Hyperinsulinism - Peds

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Disorders of Fuel Metabolism

PART 2


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IN THIS PARTChapter 4 Hyperinsulinism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 5 Mitochondrial Fatty Acid Oxidation Defects. . . . . . . . . . . . . . . . .

Chapter 6 Glycogen Storage Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 7 Organic Acidurias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 8 Ketone Synthesis and Utilization Defects . . . . . . . . . . . . . . . . . . .

Chapter 9 The Galactosemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 10 Disorders of Fructose Metabolism . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 11 Urea Cycle Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 12 Creatine Deficiency Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 13 Phenylketonuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 14 Hyperphenylalaninemias: Disorders of TetrahydrobiopterinMetabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 15 Tyrosinemia and Other Disorders of Tyrosine Degradation. . . . Chapter 16 Disorders of Transsulfuration. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 17 Inborn Errors of Folate and Cobalamin Transportand Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 18 Oxidative Phosphorylation Diseases and Mitochondrial DNADepletion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 19 Disorders of Pyruvate Metabolism and theTricarboxylic Acid Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 20 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 21 Overweight and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 22 Lipids and Lipoprotein Abnormalities. . . . . . . . . . . . . . . . . . . . . .

Chapter 23 Defects of Cholesterol Biosynthesis . . . . . . . . . . . . . . . . . . . . . . .

Chapter 24 Inborn Errors of Peroxisme Biogenesis and Function . . . . . . . .

Chapter 25 Congenital Disorders of Glycosylation . . . . . . . . . . . . . . . . . . . . .

Previous page: Healthy insulin response.


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C H A P T E R

4Glucose homeostasis is critical for meetingthe metabolic demands of the brain, and aninadequate supply of glucose can cause sei-zures and permanent brain damage. Becauseof the larger size of the infant brain relativeto the rest of the body, an infants glucose

requirement of 68 mg/kg/minute exceedsthat of an adult (2 mg/kg/minute). Since theinfant brain is undergoing rapid growth anddevelopment, it is extremely vulnerable to hy-poglycemia, which is defined in infants as inolder children and adults as a blood glucose(BG) concentration of less than 50 mg/dL,whereas concentrations of less than 60 mg/dLare considered abnormal. A failure of fasting adaptation generally isresponsible for hypoglycemia in children.The elements of fasting include 1) glycoge-nolysis, 2) gluconeogenesis, 3) lipolysis, and4) fatty acid oxidation and ketogenesis. These

pathways are strictly regulated by hormones.Insulin suppresses the fasting adaptation sys-tems, whereas counterregulatory hormones(e.g., glucagon, growth hormone, cortisol, andepinephrine) stimulate these pathways. Hyper-insulinism is the most common cause of recur-rent hypoglycemia in infancy.

Etiology/Pathophysiology Congenital hyper-insulinism refers to inherited disorders in thepathways of insulin secretion that cause hypo-glycemia. This group of disorders was referredto previously as nesidioblastosis.This term isconsidered a misnomer because nesidioblas-tosis is not specific for hyperinsulinism and isa common histological finding in pancreatictissue from normal infants. With the identifi-cation of specific genetic defects responsiblefor congenital hyperinsulinism, a more com-plete description of the clinical manifesta-tions of these disorders has become possible.In addition, the roles of these various pathwaysin normal insulin secretion are becomingbetter understood. As shown in Figure 4-1,glucose is the primary stimulant for insulinsecretion. After glucose enters the -cell viathe GLUT-2 transporter, it is phosphorylatedby glucokinase, the rate-limiting glucosen-

sor of the -cell. Subsequent metabolismof glucose generates adenosine triphosphate(ATP), leading to an increase in the ATP:ade-nosine diphosphate (ADP) ratio of the -cell.This increase closes the ATP-sensitive potas-sium (KATP) channel, which is composed of

the sulfonylurea receptor regulatory subunit(SUR1) and the inwardly rectifying potas-sium pore (KIR6.2). Depolarization of the-cell membrane ensues. Voltage-dependentcalcium channels (VDCCs) open, and cal-cium enters the -cell, leading to insulin re-lease (3). A KATPchannelindependent path-way for amplification of glucose-stimulatedinsulin secretion also exists that may dependon glutamine (4).

Amino acids stimulate insulin secretionthrough glutamate dehydrogenase (GDH)(see Figure 4-1), a mitochondrial enzymeresponsible for the oxidative deamination oglutamate to -ketoglutarate (59). GDH isallosterically activated by leucine and inhib-

ited by guanosine triphosphate (GTP) andATP. As with glucose, further metabolism of-ketoglutarate generates ATP and triggersthe KATPchanneldependent pathway of in-sulin secretion. The mechanisms by whichfatty acids stimulate insulin secretion are nowell understood. In congenital hyperinsulinism, defects inany of the preceding pathways lead to dysregulated insulin secretion (1024). Inappropriate

HyperinsulinismAndrea Kelly, MDCharles A. Stanley, MD

FIGURE 4-1.KATPchanneldependent pathways of insulin secretion.Glucoseenters the -cell through the GLUT-2

transporter and is phosphorylated by GK. Further metabolism of glucose generates ATP, leading to an increase in the -cell

ATP: ADP ratio. This increase closes the ATP-sensitive potassium (KATP) channel, and -cell membrane depolarization ensues

VDCCs open, allowing calcium entry into the-cell and, ultimately, insulin release.Amino acidsstimulate insulin secretion

through GDH, which deaminates glutamate to -ketoglutarate. GDH is allosterically activated by leucine and ADP and is

inhibited by GTP. As with glucose, further metabolism of -ketoglutarate generates ATP and triggers the KATPchannel

dependent pathway of insulin secretion. Diazoxide inhibits insulin secretion by maintaining the KATPchannel open via SUR1.

Octreotide inhibits insulin secretion downstream of the VDCC. GLUT-2glucose transporter 2; GK glucokinase;

KATPchannel is composed of SUR1 sulfonylurea receptor 1 and Kir6.2 inwardly rectifying potassium pore;

VDCCvoltage-dependent calcium channel; GDH glutamate dehydrogenase.


