BIOCHEMISTRY: A TEXTBOOK FOR UNIVERSITIES - E. S. Severin - 2004

CHAPTER 7. CARBOHYDRATE METABOLISM

VII. Regulation of Glycogen Metabolism

The processes of glucose storage as Glycogen and its breakdown must be coordinated with the body's demand for glucose as an energy source. The simultaneous operation of these metabolic pathways is impossible, as it would result in a "futile cycle," the existence of which leads solely to the wasteful expenditure of ATP.

Regulatory mechanisms involving Hormones ensure the directional shifts in glycogen METABOLISM. The switching between glycogen synthesis and mobilization occurs during the transition from the absorptive to the postabsorptive period, or from a state of rest to physical exertion. In the Liver, the hormones Insulin, Glucagon, and adrenaline participate in switching these metabolic pathways, whereas in Muscles, insulin and adrenaline are involved.

A. Characteristics of Hormones Regulating Glycogen Metabolism

The primary signal for the Synthesis and Secretion of insulin and Glucagon is a change in Blood glucose levels. Normally, blood glucose concentration ranges from 3.3 to 5.5 mmol/L (60 to 100 mg/dL).

Insulin — a protein hormone synthesized and secreted into the blood by the β-Cells of the islets of Langerhans in the Pancreas. The β-cells are sensitive to fluctuations in blood glucose levels and secrete insulin in response to its elevated postprandial concentration. The transport protein (GLUT-2), which facilitates glucose entry into β-cells, has a low affinity for glucose. Consequently, this protein transports glucose into the pancreatic Cell only when blood glucose exceeds normal levels (above 5.5 mmol/L).

In β-cells, glucose is phosphorylated by glucokinase, which also has a high K_m for glucose, equal to 12 mmol/L. The rate of glucose phosphorylation by glucokinase in β-cells is directly proportional to its concentration in the blood.

Insulin synthesis is regulated by glucose. Glucose (or its metabolites) appears to be directly involved in regulating insulin Gene Expression. The secretion of insulin and glucagon is also regulated by glucose, which stimulates insulin secretion from β-cells and suppresses glucagon secretion from α-cells. Furthermore, insulin itself decreases glucagon secretion (see Section 11).

Glucagon — the "hunger hormone," produced by the α-cells of The Pancreas in response to a drop in blood glucose levels. Chemically, glucagon is a peptide.

Adrenaline is released from The adrenal medulla in response to signals from The Nervous system originating in the Brain during emergency situations (such as flight or fight) that require sudden muscular activity. Adrenaline serves as an "alarm" signal, designed to instantaneously provide the muscles and brain with an energy source.

Class="center">Fig. 7-26. Synthesis and degradation of glycogen. 1 — hexokinase or glucokinase (liver); 2 — UDP-glucose pyrophosphorylase; 3 — glycogen synthase; 4 — amylo-1,4 —> 1,6-glucosidase (branching enzyme); 5 — Glycogen phosphorylase; 6 — debranching enzyme; 7 — glucose-6-phosphatase (liver); 8 — GLUT transport systems.

B. Regulation of Glycogen Phosphorylase and Glycogen Synthase Activity

Since Glycogen Synthesis and Degradation proceed via distinct metabolic pathways, these processes can be controlled reciprocally. Hormonal influence on glycogen synthesis and degradation is exerted by altering the activities of two Key Enzymes—Glycogen synthase and glycogen phosphorylase—in opposite directions through phosphorylation and dephosphorylation (Fig. 7-27).

Glycogen phosphorylase exists in two forms: 1) phosphorylated — active (form a); 2) dephosphorylated — inactive (form b). Phosphorylation occurs via The transfer of a phosphate group from ATP to the hydroxyl group of one of the enzyme's Serine residues. This leads to Conformational Changes in the enzyme molecule and its activation.

The interconversion of the two forms of glycogen phosphorylase is mediated by phosphorylase kinase and phosphoprotein phosphatase (an enzyme structurally associated with glycogen particles). In turn, the activities of phosphorylase kinase and phosphoprotein phosphatase are also regulated by phosphorylation and dephosphorylation.

Activation of phosphorylase kinase is brought about by protein kinase A (PKA, cAMP-dependent). cAMP first activates protein kinase A, which phosphorylates phosphorylase kinase, converting it into the active state; this kinase, in turn, phosphorylates glycogen phosphorylase. cAMP synthesis is stimulated by adrenaline and glucagon (see Section 5).

