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Mol Genet Metab. 2019 Jan 21. pii: S1096-7192(18)30764-9. doi: 10.1016/j.ymgme.2019.01.013. [Epub ahead of print]

Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier.

Author information

1
Clinic for Special Children, Strasburg, PA, USA.
2
New Leaf Center, Mount Eaton, OH, USA.
3
Community Health Clinic, Topeka, IN, USA.
4
Center for Special Children, La Farge, WI, USA.
5
Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
6
Auditory Physiology and Psychoacoustics Research Laboratory, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
7
Department of Pediatrics, Akron Children's Hospital, Akron, OH, USA.
8
Division of Pediatric Ophthalmology, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
9
Division of Pediatric Neurology, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
10
Clinic for Special Children, Strasburg, PA, USA. Electronic address: kstrauss@clinicforspecialchildren.org.

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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