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Hyperinsulinism

CONGENITAL HI GENE LOCUS INHE RITANCE OMIM

KATPHI 11p15.1 256450

Diffuse ABCC8 Recessive and dominant Focal KCNJ11 Paternal KATPmutation with loss of

heterozygosity of maternal allele

GDH HI(HI/HA) GLUD-1 10q23.3 Dominant/sporadic 606762

GK HI GCK 7p15-13 Dominant/sporadic 602485

SCHAD deficiency HADH 4q22-q26 Recessive 601609

CDG type 1B* MPI 15q22-qter Recessive 602579BeckwithWiedemann Epigenetic 11p15.5 Sporadic Epigenetic: 130650 Loss of methylation of maternal differentially

methylated region 2 (DMR2) Gain of methylation of maternal DMR1 or H19 CDKN1C Paternal uniparental disomy Dominant:

CDKN1C, maternal DMR1

ACQUIRED HI GENE LOCUS INHERITANCE OMIM

Transient

Infant of diabetic mother N/A N/A N/A N/A Peripartum stress HI N/A N/A N/A N/A

Insulinoma MEN1 11q13 131100

Sporadic N/A MEN-1 Dominant90% of MEN-1; Sporadic10% of MEN-1

FORM FINDINGS CLINICAL PRESENTATION

KATPHI

(diffuse and focal) Fasting and protein-induced hypoglycemia Typically present shortly after birth; often are LGAGDH HI Fasting and protein-induced hypoglycemia; Presents later in infancy; not usually LGA;

leucine sensitivity; hyperammonemia asymptomatic hyperammonemia

GK HI Fasting hypoglycemia; lowering of -cell glucosensor

SCHAD Fasting hypoglycemia; cPlasma 3-hydroxylbutyryl carnitine cUrine 3-hydroxyglutaric acid

CDG Hypoglycosylation, as determined by Protein-losing enteropathy; coagulation disorders; type 1b isoelectric focusing of serum transferrin hepatic fibrosis

Transient neonatal HI Peripartum stress HI Fasting hypoglycemia Present shortly after birth; typically SGA, birth asphyxiated, or other stressed neonates

Infant of diabetic mother Present shortly after birth; LGA

Insulinoma Fasting hypoglycemialeucine sensitivity Rare in childhood; 2nd most common pancreatic tumor in MEN-1

BeckwithWiedemann Fasting hypoglycemia Hypoglycemia shortly after birth; typical features include macrosomia,macroglossia, abdominal wall defect; additional features includehemihypertrphy, embryonal tumors, adrenocortical cy tomegaly,ear anomalies, visceromegaly, renal abnormalities

LGA large for gestational age; AGA appropriate for gestational age; CDG carbohydrate-deficient glycoprotein syndrome.

* single cases of hyperinsulinism associated with CDG-1d and CDG-1a have been described.

Hyperinsulinism (HI) refers to the group of con-genital and acquired disorders of hypoglycemiathat arise from dysregulated insulin secretion.Hyperinsulinism is the most common cause of per-sistent neonatal hypoglycemia. In the congenital

AT-A-GLANCEforms, specific genetic defects in the pathways ofinsulin secretion are responsible for excess insu-lin secretion. Treatment of both congenital andacquired forms is intended to normalize bloodglucose and hence prevent short- and long-term

neurocognitive sequelae of recurrent hypoglyce-mia. Treatment modalities include: 1) medicationsthat suppress endogenous insulin secretion such asdiazoxide and octreotide; and, 2) pancreatectomy.


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Hyperinsulinism

insulin secretion leads to recurrent hypogly-cemia. The triggers for hypoglycemia dependon the underlying genetic defect and will bedescribed in further detail below.

CONGENITAL HYPERINSULINISMDUE TO KATP(SUR1 AND KIR6.2)

CHANNEL MUTATIONS

Etiology/Pathophysiology Mutations of theABCC8 gene encoding SUR1 and of theKCNJ11 gene encoding Kir6.2, the subunitsof the -cell KATPchannel, are responsible forthe most common form of congenital hyperin-sulinsm (HI). More than 100 mutations of the

ABCC8 and 20 mutations of the KCNJ11have been described. The SUR1 subunit issensitive to changes in the energy state of the-cell and regulates the opening and closing ofthe potassium channel pore. Diffuse disease,in which all -cells in the pancreas have defec-

tive channels, is inherited in recessive and, lesscommonly, dominant fashion. The extent ofKATPchannel dysfunction depends on the na-ture of the genetic defect. For instance, thecommon, recessive Ashkenazi SUR1 muta-tions delF1388 and 3992-9GA cause com-plete loss of potassium channel function.Dominantly expressed KATP mutations havebeen identified in only a few families and tendto produce milder disease due partial loss ofKATPchannel function (15,25,26). Because the open state of the KATPchannelmaintains the -cell membrane potential ina hyperpolarized state until it senses an in-

crease in -cell phosphate energy charge, lossof KATP function leads to -cell membranedepolarization (Figure 4-2). In this energystate, the -cell no longer strictly regulatesinsulin secretion; insulin secretion cannot bedown regulated appropriately at low bloodglucose concentrations and also cannot beactivated appropriately at increased bloodglucose concentrations. In addition, exposureto fuels such as amino acids, which normallyonly stimulate insulin secretion in the pres-ence of glucose (27), may be sufficient totrigger -cell membrane depolarization andinsulin secretion (28,29). Focal KATPHI suffers from the same -cellmembrane depolarization issues and hencedysregulated insulin secretion, but only a sub-set of pancreatic -cells is affected. This formof congenital HI arises from inheritance of apaternal KATPchannel mutation (ABCC8 orKCNJ11) and a specific loss of maternal al-leles of the imprinted chromosome region11p15. The loss of the normal maternal alleleoccurs in a subset of pancreatic -cells and isthe result of second hit (3032). This com-bination of an inherited KATPgermline muta-tion and the postzygotic loss of heterozygosityfor the maternal allele leads to expression of

the abnormal paternal allele in a clone of -cells. Loss of normal tumor-suppressor geneson the maternal allele allows for focal expan-sion of these abnormal -cells and hence thedevelopment of a focal pancreatic lesion. Be-cause these lesions arise during fetal develop-ment, they do not disrupt the normal architec-ture of the pancreas and are not encapsulated,features typical of insulinomas. In northern Europe, the incidence of se-vere congenital HI is approximately 1 in

40,000 (33,34), but in Saudi Arabia, whereconsanguinity is common, the incidence isapproximately 1 in 3000 births (35).

