Type I Glycogen Storage Disease (Glucose-6-Phosphatase or Translocase Deficiency, Von Gierke Disease)

Type I GSD is caused by the absence or deficiency of glucose-6-phosphatase activity in the liver, kidney, and intestinal mucosa. It can be divided into two subtypes: type Ia, in which the glucose-6-phosphatase enzyme is defective; and type Ib, in which a translocase that transports glucose-6-phosphate across the microsomal membrane is defective. The defects in both type Ia and type Ib lead to inadequate hepatic conversion of glucose-6-phosphate to glucose through normal glycogenolysis and gluconeogenesis and make affected individuals susceptible to fasting hypoglycemia.

Type I GSD is an autosomal recessive disorder. The structural gene for glucose-6-phosphatase is located on chromosome 17q21; the gene for translocase is on chromosome 11q23. Common mutations responsible for the disease are known. Carrier detection and prenatal diagnosis are possible with the DNA-based diagnosis.

Type III Glycogen Storage Disease (Debrancher Deficiency, Limit Dextrinosis)

Type III GSD is caused by a deficiency of glycogen debranching enzyme activity. Debranching enzyme, together with phosphorylase, is responsible for complete degradation of glycogen. When debranching enzyme is defective, glycogen breakdown is incomplete and an abnormal glycogen with short outer branch chains and resembling limit dextrin accumulates. Deficiency of glycogen debranching enzyme causes hepatomegaly, hypoglycemia, short stature, variable skeletal myopathy, and variable cardiomyopathy. The disorder usually involves both liver and muscle and is termed type IIIa GSD. In approximately 15% of patients, the disease appears to involve only liver and is classified as type IIIb.

Type III glycogenosis is an autosomal recessive disease that has been reported in many different ethnic groups; the frequency is relatively high in Sephardic Jews from North Africa. The gene for debranching enzyme is located on chromosome 1p21. More than 30 different mutations are identified; 2 exon 3 mutations (17delAG and Q6X) are specifically associated with glycogenosis IIIb. Carrier detection and prenatal diagnosis are possible using DNA-based linkage or mutation analysis.

Clinical Manifestations

During infancy and childhood, the disease may be indistinguishable from type I GSD, because hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation are common (Fig. 81-2). Splenomegaly may be present, but the kidneys are not enlarged. Remarkably, hepatomegaly and hepatic symptoms in most patients with type III GSD improve with age and usually resolve after puberty. Progressive liver cirrhosis and failure can occur. Hepatocellular carcinoma has also been reported, more typically in patients with progressive liver cirrhosis. The frequency of adenomas in individuals with GSD III is far less, compared to GSD I. Furthermore, the relationship of hepatic adenomas and malignancy in GSD III is unclear. A single case of malignant transformation at the site of adenomas has been noted. In patients with muscular involvement (type IIIa), muscle weakness can present in childhood but can become severe after the 3rd or 4th decade of life, as evidenced by slowly progressive weakness and wasting. Because patients with GSD III can have decreased bone density, they are at an increased risk of potential fracture. Myopathy does not follow any particular pattern of involvement; both proximal and distal muscles are involved. Electromyography reveals a widespread myopathy; nerve conduction studies are often abnormal. Ventricular hypertrophy is a frequent finding, but overt cardiac dysfunction is rare. There have been some reports of life-threatening arrhythmia and need for heart transplant in some GSD III patients. Hepatic symptoms in some patients may be so mild that the diagnosis is not made until adulthood, when the patients show symptoms and signs of neuromuscular disease. The initial diagnosis has been confused with Charcot-Marie-Tooth disease. Polycystic ovaries are common; some patients can develop hirsutism, irregular menstrual cycles, and other features of polycystic ovarian syndrome. Fertility does not appear to be reduced; successful pregnancies in patients with GSD III have been reported.

Figure 81-2 Growth and development in a patient with type IIIb glycogen storage disease. The patient has debrancher deficiency in liver but normal activity in muscle. As a child, he had hepatomegaly, hypoglycemia, and growth retardation. After puberty, he no longer had hepatomegaly or hypoglycemia, and his final adult height is normal. He had no muscle weakness or atrophy; this is in contrast to type IIIa patients, in whom a progressive myopathy is seen in adulthood.

Hypoglycemia and hyperlipidemia are common. In contrast to type I GSD, elevation of liver transaminase levels and fasting ketosis are prominent, but blood lactate and uric acid concentrations are usually normal. Serum creatine kinase levels can be useful to identify patients with muscle involvement; normal levels do not rule out muscle enzyme deficiency. The administration of glucagon 2 hr after a carbohydrate meal provokes a normal increase in blood glucose; after an overnight fast, glucagon may provoke no change in blood glucose level.

Type IV Glycogen Storage Disease (Branching Enzyme Deficiency, Amylopectinosis, or Andersen Disease)

Deficiency of branching enzyme activity results in accumulation of an abnormal glycogen with poor solubility. The disease is referred to as type IV GSD or amylopectinosis because the abnormal glycogen has fewer branch points, more α 1-4 linked glucose units, and longer outer chains, resulting in a structure resembling amylopectin.

Type IV GSD is an autosomal recessive disorder. The glycogen branching enzyme gene is located on chromosome 3p21. Mutations responsible for type IV GSD have been identified, and their characterization in individual patients can be useful in predicting the clinical outcome. Some mutations are associated with a good prognosis and lack of progression of liver disease.

Type VI Glycogen Storage Disease (Liver Phosphorylase Deficiency, Hers Disease)

There are few patients with documented liver phosphorylase deficiency. Such patients usually have a benign course and present with hepatomegaly and growth retardation in early childhood; however, some cases are more severe. Hypoglycemia, hyperlipidemia, and hyperketosis are of variable severity. Lactic acid and uric acid levels are normal. The heart and skeletal muscles are not involved. The hepatomegaly and growth retardation improve with age and usually disappear around puberty; however, patients with severe hepatomegaly, recurrent severe hypoglycemia, hyperketosis, and postprandial lactic acidosis have recently been reported. Treatment is symptomatic. A high-carbohydrate diet and frequent feeding are effective in preventing hypoglycemia; most patients require no specific treatment. GSD VI is an autosomal recessive disease. Diagnosis rests on enzyme analysis of the liver biopsy. The liver phosphorylase gene (PYGL) is on chromosome 14q21-22 and has 20 exons. Many mutations are known in this gene; a splice site mutation in intron 13 has been identified in the Mennonite population.