Activation of phosphoprotein phosphatase occurs As a result of a phosphorylation reaction catalyzed by a specific protein kinase, which is subsequently activated by insulin via a cascade of Reactions Involving the Ras protein and other Proteins and Enzymes (the Ras signaling pathway, see Section 11). The insulin-activated protein kinase phosphorylates and thereby activates phosphoprotein phosphatase. Active phosphoprotein phosphatase dephosphorylates and consequently inactivates phosphorylase kinase and glycogen phosphorylase (Fig. 7-28).

Fig. 7-27. Changes in The activity of glycogen phosphorylase and glycogen synthase. Enzyme molecules are represented by circles: active ones are black, inactive ones are white. PP-phosphatase (GP) — glycogen particle phosphoprotein phosphatase.

Glycogen synthase activity is also modulated by phosphorylation and dephosphorylation (see Fig. 7-27 above). However, there are significant differences in The regulation of glycogen phosphorylase and glycogen synthase:

✵ phosphorylation of Glycogen synthase is catalyzed by PKA and results in its inactivation;

✵ dephosphorylation of glycogen synthase by phosphoprotein phosphatase, conversely, activates it.

Fig. 7-28. Effect of insulin on the activity of glycogen synthase and phosphorylase kinase. PP-phosphatase (GS) = glycogen granule protein phosphatase. PK (p90S6) = insulin-activated protein kinase.

C. Regulation of Hepatic Glycogen Metabolism

As noted previously, the primary signal for insulin and glucagon synthesis is A change in blood glucose concentration. Although insulin and glucagon are constantly present in the blood, the transition from the absorptive to the postabsorptive state shifts their relative concentrations, which serves as the main factor switching hepatic glycogen metabolism. The ratio of blood insulin concentration to glucagon concentration is referred to as the insulin-glucagon index. In the postabsorptive state, the insulin-glucagon index decreases, and glucagon concentration becomes the decisive factor in regulating blood glucose levels.

Glucagon acts as an external signal to hepatocytes, indicating the need to release glucose into the blood via glycogen breakdown (Glycogenolysis) or de novo glucose synthesis from other substances (Gluconeogenesis, a process discussed later). The hormone binds to a Plasma Membrane receptor and, via a G protein intermediary, activates adenylate cyclase, which catalyzes The formation of cAMP from ATP (see Chapter 5). This triggers a cascade of reactions in the liver that leads to the activation of glycogen phosphorylase and the inhibition of glycogen synthase (Fig. 7-29). This mechanism results in the release of glucose-1-phosphate from glycogen, which is then converted into glucose-6-phosphate. Subsequently, under the action of glucose-6-phosphatase, free Glucose is formed, capable of leaving The Cell and entering the bloodstream. Thus, by stimulating glycogen breakdown in the liver, glucagon helps maintain constant blood glucose levels.

Epinephrine stimulates the release of glucose from the liver into the bloodstream to supply Tissues (primarily the brain and muscles) with "fuel" during an emergency. The Effect of epinephrine in the liver is mediated by the phosphorylation (and activation) of glycogen phosphorylase. Epinephrine shares a similar MECHANISM OF ACTION with glucagon (Fig. 7-29). However, alternative effector systems for signal Transduction into the liver cell may also be engaged (Fig. 7-30).

Fig. 7-29. Regulation of hepatic glycogen Synthesis and Breakdown by glucagon and epinephrine. 1 — glucagon and epinephrine interact with specific Membrane Receptors. The hormone-receptor complex alters the conformation of the G protein, causing its dissociation into protomers and the replacement of GDP by GTP in the α subunit; 2 — the GTP-bound α subunit activates adenylate cyclase, which catalyzes the synthesis of cAMP from ATP; 3 — in the presence of cAMP, protein kinase A (cAMP-dependent) reversibly dissociates, releasing catalytically active C subunits; 4 — protein kinase A phosphorylates and activates phosphorylase kinase; 5 — phosphorylase kinase phosphorylates glycogen phosphorylase, converting it into its active form; 6 — protein kinase A also phosphorylates glycogen synthase, shifting it to an inactive state; 7 — as a result of glycogen synthase inhibition and glycogen phosphorylase activation, glycogen enters the degradation pathway; 8 — phosphodiesterase catalyzes The breakdown of cAMP, thereby terminating the hormonal signal. The α subunit-GTP complex subsequently dissociates, and the α, β, and y subunits of the G protein reassociate.