Clinical Presentation Infants with diffuseor focal KATP HI tend to be born large forgestational age and to present shortly af-ter birth with symptomatic hypoglycemia.

A typical-appearing patient is shown inFigure 4-3. The majority present within thefirst month of life, although in some childrenthe diagnosis is delayed until later in infancy.Hypoglycemia may manifest as a seizure,lethargy, or cyanosis or may be asymptom-atic. The hypoglycemia frequently is so se-vere that glucose infusion rates (GIR) up to30 mg/kg/minute (four to five times normal)are required to prevent hypoglycemia. Thevolumes necessary to maintain the GIR maybe so great as to cause fluid overload. FocalKATPHI and recessive KATPHI generally areresistant to diazoxide, a medication that ac-tivates SUR1 to maintain the KATP channelin the open state. This diazoxide resistancelikely reflects the underlying genetic defectsthat lead to complete or near-complete lossof channel function. Clinically, focal KATPHI is indistinguishable from diffuse KATPHI.On the other hand, children with dominant

KATPHI, a form identified only recently, mayrespond to diazoxide. This diazoxide respon-siveness likely reflects partial preservation ofKATPchannel function (25,36). In addition to fasting hypoglycemia, somechildren with KATPHI have postprandial hypo-glycemia. Studies of this form of congenital HIreveal the presence of protein-inducedhypoglycemia (Figure 4-4) (28,29). This pro-tein sensitivity occurs in the absence of leu-cine sensitivity (Figure 4-5), suggesting that a

FIGURE 4-2.KATPchannel HI.In this form of congenital HI, recessive and dominant mutations of SUR1 and Kir6.2 leadto loss of KATPchannel function. The -cell membrane is no longer hyperpolarized by the outwardly rectifying potassium

current, allowing calcium influx through the VDCC. Excess insulin secretion results.

FIGURE 4-3.Typical neonate with congenital

hyperinsulinism.This infant was born large for gesta-tional age. Within the first hour of life, the infant was found

with a blood glucose concentration of 19 mg/dL.


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Hyperinsulinism

that if a focal lesion is present, it is likely tobe found in the distribution of that particularpancreatic artery. During the procedure, BGis maintained in the 6070 mg/dL range. Apotential complication of this procedure is de-creased perfusion of the lower extremity dueto femoral artery spasm or the dislodging ofa clot following removal of the femoral artery

catheter. Following the procedure, perfusionof the right lower extremity is assessed. Transhepatic portal venous sampling(THPVS) is an alternative method of localiz-ing a pancreatic lesion (46,47). With this pro-cedure, BG is maintained at approximately50 mg/dL. Venous drainage of the pancreas isaccessed through the liver. Blood is collectedalong the length of venous drainage of thepancreas. A step-up in insulin secretion sug-gests the presence of a focal lesion in the areadrained by that vein. Limitations of these procedures includeabnormal anatomy, normal variations in

blood supply to the pancreas, and size of thepatient. In addition, they are neither 100%sensitive nor specific. For these reasons, biop-sies obtained intraoperatively and examinedby pathologists with an expertise in HI arevital. Multiple biopsies are obtained. If allthe biopsies have -cells with enlarged nu-clei, diffuse HI is most likely. If normal tissueis found, a focal lesion is suspected, and thesurgeon continues to biopsy until the focallesion is found, as shown in Figure 4-6, andcompletely resected (48). Complicationsassociated with these repeated biopsies areuncommon and are similar to those occur-

ring with routine pancreatectomy. Prelimi-nary reports suggest that [18F]dopa positron-emission tomographic (PET) scans may beable to visualize lesions in focal HI (49). Mutational analysis of the SUR1 andKir6.2 genes can confirm the presence of KATP

channel mutations. If the likely mutation(s)is known based on an affected family memberor ethnic background, mutational analysiscan be directed toward these mutations pre-operatively. The finding of two mutations isconsistent with diffuse disease. The finding ofa maternal mutation would suggest that thechild has diffuse disease (either recessive ordominant) because focal lesions are associ-ated with paternal mutations. In the settingof a paternal mutation, the affected child

may have diffuse or focal disease. Mutationalanalysis of these HI-causing gene defects isavailable through research laboratories andmore recently through a commercial labora-tory (Table 4-1).

Treatment The goal of treatment is to main-tain BG above 70 mg/dL in a safe mannerthat permits normal childhood developmentand is manageable for caretakers. Affectedpatients should be able to fast without becom-ing hypoglycemic and should demonstratenormal fasting adaptation, that is, appropri-ately increased free fatty acids and ketones

with fasting and no glycemic response to glu-cagon if BG is less than 50 mg/dL. Infantsshould be able to fast for 1824 hours beforebecoming hypoglycemic; children 23 yearsof age should tolerate 2436 hours of fasting,whereas older children should be able to fastat least 36 hours. Because medical treatmentis unlikely to completely normalize fastingadaptation, fasting tolerances that are safe aresought. An infant/child should be able to fast1012 hours (i.e., sleep overnight) withoutbecoming hypoglycemic. Medical treatment is first directed at sup-pressing insulin secretion. Diazoxide sup-presses insulin secretion by maintaining theKATPchannel in the open position. Doses of515 mg/kg/day orally generally are needed.Side effects of medication are primarilycosmetichypertrichosis and coarsening ofthe face. Fluid retention can occur, particu-larly in preterm infants and in infants receiv-ing large fluid volumes. Fluid retention maybe significant enough to require institutionof a diuretic. Rarely, leukopenia and throm-bocytopenia have been reported. If a childcontinues to have hypoglycemia following5 days of maximum doses of diazoxide, he or