Type IX Glycogen Storage Disease (Phosphorylase Kinase Deficiency)

This disorder represents a heterogeneous group of glycogenoses. Phosphorylase, the rate-limiting enzyme of glycogenolysis, is activated by a cascade of enzymatic reactions involving adenylate cyclase, cyclic adenosine monophosphate–dependent protein kinase (protein kinase A), and phosphorylase kinase. The latter enzyme has 4 subunits (α, β, γ, δ), each encoded by different genes on different chromosomes and differentially expressed in various tissues. This cascade of reactions is stimulated primarily by glucagon. This glycogenosis could be the result of any enzyme deficiency along this pathway; the most common is the deficiency of phosphorylase kinase. The phenotypic variability within each subtype is being uncovered with the availability of molecular testing.

The numeric classification of phosphorylase kinase deficiency is confusing, ranging from type VIa to VIII to IX. It is advisable to refrain from such a designation and to classify the various disorders according to organ involvement and mode of inheritance.

X-Linked Liver Phosphorylase Kinase Deficiency

X-linked liver phosphorylase kinase deficiency is the most common form of liver glycogenoses. In addition to liver, enzyme activity can also be deficient in erythrocytes, leukocytes, and fibroblasts; it is normal in muscle. Typically, a 1-5 yr old male presents with growth retardation, an incidental finding of hepatomegaly, and a slight delay in motor development. Cholesterol, triglycerides, and liver enzymes are mildly elevated. Ketosis may occur after fasting. Lactate and uric acid levels are normal. Hypoglycemia is typically mild, if present. The response in blood glucose to glucagon is normal. Hepatomegaly and abnormal blood chemistries gradually improve and can normalize with age. Most adults achieve a normal final height and are usually asymptomatic despite a persistent phosphorylase kinase deficiency. Liver histologic appearance shows glycogen-distended hepatocytes. The accumulated glycogen (β particles, rosette form) has a frayed or burst appearance and is less compact than the glycogen seen in type I or type III GSD. Fibrous septal formation and low-grade inflammatory changes may be present.

The structural gene for the common liver isoform of the phosphorylase kinase subunit, liver α subunit, is on the X chromosome (αL at Xp22.2). Several missense, nonsense, and splice-site mutations of this gene are known.

Autosomal Liver and Muscle Phosphorylase Kinase Deficiency

Several patients have been reported with phosphorylase kinase deficiency in liver and blood cells and an autosomal mode of inheritance. As with the X-linked form, hepatomegaly and growth retardation apparent in early childhood are the predominant symptoms. Some patients also exhibit muscle hypotonia. When measured in a few cases, reduced activity of the enzyme has been demonstrated in muscle. Mutations causing autosomally transmitted liver and muscle phosphorylase kinase deficiency are found in the autosomal β subunit gene of the PK gene (chromosome 16q12-q13). Several nonsense mutations, a single-base insertion, a splice-site mutation, and a large intragenic mutation have been identified. In addition, a missense mutation was discovered in an atypical patient with normal blood cell phosphorylase kinase activity.

Autosomal Liver Phosphorylase Kinase Deficiency

This form of phosphorylase kinase deficiency is due to mutations in the testis/liver isoform of the γ subunit of the gene (TL, PHKG2). In contrast to X-linked phosphorylase kinase deficiency, patients with mutations in the PHKG2 gene typically have more severe phenotypes with recurrent hypoglycemia and often develop progressive liver cirrhosis. PHKG2 maps to chromosome 16p12.1 and many disease-causing mutations are known for this gene.

Muscle-Specific Phosphorylase Kinase Deficiency

A few cases of phosphorylase kinase deficiency restricted to muscle are known. Patients, both male and female, present either with muscle cramps and myoglobinuria with exercise or with progressive muscle weakness and atrophy. Phosphorylase kinase activity is decreased in muscle but normal in liver and blood cells. There is no hepatomegaly or cardiomegaly. The structural gene for the muscle specific form α subunit (αM) is located at Xq12. Mutations of this gene have been found in male patients with this disorder. The gene for muscle γ subunit (γM, PHKG1) is on chromosome 7p12.²⁹ No mutations in this gene have been reported so far.

Phosphorylase Kinase Deficiency Limited to Heart

These patients present with cardiomyopathy in infancy and rapidly progress to heart failure and death. Phosphorylase kinase deficiency is demonstrated in the heart with normal enzyme activity in skeletal muscle and liver. Studies have questioned the existence of cardiac-specific primary phosphorylase kinase deficiency because they did not find any mutations in the 8 genes encoding the phosphorylase kinase subunits.

Glycogen Synthetase Deficiency (GSD 0)

Deficiency of hepatic glycogen synthetase (GYS2) activity leads to a marked decrease of glycogen stored in the liver. The disease appears to be very rare in humans, and in the true sense, this is not a type of GSD because the deficiency of the enzyme leads to decreased glycogen stores.

The patients present in infancy with early-morning (before eating breakfast) drowsiness, pallor, emesis, and fatigue and sometimes convulsions associated with hypoglycemia and hyperketonemia. Blood lactate and alanine levels are low, and there is no hyperlipidemia or hepatomegaly. Prolonged hyperglycemia, glycosuria, and elevation of lactate with normal insulin levels after administration of glucose or a meal suggest a possible diagnosis of deficiency of glycogen synthetase. Definitive diagnosis requires a liver biopsy to measure the enzyme activity or identification of mutations in the liver glycogen synthetase gene, located on chromosome 12p12.2. Treatment consists of frequent meals, rich in protein, and nighttime supplementation with uncooked cornstarch. Most children with GSD 0 are cognitively and developmentally normal. Short stature and osteopenia are common features. The prognosis seems good for patients who survive to adulthood, including resolution of hypoglycemia, except during pregnancy.