Fig. 7-30. Regulation of hepatic glycogen synthesis and breakdown by epinephrine and Ca²⁺. PIP₂ = phosphatidylinositol bisphosphate; IP₃ = Inositol 1,4,5-trisphosphate; DAG = diacylglycerol; ER = Endoplasmic reticulum; PS = phosphatidylserine. 1 — interaction of epinephrine with the α₁ receptor transduces the signal via G protein activation to phospholipase C, shifting it to the active state; 2 — phospholipase C hydrolyzes PIP₂ into IP₃ and DAG; 3 — IP₃ triggers Ca²⁺ mobilization from the ER; 4 — Ca²⁺, DAG, and phosphatidylserine activate protein kinase C. Protein kinase C phosphorylates glycogen synthase, converting it into an inactive state; 5 — the 4Ca²⁺-calmodulin complex activates phosphorylase kinase and calmodulin-dependent protein Kinases; 6 — phosphorylase kinase phosphorylates and thereby activates glycogen phosphorylase; 7 — the active forms of all three enzymes (calmodulin-dependent protein kinase, phosphorylase kinase, and protein kinase C) phosphorylate glycogen synthase at different sites, converting it into an inactive state.

Which intracellular signal transduction system is utilized depends on the type of receptors with which epinephrine interacts. For instance, epinephrine binding to β₂ receptors on hepatocytes engages the adenylate cyclase system. Conversely, its interaction with α₁ receptors "turns on" the inositol phosphate Mechanism of transmembrane hormonal signal transduction. The net result of both systems is the phosphorylation of key enzymes, shifting cellular processes from glycogen synthesis to degradation. Notably, the specific receptor type predominantly involved in the cellular response to epinephrine depends on its concentration in the blood.

During the postprandial (digestive) period, The Influence of insulin predominates due to an elevated insulin-glucagon index. Overall, insulin exerts effects on glycogen metabolism that are opposite to those of glucagon. Insulin lowers blood glucose concentrations during the digestive period by acting on hepatic metabolism in the following ways:

✵ it lowers intracellular cAMP levels by phosphorylating (indirectly via the Ras pathway) and thereby activating protein kinase B (which is cAMP-independent). Protein kinase B, in turn, phosphorylates and activates cAMP phosphodiesterase—an enzyme that hydrolyzes cAMP to form AMP. The mechanism by which insulin influences intracellular cAMP levels will be discussed in detail in Chapter 11;

✵ it activates (via the Ras pathway) glycogen granule protein phosphatase, which dephosphorylates and thus activates glycogen synthase. Additionally, protein phosphatase dephosphorylates and consequently inactivates phosphorylase kinase and glycogen phosphorylase;

✵ it induces glucokinase synthesis, thereby accelerating glucose phosphorylation within the cell. It is worth recalling that another regulatory factor in glycogen metabolism is the K_m value of glucokinase, which is significantly higher than that of hexokinase. The rationale behind these differences is clear: the liver should not consume glucose for glycogen synthesis unless blood glucose levels are within the normal range.

Together, these actions result in insulin simultaneously activating glycogen synthase and inhibiting glycogen phosphorylase, thereby switching The pathway of glycogen mobilization toward its synthesis.

While Allosteric Regulation of glycogen phosphorylase also exists in the liver to meet intracellular glucose demands, hormonal signals take priority over intracellular cues and serve broader physiological objectives. Earlier (see Chapter 6), we discussed The Significance of fluctuations in cellular ATP, ADP, and AMP levels as indicators of cellular energy status. A slowing of ATP utilization is accompanied by decreased glycogen phosphorylase activity and a reduced rate of glycogen breakdown. Conversely, increased ATP consumption leads to elevated AMP levels, activation of glycogen phosphorylase, and accelerated glycogenolysis. ATP and AMP act as allosteric effectors for glycogen phosphorylase. Furthermore, Metabolic control of glycogen phosphorylase activity exists: an increase in glucose-6-phosphate concentration leads to a decrease in the activity of this enzyme in liver cells.