she is considered diazoxide-unresponsiveand octreotide is initiatated. Octreotide is a somatostatin analogue andis thought to suppress insulin secretion down-stream of the voltage-dependent calciumchannel. Octreotide is delivered by subcuta-neous injection either at 6- to 8-hour intervalsor continuously through a pump at doses o520 g/kg/day. Doses larger than 20 g/kg/day generally are no more efficacious. An effectis seen frequently with the first octreotide dose

even if the child ultimately will be declaredoctreotide-unresponsive. This failure arisesbecause tachyphylaxis often occurs within 34days of octreotide initiation or dose increase de-spite an initial hyperglycemic effect. Potentialside effects include biliary sludging and alteredgut motility. Growth suppression generally isnot seen with prolonged octreotide use. Glucagon antagonizes insulin action bymobilizing hepatic glycogen stores. It is de-livered continuously at a dose of 1 mg/day,although some centers titrate the dose to be-tween 5 and 10 g/kg/hour. Glucagon is usedas a temporizing measure prior to pancreatec-

tomy. Experience with long-term outpatienuse is limited; on rare occasions (i.e., whenhypoglycemia persists following completepancreatectomy, maximum octreotide dosesand continuous dextrose), continuous gluca-gon delivered by insulin pump has preventedhypoglycemia successfully. Side effects in-clude vomiting and inhibition of pancreaticenzyme and gastric acid secretion. If medical therapy fails, pancreatectomy isindicated. Focal lesions account for 30% to70% of KATPHI cases and may be cured withfocal resection. Unfortunately, focal lesionsare not readily identified grossly and frequentlyare found in the pancreatic head, a difficult re-gion to resect without causing damage to thebile ducts and duodenum. Multiple biopsiesof the pancreas are obtained by the surgeonand examined by the pathologist intraopera-tively. The identification of normal pancreassuggests the presence of a focal lesion, andthe surgeon continues to biopsy until the focalesion is isolated. The surgeon may be guidedby preoperative localizing procedures such as

ASVS or THPVS. An experienced surgeonand pathologist are vital to identification andcomplete resection of a focal lesion.

Focal lesion Normal pancreas

FIGURE 4-6.Pancreatic Lesion in Focal KATP

channel-HI.This surgical specimen from an infant with

congenital hyperinsulinism due to focal KATPchannel-HI

is stained for insulin. On the right is normal pancreatic

tissue with islets dispersed throughout exocrine tissue. On

the left is an area of adenomatosis, the site of the focal

HI-causing lesion.

TABLE 4-1 Laboratory Findings: KATPHI

Decreased Increased

Blood glucose Free fatty acids (1.5 mmol/L) BG response to glucagon (30 mg/dL)

50 mg/dL -Hydroxybutyrate (1.5 mmol/L) GH (10 ng/mL)

IGFBP-1 (120 ng/mL) Cortisol (18 g/dL)

Insulin (2 U/mL)


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44 Part 2 | Disorders of Fuel Metabolism

In the setting of diffuse HI, a 95% to 99%pancreatectomy is performed. With less than95% pancreatectomy, sufficient -cell massremains to cause continued hypoglycemia.

With 95% to 98% pancreatectomy, a third ofpatients will have persistent hypoglycemia, athird will have improved glycemic control,and a third will have diabetes. Although pan-

createctomy may not cure diffuse HI, suffi-cient reduction in -cell mass may occur toallow more effective medical treatment. Immediate complications of pancreatec-tomy include pancreatitis, duodenal hema-toma, pseudocyst formation, and injury to thebile ducts. Postoperatively, hyperglycemia iscommon, related to the stress of surgery, andfrequently requires insulin. Only when thechild is taking full feeds can a determina-tion be made as to whether long-term insulintherapy is required. Moreover, despite thepresence of hyperglycemia postoperatively,some children will have persistent hypoglyce-

mia that is only evident when the child is onfull feeds or fasts. Additional complicationsof pancreatectomy include obstruction ofthe gastrointestinal tract due adhesions andpancreatic insufficiency; the latter usually issubclinical but should be sought in the childwith chronic diarrhea or poor growth. Late-onset diabetes can occur years after pancre-atectomy, frequently during puberty. In thesetting of pancreatectomy, diabetes has beenattributed to deceased -cell mass. However,the findings of 1) decreased insulin secretionin response to an acute glucose challenge(see Figure 4-5) and 2) hyperglycemia in

three teenagers who were treated medicallyfor recessive SUR1 HI suggest that dysregu-lated insulin secretion has a role in the devel-opment of late-onset diabetes (50). Some centers do not use pancreatectomyroutinely to treat HI that has failed pharmaco-logical therapy. Instead, continuous dextrosedelivered through intragastric tube is usedto prevent hypoglycemia. At our center, weprefer more definitive therapy through sur-gery and use continuous intragastric dextroseas a last resort (i.e., significant hypoglycemiadespite pancreatectomy and octreotide) be-cause such interventions may limit normalsocial interaction, suppress appetite, createfeeding aversions, and place the child at riskfor significant hypoglycemia should the tubebecome disconnected.

CONGENITAL HYPERINSULINISMDUE TO GDH GAIN-OF-FUNCTION MUTATIONS

Etiology/Pathophysiology Gain-of-functionmutations of the GLUD-1 gene that en-codes the mitochondrial enzyme glutamate

dehydrogenase (GDH) cause a form of hy-perinsulinism associated with hyperammo-nemia (HI/HA, also known as GDH HI)(17,20,5154). Inheritance of GDH HI isautosomal dominant, although up to 80%of cases represent de novo mutations. GDH

is responsible for the oxidative deamina-tion of glutamate to -ketoglutarate (seeFigure 4-1). It is allosterically activated byleucine and ADP and inhibited by GTP. Iteffects insulin secretion by generating -ketoglutarate, which enters the Krebs cycleto generate ATP. The increase in ATP closesthe KATP channel, -cell membrane depo-larization ensues, and insulin is secreted.