Hepatic Glycogenosis with Renal Fanconi Syndrome (Fanconi-Bickel Syndrome)

This rare autosomal recessive disorder is caused by defects in the facilitative glucose transporter 2 (GLUT-2), which transports glucose in and out of hepatocytes, pancreatic β cells, and the basolateral membranes of intestinal and renal epithelial cells. The disease is characterized by proximal renal tubular dysfunction, impaired glucose and galactose utilization, and accumulation of glycogen in liver and kidney.

The affected child typically presents in the 1st yr of life with failure to thrive, rickets, and a protuberant abdomen from hepatomegaly and nephromegaly. The disease may be confused with type I GSD because a Fanconi-like syndrome can develop in type I disease patients.

Laboratory findings include glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting, hypophosphatemia, increased serum alkaline phosphatase levels, and radiologic findings of rickets. Mild fasting hypoglycemia and hyperlipidemia may be present. Liver transaminase, plasma lactate, and uric acid levels are usually normal. Oral galactose or glucose tolerance tests show intolerance, which could be explained by the functional loss of GLUT-2 preventing liver uptake of these sugars.

Tissue biopsy results show marked accumulation of glycogen in hepatocytes and proximal renal tubular cells, presumably owing to the altered glucose transport out of these organs. Diffuse glomerular mesangial expansion along with glomerular hyperfiltration and microalbuminuria similar to nephropathy in GSD Ia and diabetes have been reported.

Fanconi-Bickel syndrome is rare. Seventy percent of patients with a detectable GLUT-2 mutation have consanguineous parents. Most patients are homozygous for the disease-related mutations; some patients are compound heterozygotes. The majority of mutations detected thus far predict a premature termination of translation. The resulting loss of the C-terminal end of the GLUT-2 protein predicts a nonfunctioning glucose transporter with an inward-facing substrate-binding site.

There is no specific treatment. Growth retardation persists through adulthood. Symptomatic replacement of water, electrolytes, and vitamin D; restriction of galactose intake; and a diet similar to that used for diabetes mellitus presented in frequent and small meals with an adequate caloric intake may improve growth.

Type II Glycogen Storage Disease (Lysosomal Acid α-1,4-Glucosidase Deficiency, Pompe Disease)

Pompe disease, also referred to as GSD type II or acid maltase deficiency, is caused by a deficiency of acid α-1,4-glucosidase (acid maltase), an enzyme responsible for the degradation of glycogen in lysosomes. This enzyme defect results in lysosomal glycogen accumulation in multiple tissues and cell types, with cardiac, skeletal, and smooth muscle cells being the most seriously affected. The disease is characterized by accumulation of glycogen in lysosomes, as opposed to its accumulation in cytoplasm in the other glycogenoses.

Pompe disease is an autosomal recessive disorder with an incidence of approximately 1/40,000 live births. The gene for acid α-glucosidase is on chromosome 17q25.2. Multiple pathogenic mutations have been identified that could be helpful in delineating the phenotypes. An example is a splice site mutation (IVS1-13T → G), commonly seen in late-onset patients of white racial groups.

Treatment

Treatment options were once limited to supportive or palliative care. Specific enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (alglucosidase alfa, [Myozyme]) is available for treatment of Pompe disease. Recombinant acid α-glucosidase is capable of preventing deterioration or reversing abnormal cardiac and skeletal muscle functions (Fig. 81-3). ERT should be initiated as soon as possible and preferably <6 mo of age; the dose is 20 mg/kg given every 2 wk. A high-protein diet and exercise therapy may also be beneficial. Nocturnal ventilatory support, when indicated, should be used. It has been shown to improve the quality of life and is particularly beneficial during a period of respiratory decompensation.

Figure 81-3 Chest x-ray and muscle histology findings of an infantile-onset Pompe disease patient before (A) and after (B) enzyme replacement therapy. Note the decrease in heart size and muscle glycogen with the therapy.

(Modified from Amalfitano A, Bengur AR, Morse RP, et al: Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial, Genet Med 3:132–138, 2001.)

Glycogen Storage Diseases Mimicking Hypertrophic Cardiomyopathy

Deficiencies of lysosomal-associated membrane protein 2 (LAMP2, also called Danon disease) and AMP-activated protein kinase γ2 (PRKAG2) result in accumulation of glycogen in the heart and skeletal muscle. These patients present primarily as a hypertrophic cardiomyopathy, but can be distinguished from the usual causes of hypertrophic cardiomyopathy due to defects in sarcomere protein genes by their electrophysiologic abnormalities, particularly ventricular pre-excitation and conduction defects. The onset of cardiac symptoms, including chest pain, palpitation, syncope, and cardiac arrest, can occur between the ages of 8 and 15 yr for LAMP2 deficiency, younger than the average age for patients with PRKAG2 deficiency, which is 33 yr. Danon disease is transmitted as a X-linked trait and PRKAG2 mutations as a dominant trait.

The prognosis for LAMP2 deficiency is poor with progressive end-stage heart failure early in adulthood. Cardiomyopathy due to PRKAG2 mutations is compatible with long-term survival, although some patients may necessitate the implantation of a pacemaker and aggressive control of arrhythmias. A congenital form presents in early infancy with severe hypertrophic cardiomyopathy and a rapidly fatal course.

Type V Glycogen Storage Disease (Muscle Phosphorylase Deficiency, Mcardle Disease)

This is caused by the deficiency of muscle phosphorylase activity. Lack of this enzyme limits muscle ATP generation by glycogenolysis, resulting in muscle glycogen accumulation, and is the prototype of muscle energy disorders. A deficiency of myophosphorylase impairs the cleavage of glucosyl molecules from the straight chain of glycogen.

