Molecular Characteristics
PHGDH (Phosphoglycerate Dehydrogenase) gene is located at 1p12 and encodes 3-Phosphoglycerate dehydrogenase enzyme, which converts 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the first and rate-limiting step in the serine biosynthesis pathway.
Mutations and pathophysiology
As indicated by El-Hattab et al. (2016), PHGDH deficiency has a spectrum of severity where NLS1 represents the severe end, but there are long term survivors with milder PHGD deficiency who typically lack the major manifestations of NLS1.
Shaheen et al. (2014) reported homozygosity for a missense mutation (c.418G>A, p. (Gly140Arg)) in two individuals from two different consanguineous families and another missense mutation (c.488G>A, p. (Arg163Gln)) in an individual from another consanguineous family. Both of these mutations localized within the NAD (P)-binding domain at the PHGDH dimer interface, which is important for the optimal functioning of PHGDH. Shaheen et al. also suggested that Neu-Laxova reflects the extreme end of the inborn error of serine metabolism.
Acuna-Hidalgo et al. (2014) reported homozygosity for missense mutations (c.160C>T, p. (Arg54Cys), c.793G>A, p. (Glu265Lys) and c.856G>C, p. (Ala286Pro)) in three individuals from three different families.
Matto et al. (2015) identified a homozygous nonsense mutation (c.1297C>T, p.(Gln433*)) in a patient with NSL presenting with lissencephaly, microcephaly, corpus callosum agenesia, and vermis hypoplasia.
El-Hattab et al. (2016) further reported a homozygous missense mutation, c.418G>A, p.(Gly140Arg), the same mutation that was previously reported in subjects with NLS by Shaheen et al. (2014); the subject in this study showed the typical NLS features, including severe IUGR, microcephaly, micrognathia, sloping forehead, protruding eyes, generalized skin edema, syndactyly with puffiness of hands, fetal akinesia, and polyhydramnios.
Recently, Poli et al. (2017) reported a homozygous missense mutation (c.164C>T, p. (Ser55Phe)) localized in the D‐isomer‐specific 2‐hydroxyacid dehydrogenase catalytic domain and a frameshift variant, c.1429dup, p. (Met477Asnfs*51), leading to a premature stop‐codon, thus PHGDH deficiency. The report indicates that epilepsy is not always present in patients with classical PHGDH deficiency, whose features include severe pre- and post‐natal microcephaly, severe cognitive impairment with regression, and progressive spasticity.