D. Regulation of Muscle Glycogen Metabolism

The regulation of Glycogen metabolism in muscles provides the energy supply required both for intense muscular exertion (such as running or combat) and for resting metabolic demands.

In emergency situations, glycogen mobilization in muscle cells is accelerated by epinephrine. Epinephrine binding to β-receptors associated with the adenylate cyclase system leads to intracellular cAMP production, followed by the phosphorylation and activation of phosphorylase kinase and glycogen phosphorylase (Fig. 7-31).

The generation of cAMP stimulated by epinephrine serves as a signal to ramp up energy production by accelerating glycogen breakdown. It is precisely through the degradation of glucose-6-phosphate derived from glycogen that ATP is synthesized.

The inactivation of glycogen synthase by epinephrine in muscle cells proceeds similarly to that in the liver.

At rest, when blood epinephrine concentrations are low, muscle glycogen phosphorylase exists in a dephosphorylated, inactive state (form B); nevertheless, glycogen breakdown still occurs. This is because glycogen phosphorylase can be activated by a mechanism independent of phosphorylation, given the low intracellular cAMP levels. Under these conditions, allosteric activation of glycogen phosphorylase B takes place. The enzyme's activators are AMP and H₃PO₄, which are generated within the cell during ATP breakdown (Fig. 7-31, pathway 1).

Fig. 7-31. Activation of muscle glycogen phosphorylase. 1 — allosteric activation of glycogen phosphorylase B. During Muscle contraction, ATP is broken down to form AMP, which acts as an allosteric activator of glycogen phosphorylase B; 2 — a Nerve Impulse triggers the release of Ca²⁺ from the sarcoplasmic reticulum. Ca²⁺ forms a complex with calmodulin capable of activating phosphorylase kinase; 3 — activation of glycogen phosphorylase by epinephrine via the adenylate cyclase system.

During moderate muscle contractions, i.e., in situations not requiring cAMP regulation, phosphorylase kinase is activated via an allosteric mechanism (Fig. 7-31, pathway 2). In this case, Ca²⁺ ions act as allosteric effectors, whose concentration spikes sharply during muscle contraction in response to motor nerve signals. Enzyme activity drops immediately as intracellular Ca²⁺ levels decrease following the relaxation signal. Thus, The Role of Ca²⁺ ions extends beyond initiating muscle contraction; they also supply the energy required for the process.

The activation of phosphorylase kinase by Ca²⁺ ions is mediated by calmodulin. Calmodulin serves here as a tightly bound subunit of the enzyme (Fig. 7-32). Muscle phosphorylase kinase consists of four types of subunits—α, β, y, and δ—assembled into a complex. The enzyme contains four such complexes. The y-subunit possesses catalytic activity, while the α and β subunits perform a regulatory function. They contain serine residues that are phosphorylated by PKA. The δ-subunit binds four Calcium Ions and is identical to the protein calmodulin. Calcium binding induces conformational changes that activate the catalytic center of the y-subunit, even though the molecule remains in a dephosphorylated state.

Fig. 7-32. Regulation of phosphorylase kinase activity. The enzyme consists of four identical Structure/178.html">Protein Complexes. Each complex contains four distinct subunits: α, β, y, and δ. The diagram shows one of the tetramers. The y-subunit possesses catalytic activity, whereas the α and β protomers serve a regulatory function and are phosphorylated by PKA. Calmodulin is the δ-subunit, which is firmly bound to the enzyme. A — activation of phosphorylase kinase via phosphorylation; B — activation of phosphorylase kinase following Ca²⁺ binding to calmodulin.

In muscles during the Digestion phase, provided it coincides with a state of rest, glycogen synthesis is stimulated. Physical exertion during digestion slows down glycogen synthesis because muscles utilize blood-borne glucose arriving from the intestines for oxidation.