Type VII Glycogen Storage Disease (Muscle Phosphofructokinase Deficiency, Tarui Disease)

Type VII GSD is caused by a deficiency of muscle phosphofructokinase, which catalyzes the ATP-dependent conversion of fructose-6-phosphate to fructose-1,6-diphosphate and is a key regulatory enzyme of glycolysis. Phosphofructokinase is composed of 3 isoenzyme subunits (M [muscle], L [liver], and P [platelet]) that are encoded by different genes and differentially expressed in tissues. Skeletal muscle contains only the M subunit, and red blood cells contain a hybrid of L and M forms. Type VII disease is due to a defective M isoenzyme, which causes a complete enzyme defect in muscle and a partial defect in red blood cells.

Type VII GSD is an autosomal recessive disorder and is prevalent among Japanese people and Ashkenazi Jews. The gene for muscle phosphofructokinase is located on chromosome 12q13.3. A splicing defect and a nucleotide deletion in the muscle phosphofructokinase gene account for 95% of mutant alleles in Ashkenazi Jews. Diagnosis based on molecular testing is thus possible in this population.

Other Muscle Glycogenoses with Muscle Energy Impairment

Six additional defects in enzymes—phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, fructose-1,6- bisphosphate aldolase A, muscle pyruvate kinase, and β-enolase in the pathway of the terminal glycolysis—cause symptoms and signs of muscle energy impairment similar to those of types V and VII GSD. The failure of blood lactate to increase in response to exercise is a useful diagnostic test and can be used to differentiate muscle glycogenoses from disorders of lipid metabolism, such as carnitine palmitoyl transferase II deficiency and very long chain acyl-CoA dehydrogenase deficiency, which also cause muscle cramps and myoglobinuria. Muscle glycogen levels can be normal in the disorders affecting terminal glycolysis and assaying the muscle enzyme activity is needed to make a definite diagnosis. There is no specific treatment. Avoidance of strenuous exercise prevents acute attacks of muscle cramps and myoglobinuria. Avoidance of drugs such as statins, and malignant hyperthermia precautions for patients undergoing anesthesia should be followed.

Galactose-1-Phosphate Uridyl Transferase Deficiency Galactosemia

Two forms of the deficiency exist: Infants with complete or near complete deficiency of the enzyme (classic galactosemia) and those with partial transferase deficiency. Classic galactosemia is a serious disease with onset of symptoms typically by the 2nd half of the 1st wk of life. The incidence is 1/60,000. The newborn infant receives high amounts of lactose (up to 40% in breast milk and certain formulas), which consists of equal parts of glucose and galactose. Without the transferase enzyme, the infant is unable to metabolize galactose-1-phosphate, the accumulation of which results in injury to kidney, liver, and brain. This injury may begin prenatally in the affected fetus by transplacental galactose derived from the diet of the heterozygous mother or by endogenous production of galactose in the fetus.

Galactokinase Deficiency

The deficient enzyme is galactokinase, which normally catalyzes the phosphorylation of galactose. The principal metabolites accumulated are galactose and galactitol. Two genes have been reported to encode galactokinase: GK1 on chromosome 17q24 and GK2 on chromosome 15. Cataracts are usually the sole manifestation of galactokinase deficiency; pseudotumor cerebri is a rare complication. The affected infant is otherwise asymptomatic. Heterozygote carriers may be at risk for presenile cataracts. Affected patients have an increased concentration of blood galactose levels, provided they have been fed a lactose-containing formula. The diagnosis is made by demonstrating an absence of galactokinase activity in erythrocytes or fibroblasts. Transferase activity is normal. Treatment is dietary restriction of galactose.

Uridine Diphosphate Galactose-4-Epimerase Deficiency

The abnormally accumulated metabolites are similar to those in transferase deficiency; however, there is also an increase in cellular UDP-galactose. There are 2 distinct forms of epimerase deficiency. The 1st is a benign form discovered incidentally through neonatal screening programs. Affected persons are healthy and without problems; the enzyme deficiency is limited to leukocytes and erythrocytes. No treatment is required. The 2nd form of epimerase deficiency is severe, and clinical manifestations resemble transferase deficiency, with the additional symptoms of hypotonia and nerve deafness. The enzyme deficiency is generalized, and clinical symptoms respond to restriction of dietary galactose. Although this form of galactosemia is rare, it must be considered in a symptomatic patient with measurable galactose-1-phosphate who has normal transferase activity. Diagnosis is confirmed by the assay of epimerase in erythrocytes.

Patients with the severe form of epimerase deficiency cannot synthesize galactose from glucose and are galactose dependent. Because galactose is an essential component of many nervous system structural proteins, patients are placed on a galactose-restricted diet rather than a galactose-free diet.

Infants with the mild form of epimerase deficiency have not required treatment. It is advisable to follow urine specimens for reducing substances and exclude aminoaciduria within a few weeks of diagnosis while the infant is still on lactose-containing formula.

The gene for UDP-galactose-4-epimerase is located on chromosome 1 at 1p36. Carrier detection is possible by measurement of epimerase activity in the erythrocytes. Prenatal diagnosis for the severe form of epimerase deficiency, using an enzyme assay of cultured amniotic fluid cells, is possible.

Deficiency of Fructokinase (Essential or Benign Fructosuria)

Deficiency of fructokinase is not associated with any clinical manifestations. It is an accidental finding usually made because the asymptomatic patient’s urine contains a reducing substance. No treatment is necessary and the prognosis is excellent. Inheritance is autosomal recessive with an incidence of 1/120,000. The gene encoding fructokinase is located on chromosome 2p23.3.

Fructokinase catalyzes the 1st step of metabolism of dietary fructose: conversion of fructose to fructose-1-phosphate (see Fig. 81-1). Without this enzyme, ingested fructose is not metabolized. Its level is increased in the blood, and it is excreted in urine because there is practically no renal threshold for fructose. Clinitest results reveal the urinary-reducing substance, which can be identified as fructose by chromatography.

