Journal article
Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier
Molecular genetics and metabolism, v 126(4), pp 475-488
Apr 2019
PMID: 30691927
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 0.7–30.5 years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7 ± 2.0 (1 min) and 8.9 ± 0.5 (5 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 30 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 23.5 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.
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Details
- Title
- Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier
- Creators
- Lauren E. Bowser - Clinic for Special ChildrenMillie Young - Clinic for Special ChildrenOlivia K. Wenger - Eaton (United States)Zineb Ammous - Community Health Clinic, Topeka, IN, USAKarlla W. Brigatti - Clinic for Special ChildrenVincent J. Carson - Clinic for Special ChildrenTeresa Moser - Community Health Clinic, Topeka, IN, USAJames Deline - Center for ChildrenKazuhiro Aoki - University of GeorgiaThierry Morlet - Alfred I. duPont Hospital for ChildrenEthan M. Scott - Akron Children's HospitalErik G. Puffenberger - Clinic for Special ChildrenDonna L. Robinson - Clinic for Special ChildrenChristine Hendrickson - Clinic for Special ChildrenJonathan Salvin - Alfred I. duPont Hospital for ChildrenSteven Gottlieb - Alfred I. duPont Hospital for ChildrenAdam D. Heaps - Clinic for Special ChildrenMichael Tiemeyer - University of GeorgiaKevin A. Strauss - Clinic for Special Children
- Publication Details
- Molecular genetics and metabolism, v 126(4), pp 475-488
- Publisher
- Elsevier Inc
- Number of pages
- 14
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Audiology - Distance
- Web of Science ID
- WOS:000470044100017
- Scopus ID
- 2-s2.0-85060445951
- Other Identifier
- 991022169840604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Endocrinology & Metabolism
- Genetics & Heredity
- Medicine, Research & Experimental