GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype

There have been a few reports of GM3 synthase deficiency since the disease of the ganglioside biosynthetic pathway was first reported in 2004. It is characterized by infantile‐onset epilepsy with severe intellectual disability, blindness, cutaneous dyspigmentation, and choreoathetosis. Here we repor...

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Published in:American journal of medical genetics. Part A 2016-08, Vol.170A (8), p.2200-2205
Main Authors: Lee, Jin Sook, Yoo, Yongjin, Lim, Byung Chan, Kim, Ki Joong, Song, Junghan, Choi, Murim, Chae, Jong-Hee
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Child, Preschool
DNA Mutational Analysis
Epilepsy - diagnosis
Epilepsy - genetics
Exome
Female
ganglioside
Genetic Association Studies
Genetic Variation
GM3 synthase
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Infant
Pedigree
Phenotype
Rett Syndrome - diagnosis
Rett Syndrome - genetics
Rett-like phenotype
Sialyltransferases - deficiency
Sialyltransferases - genetics
Siblings
ST3GAL5
whole-exome sequencing
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Summary:There have been a few reports of GM3 synthase deficiency since the disease of the ganglioside biosynthetic pathway was first reported in 2004. It is characterized by infantile‐onset epilepsy with severe intellectual disability, blindness, cutaneous dyspigmentation, and choreoathetosis. Here we report the cases of two Korean female siblings with ST3GAL5 variants, who presented with a Rett‐like phenotype. They had delayed speech, hand stereotypies with a loss of purposeful hand movements, and choreoathetosis, but no clinical seizures. One of them had microcephaly, while the other had small head circumference less than 10th centile. There were no abnormal laboratory findings with the exception of a high lactate level. MECP2/CDKL5/FOXG1 genetic tests with an array comparative genomic hybridization revealed no molecular defects. Through whole‐exome sequencing of the proband, we found compound heterozygous ST3GAL5 variants (p.Gly201Arg and p.Cys195Ser), both of which were novel. The siblings were the same compound heterozygotes and their unaffected parents were heterozygous carriers of each variant. Liquid chromatography–mass spectrometry analysis confirmed a low level of GM3 and its downstream metabolites, indicating GM3 synthase deficiency. These cases expanded the clinical and genetic spectrum of the ultra‐rare disease, GM3 synthase deficiency with ST3GAL5 variants. © 2016 Wiley Periodicals, Inc.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.37773