GDH HIcausing mutations impair normalinhibition of GDH by GTP and allowunchecked allosteric activation of GDH byleucine (Figures 4-7 and4-8) (55). Enhancedleucine-stimulated insulin secretion resultsand manifests clinically as protein-induced

hypoglycemia (56) (Figure 4-9), a hallmarkof GDH HI. Hyperammonemia, the other hallmarkof and a consistent finding in GDH HI, isthought to arise from up regulated hepaticGDH activity (see Figure 4-7) (57). Up regu-lated GDH activity depletes the hepatocyteof glutamate, which is needed to produce N-acetylglutamate (NAG), a necessary cofactor

0

10

20

30

40

50

60

PlasmaInsulin

(U/mL)

Time (min)

GDH-HI

-5 0 5

0

20

40

60

80

100

BloodGlucose(mg/dL)

-5 0 5

Time (min)

Normal Control

leucine leucine

FIGURE 4-8. Acute insulin responses to leucine in a patient with GDH HI and a normal control.Exaggeratedinsulin secretion occurs at 1 and 3 minutes in GDH HI in response to a bolus of leucine (15 mg/kg), whereas normal controls

do not respond. Blood glucose remains stable during this procedure, unlike in previous tests that required the development of

hypoglycemia to identify leucine sensitivity. Insulin is shown in circles and blood glucose concentrations along the dotted line.

FIGURE 4-7.GDH-HI.This form of congenital HI arises as a result of dominant mutations in the mitochondrial enzyme,GDH, that cause loss of normal allosteric inhibition of GDH by GTP. These gain of function mutations lead to excess oxida-

tion of glutamate to a-ketoglutarate, an increase in the ATP to ADP ratio, closure of the KATP-channel, and ultimately excess

insulin secreation. Patients with GDH-HI have protein-induced hypoglycemia as a result of unbridled leucine activation of

GDH. Hyperammonemia is thought to arise from upregulated oxidative deamination of glutamate to a-ketoglutarate in the

hepatocyte. In addition, clearance of excess ammonia via ureagenesis is limited by increased conversion of glutamate to

a-ketoglutarate; the glutamate pool that is necessary for the synthesis of N-acetyglutamate, a co-factor in the urea cycle,

is depleted.


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Hyperinsulinism

for the first step of ureagenesis. In addition,

enhanced GDH activity leads to excess pro-duction of ammonium, disposal of which ishindered by the limited availability of NAG.

Clinical Presentation Affected newborns areof normal birth weight, and their hypoglyce-mia often does not manifest until later in in-fancy. This delayed presentation likely arisesbecause 1) GDH HI is often associated withsubtle defects in fasting, and not until later ininfancy when overnight feeds are skipped isthe ability to fast challenged, and because 2)protein-rich foods such as yogurt, cows milk,and meat are not introduced into the diet un-

til later in infancy, allowing the characteristicprotein-induced hypoglycemia to be avoideduntil this time (see Figure 4-9). Differences inthese environmental exposures likely contrib-ute to the clinical severity. For instance, someGDH HI individuals, although having hypo-glycemic symptoms, have not been diagnoseduntil an affected family has been identified. GDH HI individuals appear to be asymp-tomatic from their hyperammonemia de-spite plasma concentrations two to five timesnormal. Protein intake, fasting, and bloodglucose concentration do not affect plasmaammonia (21,22,52). Unlike with urea

cycle defects, plasma amino acids and uri-nary amino acids are normal. In addition,hyperammonemia is not improved withbenzoate, an alternate-pathway treatmentused to lower plasma ammonium in ureacycle defects and liver failure (21,53,54).N-Carbamylglutamate, a NAG analogue,has been used to lower plasma ammoniumby 50% (22,53), but the clinical benefitremains to be determined.

Diagnosis As with other forms of HI, the di-agnosis depends on the finding of inappro-priate insulin action at the time of hypogly-

cemia (i.e., suppressedfree fatty acids, ketones,and IGFBP-1 and aninappropriate glycemicresponse to glucagon).

As mentioned previ-ously, the fasting toler-ance of GDH HI may

be 612 hours or lon-ger. Postprandial hypo-glycemia, particularlyfollowing high-proteinfood intake, suggestsGDH HI. Further confirmingthe diagnosis of GDHHI is hyperammonemia,usually in the range of80150 mol/L (nor-mal35 mol/L). Spu-rious hyperammonemia

may occur if the sample is not obtained appro-

priately using a free-flowing specimen that istransported on ice and assayed immediately. Toexclude laboratory error, multiple plasma am-monium concentrations should be obtainedappropriately. The acute insulin response to a leucine testis particularly useful in securing the diagnosisof GDH HI (see Figure 4-8). In response toan intravenous bolus of leucine (15 mg/kg),exaggerated insulin secretion occurs. In con-trast, normal controls and children with otherforms of HI show little to no response to leu-cine (see Figures 4-5 and 4-8). In addition,following a protein meal (11.5 g/kg Resource

protein), children with GDH HI become hy-poglycemic (see Figure 4-9). Mutational analysis for GLUD1, the geneencoding GDH, confirms the diagnosis. Mu-tations have been found in exons 6, 7, 10, 11,and 12(Table 4-2).

