Clinical and molecular findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG).

We report clinical and molecular findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG). Patient 1 exhibited a unique constellation of clinical features including marked hydrocephalus, spondyloepimetaphyseal dysplasia (SEMD), and thrombocytopenia which is comparable to that of an infant reported by Faye-Peterson et al., whereas patients 2 and 3 showed Camera-Genevieve type SMED with intellectual/developmental disability which is currently known as the sole disease name for NANS-CDG. Molecular studies revealed a maternally inherited likely pathogenic c.207del:p.(Arg69Serfs*57) variant and a paternally derived likely pathogenic c.979_981dup:p.(Ile327dup) variant in patient 1, a homozygous likely pathogenic c.979_981dup:p.(Ile327dup) variant caused by maternal segmental isodisomy involving NANS in patient 2, and a paternally inherited pathogenic c.133-12T>A variant leading to aberrant splicing and a maternally inherited likely pathogenic c.607T>C:p.(Tyr203His) variant in patient 3 (reference mRNA: NM_018946.4). The results, together with previously reported data, imply that (1) NANS plays an important role in postnatal growth and fetal brain development; (2) SMED is recognizable at birth and shows remarkable postnatal evolution; (3) NANS-CDG is associated with low-normal serum sialic acid, obviously elevated urine N-acetylmannosamine, and normal N- and O-glycosylation of serum proteins; and (4) NANS-CDG is divided into Camera-Genevieve type and more severe Faye-Peterson type.

Mass Spectrometry of Transferrin and Apolipoprotein CIII from Dried Blood Spots for Congenital Disorders of Glycosylation.

Dried blood spot (DBS) is the standard specimen for the newborn screening of inborn errors of metabolism (IEM) by tandem mass spectrometry. Availability of DBS for the mass spectrometric analysis of the diagnostic marker proteins, transferrin (Tf) and apolipoprotein CIII (apoCIII), of congenital disorders of glycosylation (CDG) was examined. Recovery of Tf from DBS was only slightly reduced compared with fresh serum. Although oxidation of the core polypeptides was observed, glycans of Tf and apoCIII were unaffected by storage of DBS in the ambient environment for at least 1 month. The combination of DBS and the triple quadrupole mass spectrometer used for IEM screening was sufficient to characterize the aberrant glycoprofiles of Tf and apoCIII in CDG. DBS or dried serum spot on filter paper can reduce the cost of sample transportation and potentially promote mass spectrometric screening of CDG.