Sulphonylurea therapy improves cognition in a patient with the V59M <i>KCNJ11 </i>mutation

Slingerland, Annabelle S.; Hurkx, W.; Noordam, C.; Flanagan, Sarah E.; Jukema, J. Wouter; Meiners, Linda C.; Bruining, G. J.; Hattersley, Andrew T.; Hadders‐Algra, Mijna

doi:10.1111/j.1464-5491.2007.02373.x

Cited by 108 publications

(65 citation statements)

References 18 publications

(26 reference statements)

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“…They might be improved by SU therapy, since K ATP channels are found in many tissues, including the brain and muscle (8,9), and play a role in membrane polarization and cell functions. Anecdotal case reports support this possibility (2,7,10).…”

mentioning

confidence: 62%

“…The concomitant presence of treatmentresistant epilepsy and muscle weakness is known as developmental delay, epilepsy and neonatal diabetes (DEND) syndrome (3,7); intermediate DEND is a less severe phenotype without epilepsy. However, we recently reported that appropriate testing methods detected developmental impairments in .70% of patients with K ATP gene mutations (3).…”

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confidence: 99%

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Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

et al. 2015

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OBJECTIVENeonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODSWe conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTSAt baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA 1c levels (median change 21.55% [range 23.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONSSU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.Neonatal diabetes is a rare condition that develops during the first months of life with an estimated incidence of 1 in 90,000 newborns (1,2). Neonatal diabetes can be permanent or transient, relapsing around puberty after a period of remission. We recently reported that 42% of patients in a large cohort had a heterozygous

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confidence: 62%

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confidence: 99%

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

et al. 2015

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“…Several mutations related to severe DEND syndrome (Q52R, G53R, V59G, I296L, G334D) are insensitive to glibenclamide (4,12,19,20); nevertheless in some forms of intermediate DEND syndrome (I167L, G53D, H46L, V59M), characterized by less severe developmental delay and without epilepsy, glibenclamide therapy has improved metabolic control, neuromuscular symptoms (17,(21)(22)(23)(24) and even cognition (V59M) (25). Evidence that sulfonylurea could change CNS blood fl ow and function was provided by the use of Figure 1.…”

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confidence: 99%

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Manna

Battistim

Radonsky

et al. 2008

Arq Bras Endocrinol Metab

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Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (PNDM) and several cases have been successfully treated with oral sulfonylureas. We report on the attempted transfer of insulin therapy to glibenclamide in a 4-year old child with PNDM and DEND syndrome, bearing a C166Y mutation in KCNJ11. An inpatient transition from subcutaneous NPH insulin (0.2 units/kg/d) to oral glibenclamide (1 mg/ kg/d and 1.5 mg/kg/d) was performed. Glucose and C-peptide responses stimulated by oral glucose tolerance test (OGTT), hemoglobin A1c levels, the 8-point self-measured blood glucose (SMBG) profi le and the frequency of hypoglycemia episodes were analyzed, before and during treatment with glibenclamide. Neither diabetes control nor neurological improvements were observed. We concluded that C166Y mutation was associated with a form of PNDM insensitive to glibenclamide. RESUMO Falha de resposta à Glibenclamida em Criança Brasileira com Diabetes MelitoNeonatal Permanente e Síndrome DEND Devido a Mutação C166Y no Gene KCNJ11 (Kir6.2). As mutações ativadoras, heterozigóticas do gene KCNJ11 (Kir6.2) são a causa mais freqüente de diabetes melito neonatal permanente (DMNP) e a terapêu-tica oral com sulfoniluréias tem sido bem sucedida em muitos destes casos. Relatamos o processo de substituição da insulinoterapia convencional para o tratamento oral com glibenclamida em uma paciente de 4 anos, portadora de DMNP e síndrome DEND devido a uma mutação C166Y no gene KCNJ11. A insulina NPH (0,2 U/kg/dia) foi substituída pela glibenclamida (1 mg/kg/dia e 1,5 mg/kg/dia) durante internação hospitalar. As respostas de glicose e peptídeo-C no teste de tolerância oral à glicose (OGTT), os níveis de hemoglobina glicada, o perfi l de glicemias capilares de 8 pontos e a freqüência de hipoglicemias foram comparados antes e durante o tratamento com glibenclamida. Não houve melhora no controle glicêmico, nem no quadro neurológico. Concluímos que a mutação C166Y associa-se a uma forma de DMNP insensível à glibenclamida.

