ESPE2023 Poster Category 2 Bone, Growth Plate and Mineral Metabolism (27 abstracts)
Clinical findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG)
Yohei Masunaga 1 , Gen Nishimura 2 , Koji Takahashi 3 , Kenichi Kashimada 4 , Machiko Kadoya 5 , Yoshinao Wada 5 , Nobuhiko Okamoto 5 , Daiju Oba 6 , Hirofumi Ohashi 6 , Mitsuru Ikeno 7 , Maki Fukami 8 , Hirotomo Saitsu 1 & Tsutomu Ogata 1
1Hamamatsu University School of Medicine, Hamamatsu, Japan. 2Saitama Medical University Hospital, Saitama, Japan. 3Tsuchiura Kyodo General Hospital, Tsuchiura, Japan. 4Tokyo Medical and Dental University, Tokyo, Japan. 5Osaka Women's and Children's Hospital, Osaka, Japan. 6Saitama Children's Medical Center, Saitama, Japan. 7Juntendo University School of Medicine, Tokyo, Japan. 8National Research Institute for Child Health and Development, Tokyo, Japan
Background: N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG) is a recently established rare autosomal recessive disease caused by pathogenic variants in NANS involved in the biosynthesis of N-acetylneuraminic acid (the most common member of sialic acids). Sialic acids are ubiquitously distributed in the body including the brain and skeletal system, and are required for the development and function of multiple organs/tissues. Consistent with this, NANS-CDG leads to Camera-Genevieve type spondyloepimetaphyseal dysplasia (SEMD) associated with infantile-onset intellectual developmental disability (IDD) as well as other various clinical features.
Patients: Patient 1 exhibited a unique constellation of clinical features including marked hydrocephalus, 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 IDD. Growth pattern analysis in patients 1-3 revealed mildly decreased birth lengths and low-normal birth weights, and severely compromised postnatal heights. Roentgenographic examinations revealed SEMD with remarkable age-dependent evolution. Skeletal hallmarks in the neonatal period included a mildly narrow thorax, mild platyspondyly with multiple coronal clefts, broad ilia with short greater sciatic notches and horizontal acetabula, and stubby long bones. In childhood, platyspondyly became more conspicuous along with development of vertebral endplate irregularities. The long bones became overtubulated together with metaphyseal flaring and subphyseal longitudinal striations with age.
Molecular studies: We performed whole exome sequencing using genomic DNA of patients 1-3 and their parents, and revealed compound heterozygous NANS variants of c.207del:p.(Arg69Serfs*57) and c.979_981dup:p.(Ile327dup) in patient 1, a homozygous NANS variant of c.979_981dup:p.(Ile327dup) in patient 2, and compound heterozygous NANS variants of c.133–12T>A, leading to aberrant splicing, and c.607T>C:p.(Tyr203His) in patient 3.
Glycosylation studies: We examined the N-glycosylation status of transferrin and the O-glycosylation status of apolipoprotein C-III by mass spectrometry. Despite the presence of NANS variants, both glycosylation patterns were normal in patients 1-3. Blood total sialic acid values were at a low-normal range, whereas urine N-acetylmannosamine (the substrate for NANS) values were obviously increased in patients 1-3.
Conclusion: 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 classic Camera-Genevieve type and more severe Faye-Peterson type.
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