Treatment The goal of treatment is to preventboth postprandial and fasting hypoglycemia.Patients with GDH HI respond to well todiazoxide (515 mg/kg/day). To monitor theefficacy of the diazoxide dose, fasting and oralprotein tests are performed (Figure 4-10).If a child is not able to fast for more than

12 hours, or if significant protein-inducedhypoglycemia occurs, the diazoxide dose is

0

20

40

60

80

100

Blood

glucose(mg/dL)

0 6 12 18 24

Time (hr)

Protein meal

Fasting

FIGURE 4-9.BG during fasting and following an oral protein challenge.In

this teenager with GDH HI, fasting tolerance is shortened to 1617 hours, as shown by

blood glucose concentrations in squares. More strikingly, however, she rapidly becomes

hypoglycemic following consumption of protein (1.5 g/kg). Blood glucose concentrations

for the protein meal are shown in diamonds.

TABLE 4-2 Laboratory Findings: GDH HI

Decreased Increased

Blood glucose Free fatty acids (1.5 mmol/L) BG response to glucagon (30 mg/dL)50 mg/dL -Hydroxybutyrate (1.5 mmol/L) GH (10 ng/mL)

Acetoacetate Cortisol (18 g/dL) IGFBP-1 (120 ng/mL) Plasma ammonia

BG response to oral protein load Leucine-AIR Glucose-AIR

Female carriers of ornithine carbamoyltrans-ferase deficiency, an X-linked disorder, mayhave asymptomatic hyperammonemia. In-creased orotic acid in urine will identify suchpatients.

Unlike with urea cycle defects, plasma ammo-

nia does not increase with a protein load. Most mutations arise sporadically

The hyperammonemia of GDH-HI appearsto be asymptomatic. Recently, generalizedseizures and behavior issues have been notedin children with GDH-HI in the absence ofhypoglycemic brain damage (2). The role ofchronic hyperammonemia in these seizures isnot known.

increased. Patients are also instructed to avoidpure protein meals and to eat carbohydrates

before protein to reduce the risk of protein-induced hypoglycemia.

CONGENITAL HYPERINSULINSMDUE TO GK GAIN-OF-FUNCTION MUTATIONS

Etiology/Pathophysiology Glucokinase(GK) catalyzes the phosphorylation of glu-cose, the first step in glycolysis. GK is ex-pressed exclusively in liver and pancreaticislet -cells, where it regulates the rate ofglucose metabolism. Because of its important

regulatory role in glucose metabolism, GK isconsidered the -cell glucosensor. Because GK HI is rare, limited informationis available regarding this form of HI. GK HIarises as a result of dominant gain-of-function

Heterozygous loss of function mutations ofGK increase the BG threshold for insulin se-cretion and lead to maturity onset diabetes ofthe young (MODY-2), a dominantly inheritedform of diabetes (1). Homozygous loss offunction mutations of GK lead to permanent

neonatal diabetes


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mutations of the GCK gene encoding GK(14,5860) (Figure 4-11). The mutations in-crease enzyme affinity for glucose, therebylowering the threshold for insulin secretion.

Clinical Presentation A few reports of GK HIare available in the literature (14,5860). In thefirst family, children presented late in infancywith mild hyperinsulinism and insulin secre-tion that was not suppressed until a BG of ap-proximately 40 mg/dL (14). In this family and asimilar family (14,58), the HI was responsive todiazoxide. More recently, a case with a de novomutation of GK was reported (59). The GK HIwas severe, unresponsive to diazoxide, and per-sistent despite subtotal pancreatectomy. Thethreshold for glucose-stimulated insulin secre-tion was reduced to approximately 15 mg/dL.

Diagnosis The diagnosis of GK HI dependson confirmation of HI and identification ofa gain-of-function mutation in GK. Otherclues suggestive of GK HI are evidence of a

lowered glucose threshold.Treatment Treatment with diazoxide hasbeen effective in most reported cases.Some children with severe defects may notrespond to diazoxide and may require pan-createctomy.

CONGENITAL HYPERINSULINSMDUE TO SCHAD DEFICIENCY

Etiology/Pathophysiology SCHAD HI is rare,with just two reports in the literature at thetime of this writing (61,62). It is inherited in

an autosomal recessive fashion and arises froma defect in enzymatic activity of short-chain3-hydroxyacyl-CoA dehydrogenase (SCHAD).SCHAD is a mitochondrial enzyme that cata-lyzes the conversionof 3-hydroxyacyl-CoA to3-ketoacyl-CoA, the third step in the fatty acid-oxidation cycle. How the defect in fatty acidoxidation causes HI is not known.

Clinical Presentation Two reports are avail-able in the literature. Both cases were infantswho presented in the neonatal period or earlyinfancy with episodes of hypoketotic hypogly-cemia. These patients did not experience thetypical clinical findings associated with mostfatty acid oxidation defects (i.e., episodes ofReye-like illness, hepatic dysfunction, cardio-myopathy, and/or skeletal muscle weakness).

Diagnosis The diagnosis of SCHAD defi-ciency is based on confirming the presence ofHI, that is, hypoglycemia in the setting of ex-cessive insulin action. To specifically diagnose

SCHAD HI, elevated 3-hydroxybutyryl(C4)-carnitine should be identified by tandemmass spectrometry on a plasma acylcarnitineprofile. In addition, gas chromatographymass spectrometry of urine reveals elevated3-hydroxyglutaric acid.

Treatment The cases in the literature werediazoxide-responsive, suggesting that diazox-ide is appropriate as a first-line agent fortreating SCHAD HI.

CONGENITAL HYPERINSULINSMDUE TO CARBOHYDRATE-

DEFICIENT GLYCOPROTEINSYNDROME TYPE 1B

Etiology/Pathophysiology Carbohydrate-deficient glycoprotein syndromes (CDGs) area heterogeneous group of disorders character-ized by psychomotor and mental retardation,blood coagulation abnormalities, and hypo-glycosylation of glycoproteins. CDG type 1bis unique in that a few affected children havehad hypoglycemia due to hyperinsulinism(63,64). Other features of CDG-1b includeprotein-losing enteropathy and congenitalhepatic fibrosis, but psychomotor retardation

and mental retardation are absent. Mutationsin phosphomannose isomerase are respon-sible for CDG-1b (65), but how such a defectcauses hyperinsulinism is not known.