Insulin participates in switching glycogen mobilization over to glucose storage. As noted previously, glucose enters muscle and adipose cells via GLUT-4 glucose transporters. In the absence of insulin, these transporters reside within the Cell Cytoplasm, and cells cannot utilize glucose since carrier proteins are absent from the membrane. Insulin stimulates the translocation of GLUT-4 and their insertion into The cell membrane. Although the exact mechanism of this insulin effect is not fully understood, its main stages have been defined. The chain of events during insulin-stimulated glucose uptake by muscle and fat cells is as follows:

✵ the insulin receptor (IR)—an insulin-stimulated Tyrosine protein kinase—acts as an obligate mediator for all insulin actions (see Section 5);

✵ the insulin-activated IR phosphorylates specific cytoplasmic proteins known as insulin receptor substrates (IRS);

✵ the phosphorylated substrate (primarily IRS-1) binds to phosphatidylinositol 3-kinase (PI3K) and activates this enzyme;

✵ active PI3K catalyzes phosphorylation at the 3-position of several components within the inositol phosphate signaling system, leading to The stimulation of GLUT translocation from the Cytosol to The Plasma Membrane;

✵ glucose enters muscle cells via GLUT-4 and is channeled into glycogen synthesis.

The effect of insulin on the rate of glycogen synthesis in muscles is mediated by altering the activities of glycogen synthase and glycogen phosphorylase—key enzymes, as discussed earlier regarding insulin's influence on hepatic glycogen metabolism.

D. Disorders of Glycogen Metabolism

Glycogen Storage Diseases—a group of hereditary disorders caused by reduced or absent activity of enzymes that catalyze glycogen synthesis or degradation, or by the dysregulation of these enzymes.

1. Glycogenoses—diseases caused by defects in enzymes involved in glycogen breakdown. They manifest either through an abnormal glycogen structure or its excessive accumulation in the liver, Heart, skeletal muscles, Kidneys, Lungs, and other Organs. Table 7-3 outlines several types of glycogenoses that differ in The Nature and localization of the enzymatic defect.

Table 7-3. Characteristics of Selected Glycogen Storage Diseases

It is worth noting that the term "glycogenosis" was first coined by G.T. Cori and C.F. Cori, who also proposed the numbering system for these diseases. However, glycogenoses are currently predominantly classified into two groups: hepatic and muscle forms.

Hepatic forms of glycogenoses impair the utilization of glycogen for maintaining blood glucose levels. Consequently, a hallmark symptom across these forms is postabsorptive hypoglycemia.

Von Gierke disease (Type I) is the most frequently diagnosed. A review of the primary symptoms of this glycogen storage disease and their underlying causes provides a solid framework for understanding other types. The ROOT cause is a hereditary deficiency of glucose-6-phosphatase, the enzyme responsible for releasing free glucose into the bloodstream after its mobilization from hepatic glycogen. Von Gierke disease manifests as hypoglycemia, hyperacylglycerolemia (elevated triacylglycerol levels), and hyperuricemia (elevated uric acid levels).

Hypoglycemia results from impaired free glucose formation from glucose-6-phosphatase deficiency. Furthermore, this enzymatic defect leads to the intracellular accumulation of the substrate glucose-6-phosphatase (glucose-6-phosphate), which enters Catabolic pathways and is converted into Pyruvate and lactate. Blood lactate levels rise, potentially resulting in acidosis. In severe cases, hypoglycemia can trigger seizures. Hypoglycemia is accompanied by a drop in insulin levels and a lowered insulin-to-glucagon ratio, which in turn accelerates adipose tissue lipolysis driven by glucagon, releasing free Fatty acids into the bloodstream (see Section 8).

Hyperacylglycerolemia develops as a result of reduced lipoprotein lipase activity in adipose tissue—an insulin-activated enzyme that facilitates the uptake of triacylglycerols (TAG) by fat cells (see Section 8).

Hyperuricemia occurs due to the following sequence of events:

✵ intracellular levels of glucose-6-phosphate rise, boosting its utilization via the Pentose Phosphate Pathway to generate ribose-5-phosphate—the precursor for purine nucleotide synthesis;

✵ uric acid production increases due to accelerated synthesis and subsequent Catabolism of Purine NUCLEOTIDES, which culminate in uric acid as the end product.

✵ decreased uric acid excretion due to elevated lactate production and acidification of urine pH, which impairs the clearance of urates—poorly soluble uric acid salts.

Diagnosis of this condition involves measuring glucose-6-phosphatase activity in liver biopsies. In addition, a glucagon or epinephrine stimulation test is performed, which yields a negative result in this disorder, meaning that the Blood Glucose Level changes only slightly following hormone injection.

Treatment consists of restricting glucose-containing foods. It is recommended to eliminate sucrose- and lactose-containing products from the diet, as the galactose and fructose derived from them are converted into glucose-6-phosphate, leading to further glycogen accumulation. Frequent feeding is used to prevent hypoglycemia and preempt its symptoms.

