vitamin e supplementation in hyperinsulinism/hyperammonemia syndrome

Conditions: Hyperinsulinism-Hyperammonemia Syndrome

Summary: investigators will assess the tolerability of oral vitamin e supplementation in subjects with congenital hyperinsulinism (hi) and hyperammonemia (ha) syndrome.

congenital hyperinsulinism (hi) is a rare disorder of pancreatic beta cell insulin secretion that causes persistent and severe hypoglycemia starting at birth. hyperinsulinism/hyperammonemia (hi/ha) syndrome is the second most common type of congenital hi and is caused by activating mutations in glutamate dehydrogenase (gdh). patients with hi/ha exhibit fasting hyperinsulinemic hypoglycemia, protein-induced hypoglycemia, hyperammonemia, seizures, and intellectual disability independent of hypoglycemia. these effects result from abnormal gdh activity in the beta cells, liver and kidney cells, neurons, and astrocytes. the only available treatment for hi/ha syndrome is diazoxide, which acts on the beta cells to decrease insulin secretion but has no effect on gdh activity itself or on other cell types. thus, there remains a significant unmet need for improved therapies for this disorder. preliminary data show that vitamin e (alpha-tocopherol) inhibits gdh activity in cell lines and improves hypoglycemia in a gdh hi mouse model. based on these preclinical studies, investigators hypothesize that vitamin e will inhibit gdh activity and may impact hyperinsulinemic hypoglycemia and hyperammonemia in subjects with hi/ha syndrome. this hypothesis will be tested in a future study. in this initial pilot study, investigators will assess the tolerability of oral vitamin e supplementation in subjects with hi/ha syndrome.

Eligibility criteria:
inclusion criteria: * individuals age ≥12 months and ≤40 years * diagnosis of hi/ha syndrome * on diazoxide therapy for treatment of hypoglycemia * females ≥11 years of age or menstruating must have a negative urine/serum pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), depo-provera, or an oral contraceptive, for the duration of the study. * informed consent for participants ≥18 years. parental/guardian permission (informed consent) and, if appropriate, child assent for participants \<18 years. exclusion criteria: * individuals age \ 40 years * individuals who have experienced an allergic reaction to vitamin e * individuals with a known allergy to dairy, whey, or soy * on concurrent therapy with a medication known to be metabolized by the cyp3a pathway * individuals with a known increased risk of bleeding (bleeding disorder or on antiplatelet or anticoagulation therapy) * vitamin e supplementation within 30 days prior to enrollment, including multivitamins containing vitamin e * severe hypoglycemia (plasma glucose \<50 mg/dl on repeat checks using home glucose meter) more than once weekly within 30 days prior to enrollment. * evidence of a medical condition that might alter results or compromise the interpretation of results, including active infection, kidney failure, severe liver dysfunction, severe respiratory or cardiac failure. * evidence of severe hematologic abnormality including severe anemia and/or thrombocytopenia. * any investigational drug use within 30 days prior to enrollment. * pregnant or lactating females. * parents/guardians or subjects who, in the opinion of the investigator, may be non-compliant with study schedules or procedures. * unable to provide informed consent (e.g. impaired cognition or judgment). * parents/guardians or subjects with limited english proficiency.

Keywords: hyperinsulinism hyperammonemia hypoglycemia vitamin e