Clinical Presentation In the few cases thathave been described, infants present in earlyinfancy with protein-losing enteropathy andhypoglycemia.

Diagnosis Missing or truncated sugar chainscause hypoglycosylation of extracellularproteins that can be identified by isoelectricfocusing of serum transferrin.

FIGURE 4-10.Diazoxide responsiveness of protein sensitivity in GDH HI.Prior to initiation of diazoxide, this patient

has significant protein-induced hypoglycemia (small open circles) using an protein drink (1.5 g/kg). Treatment with diazoxide

(10 mg/kg/day) prevented protein-induced hypoglycemia (squares). A year later she has outgrown her diazoxide dose

(7.5 mg/kg/day), and her protein sensitivity is no longer treated adequately (large open squares).

0

20

40

60

80

100

BloodG

lucose(mg/dL)

0 25 50 75 100

Time (min)

Pre-diazoxide

Diazoxide (10 mg/kg/day)

Diazoxide (7.5 mg/kg/day)

am

inoa c

i dd

rin

k

FIGURE 4-11.GK HI.Activating mutations of GK cause more avid binding of glucose to GK. Enhanced phosphorylation

of glucose results, stimulating ATP production, closure of the KATPchannel, -cell membrane depolarization, opening of

VDCCs, entry of calcium into the -cell, and insulin secretion at lower blood glucose concentrations than normal.


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Hyperinsulinism

Treatment Mannose has been used suc-cessfully to reverse the hypoglycosylation ofserum glycoproteins, as well as the vomiting,diarrhea, congenital hepatic fibrosis, andhyperinsulinism of CDG-1b (64).

INFANT OF THEDIABETIC MOTHER

Etiology/Pathophysiology Because thefetus is exposed to maternal blood glucoseconcentrations, the infant of a motherwith poorly controlled diabetes is exposedto hyperglycemia in utero. In response tothis hyperglycemia, the fetus appropriatelyup regulates insulin secretion. Enhancedinsulin secretion by the fetus manifests asmacrosomia: Glycogen, protein, and fatstores are increased. At birth, the excessiveglucose supply is abruptly interrupted. Ifinsulin secretion is not down regulated suf-ficiently, hypoglycemia results. Glucagondeficiency may contribute to the develop-ment of hypoglycemia in the infant of adiabetic mother.

Clinical Presentation Infants typically presentat birth with hypoglycemia. Maternal his-tory of diabetes and low for gestational age(LGA) birth weight are clues to the etiologyof the hypoglycemia. Hypoglycemia relatedto maternal diabetes generally resolves within2 days. If hypoglycemia is prolonged, otheretiologies for the hypoglycemia should beconsidered.

Diagnosis The diagnosis is based on ma-ternal history. For the mother with little orno prenatal care, the diagnosis of diabetesshould be entertained. In the infant, studiesperformed at the time of hypoglycemia (BG50 mg/dL) will be consistent with hyperin-sulinism: suppressed free fatty acids, ketones,and IGFBP-1 and normal bicarbonate, a gly-cemic response to glucagon, plus or minuselevated plasma insulin.

Treatment Because the hyperinsulinemia isshort-lived, the infant of the diabetic motherusually can be treated expectantly with intra-venous dextrose (510 mg/kg/minute). Lesscommonly, the hyperinsulinemia is more pro-longed, in which case other etiologies shouldbe sought. If studies remain consistent withhyperinsulinemia, diazoxide can be initiated.If the preprandial BG is normal on diazoxide,a safety fast is undertaken to ensure efficacyof the diazoxide dose. The infant then can beallowed to outgrow the diazoxide dose, andBG regulation is reassessed in 34 months toconfirm that the hyperinsulinemia was indeedtransient in nature.

PERIPARTUM STRESSHYPERINSULINISM

Etiology/Pathophysiology Infants born smallfor gestational age (SGA), preterm, or follow-ing intrauterine/peripartum stress, such asbirth asphyxia, are at risk of hypoglycemia.Excess insulin secretion, which can last for

weeks to months, is the culprit (66,67). Themechanisms for dysregulated insulin secre-tion are not understood. Not all infants withtransient neonatal HI have the typical risksfor peripartum stress hyperinsulinism; someare of normal birth weight and have had noknown stressors (68).

Clinical Presentation Affected infants tend topresent shortly after birth with hypoglycemia.In some, prolonged intravenous dextrose orcontinuous feeds obligated by underlying ill-ness can mask the hyperinsulinism for weeks.Only when intermittent bolus feeds are intro-

duced is the hypoglycemia detected.

Diagnosis As with other forms of HI, peri-partum stress HI is diagnosed by demonstrat-ing suppressed free fatty acids, ketones, andIGFBP-1 and a glycemic response to gluca-gon at the time of hypoglycemia. The specificdiagnosis of peripartum stress HI is suspectedbased on the birth history. Only when the dis-order resolves weeks to months later is oneassured of the transient nature of the HI.

Treatment Peripartum stress HI usually re-sponds to diazoxide. On rare occasions, oc-

treotide is required. Diazoxide-induced fluidretention can be a limiting factor in the useof this medication in severely ill neonates.For this reason, diuretics should be initiatedempirically with diazoxide in infants who areSGA or who have lung disease. Occasionally,diazoxide causes sufficient fluid overload tocompromise lung function. These patientsmay respond to octreotide. If octreotide is noteffective, continuous feeds are introducedto maintain BG. The infants BG regula-tion can be reassessed in 34 months to con-firm that the hyperinsulinism has resolved.Uncommonly, the HI can last as long as a

year (68).

