Efficacy and safety of sirolimus therapy in familial hypoinsulinemic hypoglycemia caused by AKT2 mutation inherited from the mosaic father

Dushar, Marya; Nowaczyk, Jędrzej; Pyrżak, Beata; Akopyan, Hayane; Śmigiel, Robert; Walczak, Anna; Rydzanicz, Małgorzata; Płoski, Rafał; Szczałuba, Krzysztof

doi:10.1016/j.ejmg.2021.104368

Cited by 3 publications

(18 citation statements)

References 20 publications

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“…7 The metabolic and quality of life implications of frequent feeding make anti-hypoglycemic agents an attractive therapeutic option (Table 3). Consistent with previous reports, 5,7 diazoxide and octreotide were ineffective in our patient as these agents target upstream insulin release, as opposed to downstream signaling. 13 Due to its action on this pathway, sirolimus was trialed in a sibling pair with activating AKT2 mutations.…”

Section: Discussionsupporting

confidence: 92%

“…Two previously published cases of AKT2 mutation were found to be mosaic for the variant, 7 and notably, two siblings inherited the variant from their unaffected father who was found to carry the variant at low level of mosaicism in his sperm. 5 Mosaicism was not detected in our patient's peripheral blood leukocytes or skin fibroblasts, although it cannot be excluded at other tissues.…”

Section: Discussionmentioning

confidence: 52%

“…This demonstrated a pathogenic heterozygous variant in AKT2, c.49G>A, p.(Glu17Lys) previously reported in other individuals with gain-of-function AKT2 variants. [4][5][6][7][8] To assess for possible mosaicism, DNA from skin fibroblasts was subsequently analyzed and found to be positive for the mutation.…”

Section: Ofmentioning

confidence: 99%

“…Although rare, gain-of-function mutations in AKT2 have been described in eight individuals with hypoketotic hypoglycemia. [4][5][6][7][8] Despite undetectable insulin levels, their biochemical profiles closely resemble hyperinsulinemic hypoglycemia due to constitutive activation of the insulin signaling cascade. Additional reported features include accelerated linear growth, hemihypertrophy, and polyhydramnios.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of hypoglycemia due to a rare pathogenic variant in AKT2 with waxy maize heat‐modified starch

Parker,

Yau

2024

Clinical Case Reports

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Key Clinical MessageThe gain‐of‐function AKT2 c.49G>A variant causes hypoketotic hypoglycemia with variable associated features. Due to lack of effective medications, treatment is primarily supportive. This report suggests waxy maize heat is a viable treatment option.AbstractThe serine–threonine kinase AKT2 is a critical mediator of insulin's anabolic effects, particularly cellular glucose uptake. The gain‐of‐function c.49G>A, p.(Glu17Lys) AKT2 variant results in hypoketotic hypoglycemia with suppressed insulin and free fatty acid levels due to constitutive activation of the insulin signaling cascade. Although biochemical similarities exist among the eight individuals identified to date, the associated phenotype varies considerably. Treatment of these patients remains challenging, consisting primarily of frequent feeds with uncooked cornstarch. We describe a female with hemihypertrophy, developmental delay, and dysmorphic features who presented to our center with hypoglycemic seizures at age 6 months. Critical sample revealed hypoketotic hypoglycemia, undetectable insulin, and suppressed free fatty acids. Molecular testing confirmed a pathogenic c.49G>A, p.(Glu17Lys) AKT2 mutation. Glycemic control was initially difficult to establish, with recurrent hypoglycemia despite high glucose infusion rates. Following in‐hospital administration of waxy maize heat‐modified starch at age 4‐years, she remained euglycemic overnight, despite a previous report showing no benefit compared to uncooked cornstarch in an infant with the same mutation. Our report suggests waxy maize heat‐modified starch is a viable treatment option for patients with activating c.49G>A AKT2 mutations and provides further evidence of a broad phenotypic spectrum.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 52%

Section: Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment of hypoglycemia due to a rare pathogenic variant in AKT2 with waxy maize heat‐modified starch

Parker,

Yau

2024

Clinical Case Reports

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“…Dushar et al. described response to sirolimus treatment in a family with familial hypoinsulinemic hypoglycemia caused by the recurrent AKT2 mutation ( 48 ).…”

Section: Resultsmentioning

confidence: 99%

Syndromic forms of congenital hyperinsulinism

2023

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Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

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Case Report: Treatment of Hypoglycemia due to a Rare Pathogenic Variant in AKT2 with Waxy Maize Heat-Modified Starch

Parker

Yau

2023

Preprint

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Introduction:The serine-threonine kinase AKT2 is a critical mediator of insulin's anabolic effects, particularly cellular glucose uptake. The gain-of-function c.49G>A, p.(Glu17Lys)AKT2 variant results in hypoketotic hypoglycemia with suppressed insulin and free fatty acid levels due to constitutive activation of the insulin signaling cascade. Although biochemical similarities exist amongst the eight individuals identified to date, the associated phenotype varies considerably. Treatment of these patients remains challenging, consisting primarily of frequent feeds with uncooked cornstarch.Case Presentation: We describe a female with hemihypertrophy, developmental delay, and dysmorphic features who presented to our center with hypoglycemic seizures at age 6-months. Critical sample revealed hypoketotic hypoglycemia, undetectable insulin, and suppressed free fatty acids. Molecular testing confirmed a pathogenic c.49G>A, p.(Glu17Lys) AKT2 mutation. Glycemic control was initially difficult to establish, with recurrent hypoglycemia despite high glucose infusion rates. Following in-hospital administration of Posted on

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Efficacy and safety of sirolimus therapy in familial hypoinsulinemic hypoglycemia caused by AKT2 mutation inherited from the mosaic father

Cited by 3 publications

References 20 publications

Treatment of hypoglycemia due to a rare pathogenic variant in AKT2 with waxy maize heat‐modified starch

Treatment of hypoglycemia due to a rare pathogenic variant in AKT2 with waxy maize heat‐modified starch

Syndromic forms of congenital hyperinsulinism

Case Report: Treatment of Hypoglycemia due to a Rare Pathogenic Variant in AKT2 with Waxy Maize Heat-Modified Starch

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