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Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier. Mol Genet Metab 2019 04;126(4):475-488

Date

01/30/2019

Pubmed ID

30691927

DOI

10.1016/j.ymgme.2019.01.013

Scopus ID

2-s2.0-85060445951   17 Citations

Abstract

GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a pathogenic ST3GAL5 c.862C>T founder allele (median age 8.1, range 0.7-30.5a??years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7a??A?a??2.0 (1a??min) and 8.9a??A?a??0.5 (5a??min). Somatic growth failure, progressive microcephaly, global developmental delay, visual inattentiveness, and dyskinetic movements developed within a few months of life. Infantile-onset epileptic encephalopathy was characterized by a slow, disorganized, high-voltage background, poor state transitions, absent posterior rhythm, and spike trains from multiple independent cortical foci; >90% of electrographic seizures were clinically silent. Hearing loss affected cochlea and central auditory pathways and 76% of children tested failed the newborn hearing screen. Development stagnated early in life; only 13 (26%) patients sat independently (median age 30a??months), three (6%) learned to crawl, and none achieved reciprocal communication. Incessant irritability, often accompanied by insomnia, began during infancy and contributed to high parental stress. Despite catastrophic neurological dysfunction, neuroimaging showed only subtle or no destructive changes into late childhood and hospitalizations were surprisingly rare (0.2 per patient per year). Median survival was 23.5a??years. Our observations corroborate findings from transgenic mice which indicate that gangliosides might have a limited role in embryonic neurodevelopment but become vital for postnatal brain growth and function. These results have critical implications for the design and implementation of ganglioside restitution therapies.

Author List

Bowser LE, Young M, Wenger OK, Ammous Z, Brigatti KW, Carson VJ, Moser T, Deline J, Aoki K, Morlet T, Scott EM, Puffenberger EG, Robinson DL, Hendrickson C, Salvin J, Gottlieb S, Heaps AD, Tiemeyer M, Strauss KA

Author

Kazuhiro Aoki PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Alleles
Apgar Score
Child
Child, Preschool
Epilepsy
Female
Gangliosides
Glycosphingolipids
Homozygote
Humans
Infant
Male
Microcephaly
Retrospective Studies
Seizures
Sialyltransferases
United States
Young Adult