INSULINOMA

Etiology/Pathophysiology Insulinomas arethe most common functioning neuroendo-crine tumor of the pancreas in adults, with anincidence of approximately 4 per 1 millionper year (69). In the pediatric population, in-sulinomas are exceedingly rare. Insulinomasmay arise sporadically or, less commonly, aspart of multiple endocrine neoplasia type 1(MEN-1), a disorder that causes neuroendo-

crine tumors of the pituitary, parathyroid, andpancreas. Insulinomas are the second most common pancreatic tumor in MEN-1. Themajority of cases of MEN-1 result fromfamilial and sporadic dominant mutationsin the coding region of the MEN1 gene lo-cated on 11q13 (70). MENIN, the protein

product of the MEN1 gene, is thought tobe a tumor-suppressor protein. Mutationsof MEN1 alone are not sufficient to causetumor formation. As with KATPHI, somaticloss of heterozygosity of 11q13 occurs inthe lesion, unmasking the germline defectin MEN1. Mutations of MEN1 and, morecommonly, loss of heterozygosity for 11q13also have been identified in sporadically oc-curring insulinomas. The mechanisms for excess insulin secre-tion by insulinomas are not well delineatedGene expression studies have found increasedexpression of a variety of genes, including is-

let amyloid peptide, proprotein convertasesubtilisin, -subunit of stimulating G proteinand a large cluster of genes in the insulin se-cretory pathway (7173).

Clinical Presentation Children with insu-linomas present with acquired hypoglyce-mic symptoms beyond the first year of lifeSymptoms include seizures, abnormal behav-ior, lethargy, and increased food consumptionand weight gain in the absence of exogenousinsulin or insulin secretagogues.

Diagnosis The diagnosis of insulinoma de-pends on identification of excess endogenous

insulin secretion at the time of hypoglycemiaand frequently requires a prolonged fast, upto 72 hours in older children and adults (74).

As with other forms of HI, free fatty acidsand ketones are suppressed, and a glycemicresponse to glucagon occurs at the time ofhypoglycemia. Care should be taken to ex-clude surreptitious insulin administrationby measuring C-peptide, proinsulin, andinsulin antibodies, as well as insulin, at atime of hypoglycemia. Increased C-peptide(0.2 nmol/L) and proinsulin (5 pmol/L)at hypoglycemia confirm endogenous in-sulin secretion (7577) but do not rule outadministration of oral hypoglycemic agentssuch as sulfonylureas. When indicated clini-cally, plasma can be assayed for the presenceof sulfonylureas; unfortunately, the second-generation sulfonylureas are more difficult tomeasure (76). Once the diagnosis of HI is secured, localization procedures are performed. Endo-scopic ultrasound is sensitive in experiencedhands but is limited when the lesion occursin the tail of the pancreas or is small (8mm); intraoperative ultrasound in combina-tion with palpation also has been useful but


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again, is limited by the experience of thestaff (78). Spiral CT scanning appears to besensitive in the detection of pancreatic neu-roendocrine masses; success with MRI alsohas been reported. When typical imagingmodalities fail to identify small lesions, ASVSand THPVS have been used successfully tolocalize insulinomas (78).

Treatment Surgical removal of the insuli-noma is definitive treatment. Rarely, medicaltherapy with diazoxide is required for childrenin whom surgery is a high-risk procedure.

BECKWITHWIEDEMANN

Et iology/Pathophysiology BeckwithWiedemann syndrome is caused by mosaicpaternal isodisomy of chromosome 11p15.5.This syndrome also may arise from mutationsin the p57 gene (79) or in the NSD1 gene (80)and from microdeletions in the H19 differen-tially methylated region (81) or in the LIT1gene (82). Mutations in these genes disruptnormal imprinting of genes on 11p15.5. Thisphenomenon is similar to that found in focalHI, in which loss of heterozygosity for the ma-ternal 11p15 causes unbalanced expressionof imprinted genes that control cell growth(32,46). Hyperinsulinism has been attributedto overexpression of IGF-2 causing organovergrowth, including-cell hyperplasia (83).More recently, overexpression of IGF-2 hasbeen proposed as the specific mechanism forhypoglycemia in BeckwithWiedeman syn-

drome. Overproduction of pro-IGF-2, IGF-2, or big IGF-2 is well described in adultswith nonislet cell tumors (8490). Increasedcirculation of this growth factor is thought tostimulate the insulin receptor and thus haveinsulin-like effects. Hence the hypoglycemiaof BeckwithWiedemann syndrome may, atleast in some cases, be a mimicker of hyper-insulinism.

Clinical Presentation Typical features ofBeckwithWiedemann syndrome includeneonatal macrosomia, macroglossia, hemi-hypertrophy, and abdominal wall defects

(Figure 4-12) Hypoglycemia within the firstfew days of life is not uncommon (91,92).More persistent hypoglycemia is less commonand has been attributed to hyperinsulinism(93) that is variably diazoxide-responsive andmay require pancretatectomy.

Diagnosis The diagnosis of Beckwith-Wiedemann syndrome depends on thepresence of clinical manifestations andpaternal isodisomy of 11p15.5 or otherrelevant mutations. The diagnosis of HI issimilar to that for other HI disorders: at thetime of hypoglycemia, suppressed free fatty

acids, ketones, and IGFBP-1 and a glycemicresponse to glucagon. Since IGF-2-relatedhypoglycemia will mimic HI, additionalstudies specifically for IGF-2, big IGF-2, and pro-IGF-2 should be sought in thecase of BeckwithWiedemann syndrome.Overexpression of IGF-2 may suppress the

growth hormone axis, leading to suppres-sion of IGF-1 and IGFBP-3. Therefore,determination of these growth factors alsoshould be done to aid in the diagnosis.

Treatment Treatment depends on the under-lying etiology of the hypoglycemia. Diazoxideadministration should be attempted for HI. Ifdiazoxide fails and excess IGF-2 has not beenconsidered previously, or if IGF-2 is knownto be elevated, a trial with growth hormonemay increase growth factorbinding proteinssufficiently to limit IGF-2 bioavailability andprevent hypoglycemia.

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A

C

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FIGURE 4-12. Features of BeckwithWiedemann syndrome:(A)macroglossia and microcephaly in a newborn;

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