Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage

Orphanet Journal of Rare Diseases

Carlo Dionisi-Vici¹  Stefania Caviglia⁵  Raffaella Cusmai⁴  Giorgia Gallo¹  Silvia Bernabei²  Fabrizio Barbetti³  Lucilla Manganozzi¹  Arianna Maiorana¹ 

[1] Metabolic Unit, Department of Pediatric Medicine, Bambino Gesù Children’s Hospital, piazza S. Onofrio 4, Rome, 00165, Italy;Clinical Nutrition, Gastroenterology Department, Bambino Gesù Children’s Hospital, Rome, Italy;Department of Experimental Medicine, University of Tor Vergata and Bambino Gesù Children’s Hospital, Rome, Italy;Neurology, Neuroscience Department, Bambino Gesù Children’s Hospital, Rome, Italy;Psychology Unit, Neuroscience Department, Bambino Gesù Children’s Hospital, Rome, Italy

关键词: Neurodevelopment;    Epilepsy;    Hypoglycemia;    Ketogenic diet;    Congenital hyperinsulinism;   

Others  :  1228805
DOI  :  10.1186/s13023-015-0342-6

 received in 2015-06-23, accepted in 2015-09-10,  发布年份 2015

【 摘 要 】

Background

Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children. In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae. Patients with CHI unresponsive to medical treatment can be subjected to near-total pancreatectomy with increased risk of secondary diabetes. Ketogenic diet (KD), by reproducing a fasting-like condition in which body fuel mainly derives from beta-oxidation, is intended to provide alternative cerebral substrates such ketone bodies. We took advantage of known protective effect of KD on neuronal damage associated with GLUT1 deficiency, a disorder of impaired glucose transport across the blood-brain barrier, and administered KD in a patient with drug-unresponsive CHI, with the aim of providing to neurons an energy source alternative to glucose.

Methods

A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs.

Results

We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life.

Conclusions

KD could represent an effective treatment to support brain function in selected cases of CHI.

