[2014 seems to have been a good year for Neu-Laxova
syndrome]
Shaheen R, Rahbeeni Z, Alhashem A, Faqeih E, Zhao Q, Xiong
Y, Almoisheer A, Al-Qattan SM, Almadani HA, Al-Onazi N, Al-Baqawi BS, Saleh
MA, Alkuraya FS. Neu-Laxova syndrome, an inborn error of serine metabolism,
is caused by mutations in PHGDH. Am J Hum Genet. 2014 Jun 5;94(6):898-904.
Abstract
Neu-Laxova syndrome (NLS) is a rare autosomal-recessive
disorder characterized by severe fetal growth restriction, microcephaly, a
distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal
lethality. The pathogenesis of NLS remains unclear despite extensive clinical
and pathological phenotyping of the >70 affected individuals reported to
date, emphasizing the need to identify the underlying genetic etiology, which
remains unknown. In order to identify the cause of NLS, we conducted a
positional-mapping study combining autozygosity mapping and whole-exome
sequencing in three consanguineous families affected by NLS. Surprisingly, the
NLS-associated locus identified in this study was solved at the gene level to
reveal mutations in PHGDH, which is known to be mutated in individuals with
microcephaly and developmental delay. PHGDH encodes the first enzyme in the
phosphorylated pathway of de novo serine synthesis, and complete deficiency of
its mouse ortholog recapitulates many of the key features of NLS. This study
shows that NLS represents the extreme end of a known inborn error of serine
metabolism and highlights the power of genomic sequencing in revealing the
unsuspected allelic nature of apparently distinct clinical entities.
Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A,
Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A,
Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N,
Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt
R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR,
Hoischen A, Zenker M. Neu-Laxova syndrome is a heterogeneous metabolic disorder
caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum
Genet. 2014 Sep 4;95(3):285-93.
Abstract
Neu-Laxova syndrome (NLS) is a rare autosomal-recessive
disorder characterized by a recognizable pattern of severe malformations
leading to prenatal or early postnatal lethality. Homozygous mutations in
PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis,
were recently identified as the cause of the disease in three families. By
studying a cohort of 12 unrelated families affected by NLS, we provide evidence
that NLS is genetically heterogeneous and can be caused by mutations in all
three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent
with recently reported findings, we could identify PHGDH missense mutations in
three unrelated families of our cohort. Furthermore, we mapped an overlapping
homozygous chromosome 9 region containing PSAT1 in four consanguineous
families. This gene encodes phosphoserine aminotransferase, the enzyme for the
second step in L-serine biosynthesis. We identified six families with three
different missense and frameshift PSAT1 mutations fully segregating with the
disease. In another family, we discovered a homozygous frameshift mutation in
PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last
step of L-serine biosynthesis. Interestingly, all three identified genes have
been previously implicated in serine-deficiency disorders, characterized by
variable neurological manifestations. Our findings expand our understanding of
NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS
represents the severe end of serine-deficiency disorders, demonstrating that
certain complex syndromes characterized by early lethality could indeed be the
extreme end of the phenotypic spectrum of already known disorders.
El-Hattab AW, Shaheen R, Hertecant J, Galadari HI, Albaqawi
BS, Nabil A, Alkuraya FS. On the phenotypic spectrum of serine
biosynthesis defects. J Inherit Metab Dis. 2016 May;39(3):373-81.
Abstract
L-serine is a non-essential amino acid that is de novo
synthesized via the enzymes phosphoglycerate dehydrogenase (PGDH),
phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP).
Besides its role in protein synthesis, L-serine is a precursor of a number of
important compounds. Serine biosynthesis defects result from deficiencies in
PGDH, PSAT, or PSP and have a broad phenotypic spectrum ranging from Neu-Laxova
syndrome, a lethal multiple congenital anomaly disease at the severe end to a
childhood disease with intellectual disability at the mild end, with infantile
growth deficiency, and severe neurological manifestations as an intermediate
phenotype. In this report, we present three subjects with serine biosynthesis
effects. The first was a stillbirth with Neu-Laxova syndrome and a homozygous
mutation in PHGDH. The second was a neonate with growth deficiency,
microcephaly, ichthyotic skin lesions, seizures, contractures, hypertonia,
distinctive facial features, and a homozygous mutation in PSAT1. The third
subject was an infant with growth deficiency, microcephaly, ichthyotic skin
lesions, anemia, hypertonia, distinctive facial features, low serine and
glycine in plasma and CSF, and a novel homozygous mutation in PHGDH gene.
Herein, we also review previous reports of serine biosynthesis defects and
mutations in the PHGDH, PSAT1, and PSPH genes, discuss the variability in the
phenotypes associated with serine biosynthesis defects, and elaborate on the vital
roles of serine and the potential consequences of its deficiency.
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