Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges

Abstract

Serine biosynthesis defects can present in a broad phenotypic spectrum ranging from Neu-Laxova syndrome, a lethal disease with multiple congenital anomalies at the severe end, to an infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype, to a childhood disease with intellectual disability at the mild end. In this report we present 6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency who presented with psychomotor delay, growth failure, microcephaly, and spasticity. The phenotype was variable with absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3. The initiation of serine treatment had pronounced effect on seizures and spasticity in the sisters in family 3, but minimal developmental effects on the children in families 1 and 2. With such phenotypic variability, the diagnosis of PGDH deficiency can be challenging.

Mild phenotypes of phosphoglycerate dehydrogenase deficiency by a novel mutation of PHGDH gene: Case report and literature review

“…Their brain MRI did not show evidence of corpus callosum atrophy and hypomyelination in the infantile form. Remarkably, three patients had been reported to lose the ability to walk independently (Benke et al, 2017). We speculated that regression could also be a feature of this disease.…”

“…PHGDH gene mutations are associated with two kinds of disease phenotypes: classical PHGDH deficiency (OMIM: 601815) and Neu–Laxova syndrome (NLS, OMIM: 256520). Since first reported by Jaeken et al (1996), a total of 43 patients with the PHGDH gene variants were identified in 23 articles (Abdelfattah et al, 2020; Acuna‐Hidalgo et al, 2014; Benke et al, 2017; Brassier et al, 2016; Cavole et al, 2020; de Koning et al, 1998; el‐Hattab et al, 2016; Glinton et al, 2018; Häusler et al, 2001; Jaeken et al, 1996; Klomp et al, 2000; Kraoua et al, 2013; Mattos et al, 2015; Méneret et al, 2012; Ni et al, 2019; Pind et al, 2002; Pineda et al, 2000; Poli et al, 2017; Shaheen et al, 2014; Tabatabaie et al, 2009, 2011; Takeichi et al, 2018; Tao & Lu, 2021). An overview of clinical characteristics in patients who were reported with clear genetic etiology of PHGDH gene mutations is summarized in Data S1.…”

“…Symptoms of infantile PHGDH deficiency were microcephaly, early‐onset seizures, and severe psychomotor retardation. Infantile patients appeared with seizures within a few months to 1 year after birth and then probably developed different types of intractable seizures including infantile spasms (Klomp et al, 2000; Kraoua et al, 2013; Pineda et al, 2000), generalized tonic–clonic seizures (Benke et al, 2017; de Koning et al, 1998), atonic seizures (Brassier et al, 2016; de Koning et al, 1998; Häusler et al, 2001), and myoclonic seizure (Brassier et al, 2016). The majority of infantile patients developed hyperexcitability and feeding difficulties during the first months of life and subsequently developed severe psychomotor delay.…”

Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps

“…In contrast, CSF serine and glycine concentrations are not affected by meals, however, CSF amino acid analysis is not typically done in the absence of seizures. Therefore, the metabolic work up may fail to identify children with serine biosynthesis defects [27,33].…”

Biochemical and Biophysical Characterization of Recombinant Human 3-Phosphoglycerate Dehydrogenase

“…PHGDH is involved in nucleotide synthesis by supporting central one-carbon metabolism [16]. Furthermore, in the last decade, several mutations have been correlated to PHGDH deficiency [17][18][19]. Five homozygous missense mutations have been identified in several individuals with congenital microcephaly, psychomotor retardation and variable presence of seizures [17,[20][21][22].…”