【 授权许可】

   
2015 Maiorana et al.

【 图 表 】

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【 参考文献 】

• [1]Arnoux JB, de Lonlay P, Ribeiro MJ, Hussain K, Blankenstein O, Mohnike K et al.. Congenital hyperinsulinism. Early Hum Dev. 2010; 86(5):287-94.
• [2]Hussain K, De Lonlay P. Hyperinsulinism. In: Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Blau N, Duran M, Gibson KM, Dionisi-Vici C, editors. Springer-Vergal, Berlin Heidelberg; 2014: p.323-36.
• [3]Li C, Buettger C, Kwagh J, Matter A, Daikhin Y, Nissim IB et al.. A signaling role of glutamine in insulin secretion. J Biol Chem. 2004; 279(14):13393-401.
• [4]Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V et al.. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics. 2001; 107(3):476-9.
• [5]Auer RN, Hugh J, Cosgrove E, Curry B. Neuropathologic findings in three cases of profound hypoglycemia. Clin Neuropathol. 1989; 8(2):63-8.
• [6]McNay EC, Williamson A, McCrimmon RJ, Sherwin RS. Cognitive and neural hippocampal effects of long-term moderate recurrent hypoglycemia. Diabetes. 2006; 55(4):1088-95.
• [7]Yamada KA, Rensing N, Izumi Y, De Erausquin GA, Gazit V, Dorsey DA et al.. Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation. Pediatr Res. 2004; 55(3):372-9.
• [8]Ryan C, Gurtunca N, Becker D. Hypoglycemia: a complication of diabetes therapy in children. Pediatr Clin North Am. 2005; 52(6):1705-33.
• [9]Blasetti A, Chiuri RM, Tocco AM, Di Giulio C, Mattei PA, Ballone E et al.. The effect of recurrent severe hypoglycemia on cognitive performance in children with type 1 diabetes: a meta-analysis. J Child Neurol. 2011; 26(11):1383-91.
• [10]Suh SW, Hamby AM, Swanson RA. Hypoglycemia, brain energetics, and hypoglycemic neuronal death. Glia. 2007; 55(12):1280-6.
• [11]Haces ML, Hernandez-Fonseca K, Medina-Campos ON, Montiel T, Pedraza-Chaverri J, Massieu L. Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp Neurol. 2008; 211(1):85-96.
• [12]Yamada KA, Rensing N, Thio LL. Ketogenic diet reduces hypoglycemia-induced neuronal death in young rats. Neurosci Lett. 2005; 385(3):210-4.
• [13]Page KA, Williamson A, Yu N, McNay EC, Dzuira J, McCrimmon RJ et al.. Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia. Diabetes. 2009; 58(5):1237-44.
• [14]Veggiotti P, De Giorgis V. Dietary Treatments and New Therapeutic Perspective in GLUT1 Deficiency Syndrome. Curr Treat Options Neurol. 2014; 16(5):291.
• [15]Pearson TS, Akman C, Hinton VJ, Engelstad K, De Vivo DC. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 2013; 13(4):342.
• [16]Gataullina S, Dellatolas G, Perdry H, Robert JJ, Valayannopoulos V, Touati G et al.. Comorbidity and metabolic context are crucial factors determining neurological sequelae of hypoglycaemia. Dev Med Child Neurol. 2012; 54(11):1012-7.
• [17]Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K et al.. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015; 167(2):238-45.
• [18]Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A et al.. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998; 338(4):226-30.
• [19]Gilbert DL, Pyzik PL, Freeman JM. The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J Child Neurol. 2000; 15(12):787-90.
• [20]Maiorana A, Barbetti F, Boiani A, Rufini V, Pizzoferro M, Francalanci P et al.. Focal congenital hyperinsulinism managed by medical treatment: a diagnostic algorithm based on molecular genetic screening. Clin Endocrinol (Oxf). 2014; 81(5):679-88.
• [21]Christesen HB, Tribble ND, Molven A, Siddiqui J, Sandal T, Brusgaard K et al.. Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. Eur J Endocrinol. 2008; 159(1):27-34.
• [22]Meissner T, Marquard J, Cobo-Vuilleumier N, Maringa M, Rodriguez-Bada P, Garcia-Gimeno MA et al.. Diagnostic difficulties in glucokinase hyperinsulinism. Horm Metab Res. 2009; 41(4):320-6.
• [23]Dullaart RP, Hoogenberg K, Rouwe CW, Stulp BK. Family with autosomal dominant hyperinsulinism associated with A456V mutation in the glucokinase gene. J Intern Med. 2004; 255(1):143-5.
• [24]Sayed S, Langdon DR, Odili S, Chen P, Buettger C, Schiffman AB et al.. Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations. Diabetes. 2009; 58(6):1419-27.
• [25]Cuesta-Munoz AL, Huopio H, Otonkoski T, Gomez-Zumaquero JM, Nanto-Salonen K, Rahier J et al.. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes. 2004; 53(8):2164-8.
• [26]Christesen HB, Jacobsen BB, Odili S, Buettger C, Cuesta-Munoz A, Hansen T et al.. The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy. Diabetes. 2002; 51(4):1240-6.
• [27]Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007; 48(1):43-58.
• [28]McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia. 2011; 52(3):e7-11.
• [29]Diano S, Matthews RT, Patrylo P, Yang L, Beal MF, Barnstable CJ et al.. Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology. 2003; 144(11):5014-21.
• [30]Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C et al.. Metabolic control of vesicular glutamate transport and release. Neuron. 2010; 68(1):99-112.
• [31]Schutz PW, Struys EA, Sinclair G, Stockler S. Protective effects of d-3-hydroxybutyrate and propionate during hypoglycemic coma: clinical and biochemical insights from infant rats. Mol Genet Metab. 2011; 103(2):179-84.
• [32]Van Hove JL, Grunewald S, Jaeken J, Demaerel P, Declercq PE, Bourdoux P et al.. D, L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). Lancet. 2003; 361(9367):1433-5.