Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders

Abstract

Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu–Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre‐ or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders. We identified likely disease‐causing variants in the PHGDH and PSAT1 genes, several of which have not been reported previously. Phenotype analysis and a comprehensive review of the literature corroborates the evidence that serine biosynthesis disorders represent a continuum with varying degrees of phenotypic expression and suggest that even gradual differences at the severe end of the spectrum may be correlated with particular genotypes. We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability, but further functional studies are needed to explore effects at the enzyme protein level.

Juvenile-onset PSAT1-related neuropathy: A milder phenotype of serine deficiency disorder

“…In addition to the two patients in this study, PSAT1 -related serine deficiency disorder have been reported in other 29 individuals including 13 males, 15 females, and one unidentified gender died in utero ( Table 2 ) ( Hart, et al, 2007 ; Acuna-Hidalgo, et al, 2014 ; Brassier et al, 2016 ; El-Hattab, et al, 2016 ; Glinton et al, 2018 ; Ni et al, 2019 ; Abdelfattah et al, 2020 ; Debs, et al, 2021 ). Fourteen patients came from consanguineous families.…”

Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency

“…The plasma and CSF serine levels of the proband were comparable to those found in severely affected infants ( Table 2 ). Moreover, studies have indicated that phenotypic variability in serine deficiency disorders is mainly linked to the degree of PHGDH enzyme activity [ 16 , 38 ]. Here, we reported childhood phenotypes of PHGDH deficiency with microcephaly, intractable seizure, and developmental regression without hypomyelination.…”

“…PHGDH deficiency (MIM# 601815) is a rare, autosomal recessive disorder, characterized biochemically by low concentration of serine in the plasma and cerebrospinal fluid (CSF) and clinically by serious neurological problems [ 12 , 13 , 14 ]. The clinical phenotype varies from nonspecific neurodevelopmental delays to Neu–Laxova syndrome (NLS), an extremely lethal disease [ 15 , 16 ]. NLS has been identified in over 100 cases so far [ 16 ].…”

“…The clinical phenotype varies from nonspecific neurodevelopmental delays to Neu–Laxova syndrome (NLS), an extremely lethal disease [ 15 , 16 ]. NLS has been identified in over 100 cases so far [ 16 ]. NLS is mostly presented with several congenital defects and ectodermal abnormalities.…”

A Novel Assay for Phosphoserine Phosphatase Exploiting Serine Acetyltransferase as the Coupling Enzyme

“…In consideration of the importance of PSP in the brain, it is not surprising that inborn deficiencies of PSP, as well as of the other enzymes in the phosphorylated pathway, are associated with neurological symptoms [11][12][13][14][15][16]. In mice, the knockout of both copies of associated with neurological symptoms [11][12][13][14][15][16]. In mice, the knockout of both copies of the PSP-encoding gene is apparently lethal [17], further confirming the crucial biological role of this enzyme and of the phosphorylated pathway.…”