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

Bowser, Lauren E.; Young, Millie; Wenger, Olivia; Ammous, Zineb; Brigatti, Karlla W.; Carson, Vincent J; Moser, Teresa; Deline, James; Aoki, Kazuhiro; Morlet, Thierry; Scott, Ethan M.; Puffenberger, Erik G.; Robinson, Donna L.; Hendrickson, Christine; Salvin, Jonathan; Gottlieb, Steven; Heaps, Adam D.; Tiemeyer, Michael; Strauss, Kevin A.

doi:10.1016/j.ymgme.2019.01.013

Cited by 39 publications

(46 citation statements)

References 73 publications

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“…Progressive microcephaly has been reported in patients with ST3GAL5 deficiency (Simpson et al, 2004;Bowser et al, 2019). To investigate if ST3GAL5 KO mice also showed a similar phenotype, the histology of brain slices was investigated for control and ST3GAL5-KO mice using immunostaining with parvalbumin (PV) and NeuN antibodies ( Figure 1C).…”

Section: Loss Of St3gal5 Does Not Impair the Macroscopic Histology Ofmentioning

confidence: 99%

“…The lack of a-, b-, and c-series gangliosides are replaced by overexpression of asialo-and a-series gangliosides (Seyfried et al, 1994;Huang et al, 2016). The discovery of ST3GAL5 deficiency, a recessive genetic disorder, provided the first evidence for a congenital disorder of glycosylation that affects the biosynthesis of complex glycosphingolipids (Bowser et al, 2019). An additional report from France focused on a family with two members suffering from early onset of epilepsy, deafness, and blindness (Fragaki et al, 2013).…”

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confidence: 99%

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Enhanced Susceptibility to Chemoconvulsant-Induced Seizures in Ganglioside GM3 Synthase Knockout Mice

et al. 2020

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Ganglioside GM3 synthase (α-2,3-sialyltransferase, ST3GAL5, GM3S) is a key enzyme involved in the biosynthesis of gangliosides. ST3GAL5 deficiency causes an absence of GM3 and all downstream biosynthetic derivatives. The affected individuals manifest deafness, severe irritability, intractable seizures, and profound intellectual disability. To investigate whether deficiency of GM3 is involved in seizure susceptibility, we induced seizures with different chemoconvulsants in ST3GAL5 knockout mice. We report here that ST3GAL5 knockout mice are hyperactive and more susceptible to seizures induced by chemoconvulsants, including kainate and pilocarpine, compared with normal controls. In the hippocampal dentate gyrus, loss of GM3 aggravates seizure-induced aberrant neurogenesis. These data indicate that GM3 and gangliosides derived from GM3 may serve as important regulators of epilepsy and may play an important role in aberrant neurogenesis associated with seizures.

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Section: Loss Of St3gal5 Does Not Impair the Macroscopic Histology Ofmentioning

confidence: 99%

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confidence: 99%

Enhanced Susceptibility to Chemoconvulsant-Induced Seizures in Ganglioside GM3 Synthase Knockout Mice

et al. 2020

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“…There are over 50 types of LSDs, 61 however, few are present in the neonatal period. [62][63][64] Those that do may have a primary neurologic phenotype with severe myoclonic epilepsy and varied presence of irritability, increased tone, and/or a movement disorder (►Table 2). Others are critically ill with a multisystem presentation including congenital anomalies, detected prenatally in some, and poor growth.…”

Section: Lysosomal Storage Disordersmentioning

confidence: 99%

“…66,67 This subset of LSDs with very early onset generally has a poor prognosis with minimal neurodevelopment from birth and significant risk of mortality. 62,63,65,68…”

Section: Lysosomal Storage Disordersmentioning

confidence: 99%

Metabolic Disorders Presenting with Seizures in the Neonatal Period

Brimble

Ruzhnikov

2020

Semin Neurol

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Metabolic disorders represent rare but often treatable causes of seizures and epilepsy of neonatal onset. As seizures are relatively common in the neonatal period, systemic clues to a specific diagnosis may be lacking or shrouded by acute illness. An important role of the consulting pediatric neurologist is to identify neonates with a possible metabolic or otherwise genetic diagnosis. In this review, the authors describe presenting signs and symptoms, a diagnostic framework, and disorder-specific treatment options for inborn errors of metabolism that may present in the neonatal period. Specific attention is given to the neurologic aspects of each condition, including the electroclinical phenotype and findings on brain imaging. As expedited diagnosis and prompt initiation of available therapies have been demonstrated to result in improved epilepsy and developmental outcomes, this work acts as a framework to guide evaluation when an inherited metabolic disorder is suspected. In addition to informing treatment, a definitive diagnosis allows for appropriate counseling regarding prognosis, any associated screening or preventive measures, and family planning.

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“…In a new paper, researchers have combined the largest description of ST3GAL5 defi ciency, using detailed natural history data obtained from 104 individuals in the Amish community who were born between 1986 and 2017 and who have a defi nite or probable diagnosis of ST3GAL5 defi ciency (Bowser et al, ). The study evaluated objective measures of biochemistry, auditory function, and brain development, as well as the burden on caregivers.…”

mentioning

confidence: 99%

Largest Description of ST3GAL5 (GM3 synthase) Deficiency May Provide Baseline for Future Therapies: Detailed natural history data combined with objective measures of tissue function was used to create the largest description of ST2GAL5 defi ciency to date

2019

American J of Med Genetics Pt A

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

Cited by 39 publications

References 73 publications

Enhanced Susceptibility to Chemoconvulsant-Induced Seizures in Ganglioside GM3 Synthase Knockout Mice

Enhanced Susceptibility to Chemoconvulsant-Induced Seizures in Ganglioside GM3 Synthase Knockout Mice

Metabolic Disorders Presenting with Seizures in the Neonatal Period

Largest Description of ST3GAL5 (GM3 synthase) Deficiency May Provide Baseline for Future Therapies: Detailed natural history data combined with objective measures of tissue function was used to create the largest description of ST2GAL5 defi ciency to date

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