Deficiency of Fructose-1,6-Bisphosphate Aldolase (Aldolase B, Hereditary Fructose Intolerance)

Deficiency of fructose-1,6-bisphosphate aldolase is a severe condition of infants that appears with the ingestion of fructose-containing food and is caused by a deficiency of fructose aldolase B activity in the liver, kidney, and intestine. The enzyme catalyzes the hydrolysis of fructose-1,6-bisphosphate into triose phosphate and glyceraldehyde phosphate. The same enzyme also hydrolyzes fructose-1-phosphate. Deficiency of this enzyme activity causes a rapid accumulation of fructose-1-phosphate and initiates severe toxic symptoms when exposed to fructose.

Deficiency of Glucose-6-Phosphatase (Type I Glycogen Storage Disease)

Type I GSD is the only glycogenosis associated with significant lactic acidosis. The chronic metabolic acidosis predisposes these patients to osteopenia; after prolonged fasting, the acidosis associated with hypoglycemia is a life-threatening condition (Chapter 81.1).

Fructose-1,6-Diphosphatase Deficiency

Fructose-1,6-diphosphatase deficiency impairs the formation of glucose from all gluconeogenic precursors, including dietary fructose. Hypoglycemia occurs when glycogen reserves are limited or exhausted. The clinical manifestations are characterized by life-threatening episodes of acidosis, hypoglycemia, hyperventilation, convulsions, and coma. In about half of the cases, the deficiency presents in the 1st wk of life. In infants and small children, episodes are triggered by febrile infections and gastroenteritis if oral food intake decreases. The frequency of the attacks decreases with age. Laboratory findings include low blood glucose, high lactate and uric acid levels, and metabolic acidosis. In contrast to HFI, there is usually no aversion to sweets; renal tubular and liver functions are normal.

The diagnosis is established by demonstrating an enzyme deficiency in either liver or intestinal biopsy. The enzyme defect can also be demonstrated in leukocytes in some cases. The gene coding for fructose-1,6-diphosphatase is located on chromosome 9q22; mutations are characterized, making carrier detection and prenatal diagnosis possible. Treatment of acute attacks consists of correction of hypoglycemia and acidosis by intravenous glucose infusion; the response is usually rapid. Avoidance of fasting, aggressive management of infections and restriction of fructose and sucrose from the diet can prevent further episodes. For long-term prevention of hypoglycemia, a slowly released carbohydrate such as cornstarch is useful. Patients who survive childhood develop normally.

Phosphoenolpyruvate Carboxykinase (PEPCK) Deficiency

PEPCK is a key enzyme in gluconeogenesis. It catalyzes the conversion of oxaloacetate to phosphoenolpyruvate (see Fig. 81-4). PEPCK deficiency is both a mitochondrial enzyme deficiency and a cytosolic enzyme deficiency, encoded by 2 distinct genes.

The disease has been reported in only a few cases. The clinical features are heterogeneous, with hypoglycemia, lactic acidemia, hepatomegaly, hypotonia, developmental delay, and failure to thrive as the major manifestations. There may be multisystem involvement, with neuromuscular deficits, hepatocellular damage, renal dysfunction, and cardiomyopathy. The diagnosis is based on the reduced activity of PEPCK in liver, fibroblasts, or lymphocytes. Fibroblasts and lymphocytes are not suitable for diagnosing the cytosolic form of PEPCK deficiency because these tissues possess only mitochondrial PEPCK. To avoid hypoglycemia, patients should be treated with slow-release carbohydrates such as cornstarch, and fasting should be avoided.

Pyruvate Dehydrogenase Complex Deficiency

After entering the mitochondria, pyruvate is converted into acetyl coenzyme A (acetyl CoA) by the pyruvate dehydrogenase complex (PDHC), which catalyzes the oxidation of pyruvate to acetyl CoA, which then enters the tricarboxylic acid cycle for ATP production. The complex comprises 5 components: E₁, an α-keto acid decarboxylase; E₂, a dihydrolipoyl transacylase; E₃, a dihydrolipoyl dehydrogenase; protein X, an extra lipoate-containing protein; and pyruvate dehydrogenase phosphatase. The most common is a defect in the E₁ (see Fig. 81-4).

Deficiency of the PDHC is the most common of the disorders leading to lactic acidemia and central nervous system dysfunction. The central nervous system dysfunction is because the brain obtains its energy primarily from oxidation of glucose. Brain acetyl CoA is synthesized nearly exclusively from pyruvate.

The E₁ defects are caused by mutations in the gene coding for E₁ α subunit, which is X-linked. Although X-linked, its deficiency is a problem in both males and females even though only 1 E₁ α allele in females carries a mutation.

Deficiency of Pyruvate Carboxylase

Pyruvate carboxylase is a mitochondrial, biotin-containing enzyme essential in the process of gluconeogenesis; it catalyzes the conversion of pyruvate to oxaloacetate. The enzyme is also essential for Krebs cycle function as a provider of oxaloacetate and is involved in lipogenesis and formation of nonessential amino acids. Clinical manifestations of this deficiency have varied from neonatal severe lactic acidosis accompanied by hyperammonemia, citrullinemia, and hyperlysinemia (type B) to late-onset mild to moderate lactic acidosis and developmental delay (type A). In both types, patients who survived usually had severe psychomotor retardation with seizures, spasticity, and microcephaly. Some patients have pathologic changes in the brainstem and basal ganglia that resemble Leigh disease (see later). The clinical severity appears to correlate with the level of the residual enzyme activity. A “benign” form of PC deficiency characterized by recurrent attacks of lactic acidosis and mild neurologic deficits has also been described. Laboratory findings are characterized by elevated levels of blood lactate, pyruvate, alanine, and ketonuria. In the case of type B, blood ammonia, citrulline, and lysine levels are also elevated, which might suggest a primary defect of the urea cycle. The mechanism is likely caused by depletion of oxaloacetate, which leads to reduced levels of aspartate, a substrate for argininosuccinate synthetase in the urea cycle (Chapter 79.12).