Type I glycogen storage disease is inherited in an autosomal recessive manner. Hepatomegaly is the most prominent sign already in early infancy. Affected children have a short trunk, a protuberant abdomen, and enlarged kidneys, and they lag behind in physical development.

The described disorder is sometimes designated as type Ia glycogen storage disease, as a variant—type Ib—exists. Type Ib glycogen storage disease is a rare pathology characterized by a deficiency of the glucose-6-phosphate translocase enzyme, which ensures The transport of phosphorylated glucose into the ER. Therefore, despite sufficient glucose-6-phosphatase activity, the Cleavage of inorganic phosphate and the release of glucose into the bloodstream are impaired. The Clinical presentation of type Ib glycogen storage disease is identical to that of type Ia.

Cori disease (Type III) is quite common, accounting for 1/4 of all hepatic glycogenoses. The accumulated glycogen has an abnormal structure due to a deficiency of amylo-1,6-glucosidase, the enzyme that hydrolyzes glycosidic bonds at branch points (known as the "debranching enzyme"). Blood glucose deficiency manifests rapidly because glycogenolysis is possible only to a minor extent. Unlike type I glycogen storage disease, lactic acidosis and hyperuricemia are not observed, and the clinical course is milder.

Andersen disease (Type IV) is an extremely rare autosomal recessive disorder caused by a deficiency of the branching enzyme, amylo-1,4-1,6-glucosyltransferase. The hepatic glycogen content is not significantly elevated, but its structure is altered, which impedes its degradation. The glycogen molecule has few branch points and features very long, sparse side chains. Meanwhile, hypoglycemia is moderately pronounced. The disease progresses rapidly, is complicated by early liver cirrhosis, and is practically untreatable. The branching enzyme defect is detected not only in the liver but also in leukocytes, muscles, and fibroblasts; however, the early and predominant clinical manifestations are driven by impaired liver function.

Hers disease (Type VI) also manifests with symptoms caused by liver damage. This glycogen storage disease results from a glycogen phosphorylase defect. Hepatocytes accumulate glycogen of normal structure. The clinical course resembles type I glycogen storage disease, but the symptoms are less pronounced. Reduced glycogen phosphorylase activity is also detected in leukocytes. Hers disease is a rare type of glycogenosis and is inherited in an autosomal recessive manner.

Phosphorylase kinase deficiency (Type IX) occurs exclusively in males because this trait is X-linked.

Protein kinase A deficiency (Type X), much like phosphorylase kinase deficiency, manifests with symptoms similar to Hers disease.

Muscular forms of glycogenoses are characterized by impaired energy supply to skeletal muscles. These disorders manifest during physical exertion and are accompanied by muscle pain and cramps, weakness, and rapid fatigability.

McArdle disease (Type V) is an autosomal recessive pathology characterized by a complete absence of glycogen phosphorylase activity in skeletal muscles. Since the activity of this enzyme in hepatocytes is normal, hypoglycemia is not observed (the enzymes in The Liver and muscles are encoded by different genes). Heavy physical exertion is poorly tolerated and may be accompanied by cramps; however, hyperlactatemia is not observed during exercise, which highlights The Importance of extramuscular Energy Sources for muscle contraction, such as fatty acids substituting for glucose in this condition (see Section 8). Although the disease is not sex-linked, a higher prevalence is observed in males.

Phosphofructokinase deficiency is characteristic of type VII glycogen storage disease. Patients are able to perform moderate physical exertion. The clinical course resembles type V glycogen storage disease, but the main manifestations are less severe.

Phosphoglyceromutase deficiency and LDH M-subunit deficiency (unclassified in the Cori system, see Table 7-3) are characteristic of muscular forms of glycogenoses. The manifestations of these pathologies are similar to McArdle disease. Muscle phosphoglyceromutase deficiency has been described in only one patient.

2. Aglycogenoses

Aglycogenose (glycogen storage disease type 0 According to the Classification) is a disorder resulting from a glycogen synthase deficiency. A very low glycogen content is observed in the liver and other tissues of affected patients, manifesting as pronounced hypoglycemia in the postabsorptive period. A characteristic symptom is muscle cramps, particularly in the mornings. The disease is compatible with life, but affected children require frequent feedings.