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“…Slingerland A.S. с соавт. (2006) также был описан больной НСД и DEND-синдромом с мутацией V59M в гене KCNJ11 [6].…”

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Feasibility of efficacious therapy of diabetes mellitus by sulfonylurea agents in neonates with KCNJII gene mutation: originalobservation

et al. 2009

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И И нтерес к неаутоиммунным, в том числе к синдромаль-ным формам сахарного диабета, значительно повы-сился в последнее десятилетие на фоне бурного развития молекулярной генетики, позволяющей установить природу заболевания. Особый интерес представляет неонаталь-ный сахарный диабет (НСД) -очень редкое клинически поли-морфное заболевание.НСД встречается с частотой от 1/300 000 до 1/500 000 ново-рожденных. Выделяют две основные формы, характеризую-щиеся главным образом клиническими различиями по продолжительности инсулинозависимости после манифеста-ции: транзиторный НСД (ТНСД) и перманентный НСД (ПНСД) [1]. Согласно данным Aguillar-Brayn, ~57% случаев приходится на ТНСД, когда изначально требуется инсулиноте-рапия, но менее чем через 18 месяцев заболевание проходит и возвращается вновь через несколько лет [2].При всей своей редкости НСД оказался удивительно гете-рогенным заболеванием. К настоящему времени выявлено по-рядка десяти локусов, мутации в которых ведут к развитию неонатального сахарного диабета. Stоy с соавт. (2008) провели генетическое исследование 77 пациентов с сахарным диабетом в возрасте до 1 года. Из них у 32 детей НСД был диагностирован в возрасте до 6 месяцев, у 45 детей -в возрасте 6-12 месяцев. Проводилось секвенирование генов KCNJ11, INS и ABCC8. Му-тации были обнаружены у 63% пациентов в возрасте до 6 меся-цев, из них у 50% -в гене KCNJ11, у 13% -в гене INS, у остальных мутации не найдены. Интересно, что в руппе па-циентов старше 6 месяцев мутации в гене KCNJ11 найдены не были, мутации в гене INS найдены у 6,5% пациентов [3]. В исследовании Babenko с соавт. (2006), проведенном у 34 па-циентов с НСД, в гене ABCC8, кодирующем SUR1 (сульфонил-мочевинный рецептор), мутации были выявлены у семи пациентов [4].Наиболее клинически значимыми среди известных генов являются мутации в генах KCNJ11 и ABCC8, отвечающих за ак-тивность АТФ-зависимых калиевых каналов.АТФ-зависимые калиевые каналы играют центральную роль в глюкозо-стимулированной секреции инсулина в β-клетках поджелудочной железы: секреция инсулина инициируется за-крытием каналов и ингибируется их открытием (рис. 1). Калие-вые каналы состоят из четырех субъединиц SUR1 и четырех субъединиц Kir6.2 сульфонилмочевинных рецепторов. При по-ступлении глюкозы в β-клетку с помощью GLUT-2 глюкозного транспортера она метаболизируется, что приводит к накопле-нию АТФ. Последний, в свою очередь, ингибирует АТФ-зави-симые калиевые каналы, приводя к их закрытию. Закрытие каналов ведет к деполяризации клеточной мембраны. Этот про-цесс вызывает изменение потенциалов кальциевых каналов, приводя к увеличению концентрации ионов Са++ внутри клетки. Повышение концентрации ионов кальция является пусковым механизмом для выхода инсулина из клетки. При ак-тивирующей мутации в гене калиевые каналы остаются откры-тыми, несмотря на поступление глюкозы в клетку, вследствие

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Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation

Cited by 108 publications

References 18 publications

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Feasibility of efficacious therapy of diabetes mellitus by sulfonylurea agents in neonates with KCNJII gene mutation: originalobservation

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