Treatment consists of avoidance of fasting, and eating a carbohydrate meal before bedtime. During acute episodes of lactic acidosis, patients should receive continuous intravenous glucose. Aspartate and citrate supplements restore the metabolic abnormalities; whether this treatment can prevent the neurologic deficits is not known. Liver transplantation has been attempted; its benefit remains unknown. Diagnosis of pyruvate carboxylase deficiency is made by the measurement of enzyme activity in liver or cultured skin fibroblasts and must be differentiated from holocarboxylase synthetase or biotinidase deficiency.

Deficiency of Pyruvate Carboxylase Secondary to Deficiency of Holocarboxylase Synthetase or Biotinidase

Deficiency of either holocarboxylase synthetase (HCS) or biotinidase, which are enzymes of biotin metabolism, result in multiple carboxylase deficiency (pyruvate carboxylase and other biotin-requiring carboxylases and metabolic reactions) and in clinical manifestations associated with the respective deficiencies, as well as rash, lactic acidosis, and alopecia (Chapter 79.6). The course of HCS or biotinidase deficiency can be protracted, with intermittent exacerbation of chronic lactic acidosis, failure to thrive, seizures, and hypotonia leading to spasticity, lethargy, coma, and death. Auditory and optic nerve dysfunction can lead to deafness and blindness, respectively. Late-onset milder forms have also been reported. Laboratory findings include metabolic acidosis and abnormal organic acids in the urine. In HCS deficiency, biotin concentrations in plasma and urine are normal. Diagnosis can be made in skin fibroblasts or lymphocytes by assay for HCS activity, and in the case of biotinidase, in the serum by a screening blood spot.

Treatment consists of biotin supplementation, 5-20 mg/day, and is generally effective if treatment is started before the development of brain damage. Patients identified through newborn screening and treated with biotin have remained asymptomatic.

Both enzyme deficiencies are autosomal recessive traits. HCS and biotinidase are located on chromosome 21q22 and 3p25, respectively. Ethnic-specific mutations in the HCS gene have been identified. Two common mutations (del7/ins3 and R538C) in the biotinidase gene account for 52% of all mutant alleles in symptomatic patients with biotinidase deficiency.

Mitochondrial Respiratory Chain Defects (Oxidative Phosphorylation Disease)

The mitochondrial respiratory chain catalyzes the oxidation of fuel molecules and transfers the electrons to molecular oxygen with concomitant energy transduction into ATP (oxidative phosphorylation). The respiratory chain produces ATP from nicotinamide adenine dinucleotide (NADH) or FADH₂ and includes 5 specific complexes (I: NADH–coenzyme Q reductase; II: succinate–coenzyme Q reductase; III: coenzyme QH₂ cytochrome C reductase; IV: cytochrome C oxidase; V: ATP synthase). Each complex is composed of 4-35 individual proteins and, with the exception of complex II (which is encoded solely by nuclear genes), is encoded by nuclear or mitochondrial DNA (inherited only from the mother by mitochondrial inheritance). Defects in any of these complexes or assembly systems produce chronic lactic acidosis presumably due to a change of redox state with increased concentrations of NADH. In contrast to PDHC or pyruvate carboxylase deficiency, skeletal muscle and heart are usually involved in the respiratory chain disorders, and in muscle biopsy, “ragged red fibers” (indicating mitochondrial proliferation) are very suggestive when present (see Fig. 81-5). Because of the ubiquitous nature of oxidative phosphorylation, a defect of the mitochondrial respiratory chain accounts for a vast array of clinical manifestations and should be considered in patients in all age groups presenting with multisystem involvement. Some deficiencies resemble Leigh disease (see later), whereas others cause infantile myopathies such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), MERRF (myoclonus epilepsy, with ragged red fibers), and Kearns-Sayre syndrome (external ophthalmoplegia, acidosis, retinal degeneration, heart block, myopathy, and high cerebrospinal fluid protein) (Table 81-2; Chapters 591.2 and 603.4). There is a higher incidence of psychiatric disorders in adults with a primary oxidative phosphorylation disease than in the general population. Diagnosis requires demonstration of abnormalities of oxidative phosphorylation enzyme complex activities in tissues or of mitochondrial DNA (mtDNA) or a nuclear gene coding form mitochondrial functions, or both (Fig. 81-6). Analysis of oxidative phosphorylation complexes I-IV from intact mitochondria isolated from fresh skeletal muscle is the most sensitive assay for mitochondrial disorders. Specific criteria may assist in making a diagnosis (Table 81-3). Clues to the diagnosis of mitochondrial diseases are noted in Table 81-4.

Figure 81-6 Mutations in the human mitochondrial genome that are known to cause disease. Disorders that are frequently or prominently associated with mutations in a particular gene are shown in bold. Diseases due to mutations that impair mitochondrial protein synthesis are shown in blue. Diseases due to mutations in protein-coding genes are shown in red. ECM, encephalomyopathy; FBSN, familial bilateral striatal necrosis; LHON, Leber hereditary optic neuropathy; LS, Leigh syndrome; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy with ragged-red fibers; MILS, maternally inherited Leigh syndrome; NARP, neuropathy, ataxia, and retinitis pigmentosa; PEO, progressive external ophthalmoplegia; PPK, palmoplantar keratoderma; and SIDS, sudden infant death syndrome.

(From DiMauro S, Schon EA: Mitochondrial respiratory-chain diseases, N Engl J Med 348:2656–2668, 2003.

Table 81-3 MODIFIED WALKER CRITERIA APPLIED TO CHILDREN REFERRED FOR EVALUATION OF MITOCHONDRIAL DISEASE

ATP, adenosine triphosphate; RC, respiratory chain; SSAM, subsarcolemmal accumulation of mitochondria.

* Leigh disease, Alpers disease, LIMD, Pearson syndrome, Kearns-Sayre syndrome, MELAS, MERRF, NARP, MNGIE, and LHON.

^† (1) Unexplained combination of multisystemic symptoms that is essentially pathognomonic for an RC disorder, (2) a progressive clinical course with episodes of exacerbation or a family history strongly indicative of an mtDNA mutation, and (3) other possible metabolic or nonmetabolic disorders have been excluded by appropriate testing.

