways ([PMID:11751922]; [PMID:19114063]).

Integration of genetic and experimental data across >9 probands and multiple families supports a strong autosomal recessive association of PHGDH with serine deficiency disorder. Early measurement of plasma and CSF serine in neonates with severe microcephaly is critical, as prompt l-serine therapy can mitigate seizures and spasticity.

Key Take-home: Measurement of serine levels in severe congenital microcephaly should be standard to enable early diagnosis and initiation of l-serine supplementation to improve neurological outcomes.

References

• European journal of paediatric neurology • 2016 • Two new cases of serine deficiency disorders treated with l-serine. PMID:26610677
• American journal of human genetics • 2000 • Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis. PMID:11055895
• Human Mutation • 2009 • Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. PMID:19235232
• 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

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