Publications by authors named "Sommer Gaughan"

5 Publications

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Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor.

Blood 2020 Aug;136(9):1033-1043

Groupe de Recherches Metaboliques, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.

Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P.
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http://dx.doi.org/10.1182/blood.2019004465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530374PMC
August 2020

Impact on Isoleucine and Valine Supplementation When Decreasing Use of Medical Food in the Nutritional Management of Methylmalonic Acidemia.

Nutrients 2020 Feb 13;12(2). Epub 2020 Feb 13.

Department of Pediatrics Section of Clinical Genetics and Metabolism, Aurora, Children's Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Background: Methylmalonic acidemia (MMA) is an autosomal recessive disorder treated with precursor-free medical food while limiting natural protein. This retrospective chart review was to determine if there was a relationship between medical food, valine (VAL) and/or isoleucine (ILE) supplementation, total protein intake, and plasma amino acid profiles. Methods A chart review, of patients aged 31 days or older with MMA treated with dietary intervention and supplementation of VAL and/or ILE and followed at the Children's Hospital Colorado Inherited Metabolic Diseases Clinic. Dietary prescriptions and plasma amino acid concentrations were obtained at multiple time points.

Results: Baseline mean total protein intake for five patients was 198% of Recommended Dietary Allowance (RDA) with 107% natural protein and 91% medical food. Following intervention, total protein intake ( = 0.0357), protein from medical food ( = 0.0142), and leucine (LEU) from medical food ( = 0.0276) were lower, with no significant change in natural protein intake ( = 0.2036). At baseline, 80% of patients received VAL supplementation and 100% received ILE supplementation. After intervention, only one of the cohort remained on supplementation. There was no statistically significant difference in plasma propiogenic amino acid concentrations.

Conclusions: Decreased intake of LEU from medical food allowed for discontinuation of amino acid supplementation, while meeting the RDA for protein.
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http://dx.doi.org/10.3390/nu12020473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071216PMC
February 2020

Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia.

J Pediatr 2016 Mar 1;170:234-9. Epub 2016 Jan 1.

Department of Pediatrics, University of Colorado, Aurora, CO. Electronic address:

Objective: To evaluate the impact of sodium benzoate and dextromethorphan treatment on patients with the attenuated form of nonketotic hyperglycinemia.

Study Design: Families were recruited with 2 siblings both affected with attenuated nonketotic hyperglycinemia. Genetic mutations were expressed to identify residual activity. The outcome on developmental progress and seizures was compared between the first child diagnosed and treated late with the second child diagnosed at birth and treated aggressively from the newborn period using dextromethorphan and benzoate at dosing sufficient to normalize plasma glycine levels. Both siblings were evaluated with similar standardized neurodevelopmental measures.

Results: In each sibling set, the second sibling treated from the neonatal period achieved earlier and more developmental milestones, and had a higher developmental quotient. In 3 of the 4 sibling pairs, the younger sibling had no seizures whereas the first child had a seizure disorder. The adaptive behavior subdomains of socialization and daily living skills improved more than motor skills and communication.

Conclusions: Early treatment with dextromethorphan and sodium benzoate sufficient to normalize plasma glycine levels is effective at improving outcome if used in children with attenuated disease with mutations providing residual activity and when started from the neonatal period.
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http://dx.doi.org/10.1016/j.jpeds.2015.12.027DOI Listing
March 2016

Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome.

Mol Genet Metab 2015 Sep-Oct;116(1-2):35-43. Epub 2015 May 23.

Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, CO, United States. Electronic address:

Pyridoxine-dependent epilepsy (PDE) is an epileptic encephalopathy characterized by response to pharmacologic doses of pyridoxine. PDE is caused by deficiency of α-aminoadipic semialdehyde dehydrogenase resulting in impaired lysine degradation and subsequent accumulation of α-aminoadipic semialdehyde. Despite adequate seizure control with pyridoxine monotherapy, 75% of individuals with PDE have significant developmental delay and intellectual disability. We describe a new combined therapeutic approach to reduce putative toxic metabolites from impaired lysine metabolism. This approach utilizes pyridoxine, a lysine-restricted diet to limit the substrate that leads to neurotoxic metabolite accumulation and L-arginine to compete for brain lysine influx and liver mitochondrial import. We report the developmental and biochemical outcome of six subjects who were treated with this triple therapy. Triple therapy reduced CSF, plasma, and urine biomarkers associated with neurotoxicity in PDE. The addition of arginine supplementation to children already treated with dietary lysine restriction and pyridoxine further reduced toxic metabolites, and in some subjects appeared to improve neurodevelopmental outcome. Dietary lysine restriction was associated with improved seizure control in one subject, and the addition of arginine supplementation increased the objective motor outcome scale in two twin siblings, illustrating the contribution of each component of this treatment combination. Optimal results were noted in the individual treated with triple therapy early in the course of the disease. Residual disease symptoms could be related to early injury suggested by initial MR imaging prior to initiation of treatment or from severe epilepsy prior to diagnosis. This observational study reports the use of triple therapy, which combines three effective components in this rare condition, and suggests that early diagnosis and treatment with this new triple therapy may ameliorate the cognitive impairment in PDE.
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http://dx.doi.org/10.1016/j.ymgme.2015.05.011DOI Listing
July 2016