^‡ Added pediatric features: stillbirth associated with a paucity of intrauterine movement, neonatal death or collapse, movement disorder, severe failure to thrive, neonatal hypotonia, and neonatal hypertonia as minor clinical criteria.

From Scaglia F, Towbin JA, Craigen WJ, et al: Clinical spectrum, morbidity and mortality in 113 pediatric patients with mitochondrial disease, Pediatrics 114:925–931, 2004.

Treatment remains largely symptomatic and does not significantly alter the outcome of disease. Some patients appear to respond to cofactor supplements, typically coenzyme Q₁₀ plus L-carnitine at pharmacologic doses. The addition of creatine monohydrate and alpha-lipoic acid supplementation may add a significant benefit.

Leigh Disease (Subacute Necrotizing Encephalomyelopathy)

Leigh disease is a heterogenous neurologic disease that remains a neuropathologic description characterized by demyelination, gliosis, necrosis, relative neuronal sparing, and capillary proliferation in specific brain regions. In decreasing order of severity, the affected areas are the basal ganglia, brainstem cerebellum, and cerebral cortex (Chapter 591). The classic presentation is of an infant who presents with central hypotonia, developmental regression or arrest, and signs of brainstem or basal ganglia involvement. The clinical presentation is highly variable. Diagnosis is usually confirmed by radiologic or pathologic evidence of symmetric lesions affecting the basal ganglia, brainstem, and subthalamic nuclei. Patients with Leigh disease have defects in several enzyme complexes. Dysfunction in cytochrome C oxidase (complex IV) is the most commonly reported defect, followed by NADH-coenzyme Q reductase (complex I), PDHC, and pyruvate carboxylase. Mutations in the nuclear SURF1 gene, which encodes a factor involved in the biogenesis of cytochrome C oxidase and mitochondrial DNA mutations in the ATPase 6 coding region, are common molecular findings in patients with Leigh disease. Patients with Leigh disease frequently present with developmental delay, seizures, altered consciousness, failure to thrive, pericardial effusion, and dilated cardiomyopathy. The prognosis for Leigh syndrome is poor. In a study of 14 cases, there were 7 fatalities before the age of 1.5 yr.

Essential Pentosuria

Essential pentosuria is a benign disorder encountered principally in Ashkenazi Jews and is an autosomal recessive trait. The urine contains L-xylulose, which is excreted in increased amounts because of a block in the conversion of L-xylulose to xylitol due to xylitol dehydrogenase deficiency. The condition is usually discovered accidentally in a urine test for reducing substances; no treatment is required.

Transaldolase Deficiency

Few patients have reported symptoms that include liver cirrhosis, hepatosplenomegaly, severe neonatal hepatopathy, and cardiomyopathy. Biochemical abnormalities revealed elevated levels of arabitol, ribitol, and erythritol in the urine. Enzyme assay in the lymphoblasts and fibroblasts demonstrated low transaldolase activity, which was confirmed by mutations in the transaldolase gene. Transaldolase deficiency can be diagnosed by assessing urinary concentrations of polyols.

Ribose-5-Phosphate Isomerase Deficiency

Only 1 case of this disorder has been reported. The affected male had psychomotor retardation from early in life and developed epilepsy at 4 yr of age. Thereafter, a slow neurologic regression developed, with prominent cerebellar ataxia, some spasticity, optic atrophy, and a mild sensorimotor neuropathy. MRI of the brain at ages 11 yr and 14 yr showed extensive abnormalities of the cerebral white matter. Proton magnetic resonance spectroscopy (MRS) of the brain revealed elevated levels of ribitol and D-arabitol. These pentitols were also increased in urine and plasma similar to the patient found in transaldolase deficiency. Enzyme assays in cultured fibroblasts showed deficient ribose-5-phosphate isomerase activity, which was confirmed by a molecular study.

Sialidosis and Galactosialidosis

Sialidosis is an autosomal recessive disorder that results from the primary deficiency of neuraminidase due to mutations in the gene that encodes this protein, which is located on chromosome 10. In contrast, galactosialidosis is due to the deficiency of 2 lysosomal enzymes, neuraminidase and β-galactosidase. The loss of these enzymatic activities results from mutations in a gene located on chromosome 20 that encodes protective protein/cathepsin A (PPCA), which functions to stabilize these enzymatic activities. Neuraminidase normally cleaves terminal sialyl linkages of several oligosaccharides and glycoproteins. Its deficiency results in the accumulation of oligosaccharides, and the urinary excretion of sialic acid terminal oligosaccharides and sialylglycopeptides. Examination of tissues from affected individuals reveals pathologic storage of substrate in many tissues including liver, bone marrow, and brain.

The clinical phenotype associated with neuraminidase deficiency is variable and includes type I sialidosis which usually presents in the 2nd decade of life with myoclonus and the presence of a cherry red spot. These patients typically come to attention secondary to gait disturbances, myoclonus, or visual complaints. In contrast, type II sialidosis occurs as congenital, infantile, and juvenile forms. The congenital and infantile forms result from isolated neuraminidase deficiency, whereas the juvenile form results from both neuraminidase and β-galactosidase deficiency. The congenital type II disease is characterized by hydrops fetalis, neonatal ascites, hepatosplenomegaly, stippling of the epiphyses, periosteal cloaking, and stillbirth or death in infancy. The type II infantile form presents in the 1st yr of life with dysostosis multiplex, moderate mental retardation, visceromegaly, corneal clouding, cherry red spot, and seizures. The juvenile type II form of sialidosis, which is sometimes designated galactosialidosis, has a variable age of onset ranging from infancy to adulthood. In infancy, the phenotype is similar to that of GM₁ gangliosidosis, with edema, ascites, skeletal dysplasia, and cherry red spot. Patients with later-onset disease have dysostosis multiplex, visceromegaly, mental retardation, dysmorphism, corneal clouding, progressive neurologic deterioration, and bilateral cherry red spots. No specific therapy exists for any form of the disease, although studies in animal models have demonstrated improvement in the phenotype after bone marrow transplantation. The diagnosis of sialidosis and galactosialidosis is achieved by the demonstration of the specific enzymatic deficiency. Prenatal diagnosis using cultured amniotic cells is also possible.

Aspartylglucosaminuria (AGU)

This is a rare autosomal recessive lysosomal storage disorder, except in Finland, where the carrier frequency is estimated at 1/36. The disorder results from the deficient activity of aspartylglucosaminidase and the subsequent accumulation of aspartylglucosamine, particularly in the liver, spleen, and thyroid. The gene for the enzyme has been localized to the long arm of chromosome 4 and the cDNA has been cloned and sequenced. In the Finnish population, a single mutation in the gene (C163S) accounts for most mutant alleles, whereas outside of Finland, a large number of private mutations have been described. Affected individuals with AGU typically present in the 1st yr of life with recurrent infections, diarrhea, and hernias. Coarsening of the facies and short stature usually develop later. Other features include joint laxity, macroglossia, hoarse voice, crystal-like lens opacities, hypotonia, and spasticity. Psychomotor development is usually near normal until the age of 5 yr when a decline is noted. Behavioral abnormalities are typical and IQ values in affected adults are usually <40. Survival to adulthood is common, with most early deaths attributable to pneumonia or other pulmonary causes. Definitive diagnosis requires measurement of the enzyme in peripheral blood leukocytes. Molecular diagnosis by analysis of DNA for the C163S mutation is possible for Finnish patients. Several patients have undergone allogeneic bone marrow transplants with some reports of stabilization of the neurologic phenotype, but this approach has not been proven effective and no specific treatment is available. Prenatal diagnosis by the determination of the level of aspartylglucosaminidase in cultured amniocytes or chorionic villi has been reported.

α-Mannosidosis

This autosomal recessive disorder results from the deficient activity of α-mannosidase and the accumulation of mannose-rich compounds. The gene encoding the enzyme has been localized to chromosome 19p13.2-q12, although the cDNA has not been cloned. Affected patients with this disorder display clinical heterogeneity. There is a severe infantile form, or type I disease, and a milder juvenile variant, type II disease. All patients have psychomotor retardation, facial coarsening, and dysostosis multiplex. The infantile form of the disorder, however, is characterized by more rapid mental deterioration, with death occurring between the ages of 3 and 10 yr. Patients with the infantile form also have more severe skeletal involvement and hepatosplenomegaly. The juvenile disorder is characterized by onset of symptoms in early childhood or adolescence with milder somatic features and survival to adulthood. Hearing loss, destructive synovitis, pancytopenia, and spastic paraplegia have been reported in type II patients. No specific therapy exists for the disorder. The diagnosis is made by the demonstration of the deficiency of α-mannosidase activity in white blood cells or cultured fibroblasts, and prenatal diagnosis has also been achieved.

Congenital Disorders of Glycosylation (CDGs)

These are a heterogenous group of autosomal recessive disorders that result from defective protein and lipid glycosylation. The protein glycosylation disorders result from defects of N-glycosylation, combined N- and O-glycosylation, the dolichol pathway and the conserved oligomeric Golgi complex (COG). The more recently discovered lipid-glycosylation disorders include defects of ganglioside synthesis (GM3 synthase deficiency) and the GPI anchor system. In addition, there are patients with glycosylation defects for which the molecular and biochemical bases are not yet known.

To date, more than 30 CDG subtypes have been identified (Table 81-5). In general most CDG disorders are multisystemic and present with variable involvement of the central nervous system (most often hypotonia and ataxia), abnormal fat distribution, ocular movement defects, coagulation abnormalities, gastrointestinal symptoms including protein-losing enteropathy, retinitis pigmentosa, hormonal abnormalities, and in some cases dysmorphic features. CDG Type Ia, which results from mutations in the gene that encodes phosphomannomutase, is the most common form. The most consistent clinical features of this disorder include variable degrees of psychomotor retardation, subcutaneous fat pads and inverted nipples. Frequent neurologic findings in infancy include cerebellar atrophy (Fig. 81-7), hypotonia, weakness, hyperreflexia, and strokelike episodes.

Figure 81-7 Sagittal T2-weighted MR image shows severe spinal cord compression with myelopathy (white arrow), together with cerebellar atrophy (black arrow), and cortical atrophy of the parietal lobe (red arrow).

(From Schade van Westrum SM, Nederkoorn PJ, Schuurman PR, et al: Skeletal dysplasia and myelopathy in congenital disorder of glycosylation type 1A, J Pediatr 148:115–117, 2006.)

In childhood, ataxia, muscle atrophy, decreased deep tendon reflexes, toe walking, and continued strokelike episodes are observed. The latter events may be related to coagulopathies characterized by reduced antithrombin III, protein C and S in conjunction with abnormal levels of factors VIII, IX, XI, and XIII, which together increase risk for bleeding and thrombosis. Growth failure, liver dysfunction, retinal degeneration, and skeletal abnormalities have also been described. The skeletal features can include contractures, kyphoscoliosis, and pectus carinatum, all of which may be secondary to the neurologic effects of the disorder. Pericardial effusion in older patients and hypertrophic obstructive cardiomyopathy in the infant also may occur.

Among the other types, few have distinctive phenotypes. These include CDG Ib, which is characterized by protein-losing enteropathy and normal neurologic function; CDG If, which includes ichthyosis and growth retardation; and CDG IIf, in which macrothrombocytopenia is present.

Diagnostic testing for CDG types that result from defects of N-glycosylation begins with isoelectric focusing of N-glycosylated serum transferring. For some types further confirmation of the diagnosis by enzymatic analysis in fibroblasts or leukocytes and/or mutation analysis of the relevant gene is available. Although prenatal diagnosis by analysis of transferrin has been attempted, it has not proven reliable. Treatment of these disorders is symptomatic, except for CDGIb, which responds to oral mannose (100-150 mg/kg/day every 4-6 hr).