Defects in Metabolism of Carbohydrates

Clinical Manifestations

Patients with type I GSD may present in the neonatal period with hypoglycemia and lactic acidosis but more often present at 3-4 mo of age with hepatomegaly, hypoglycemic seizures, or both. Affected children often have a doll-like face with fat cheeks, relatively thin extremities, short stature, and a protuberant abdomen that is a consequence of massive hepatomegaly. The kidneys are also enlarged, whereas the spleen and heart are not involved.

The biochemical characteristics of type I GSD are hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Hypoglycemia and lactic acidosis can develop after a short fast. Hyperuricemia is present in young children; it rarely progresses to symptomatic gout before puberty. Despite marked hepatomegaly, the liver transaminase levels are usually normal or only slightly elevated. Intermittent diarrhea may occur in GSD I. In patients with GSD Ib, the loss of mucosal barrier function as a result of inflammation, which is likely related to the disturbed neutrophil function, seems to be the main cause of diarrhea. Easy bruising and epistaxis are common and are associated with a prolonged bleeding time as a result of impaired platelet aggregation and adhesion.

The plasma may be “milky” in appearance due to strikingly elevated triglyceride levels. Cholesterol and phospholipids are also elevated, but less prominently. The lipid abnormality resembles type IV hyperlipidemia and is characterized by increased levels of very-low-density lipoprotein, low-density lipoprotein, and a unique apolipoprotein profile consisting of increased levels of apolipoproteins B, C, and E, with relatively normal or reduced levels of apolipoproteins A and D. The histologic appearance of the liver is characterized by a universal distention of hepatocytes by glycogen and fat. The lipid vacuoles are particularly large and prominent. There is no associated liver fibrosis.

Although type I GSD affects mainly the liver, multiple organ systems are involved. Delayed puberty is often seen. Females can have ultrasound findings consistent with polycystic ovaries even though other features of polycystic ovary syndrome (acne, hirsutism) are not seen. Nonetheless, fertility appears to be normal, as evidenced in several reports of successful pregnancy in women with GSD I. Increased bleeding during menstrual cycles, including life-threatening menorrhagia, has been reported and could be related to the impaired platelet aggregation. Symptoms of gout usually start around puberty from long-term hyperuricemia. There is an increased risk of pancreatitis, secondary to the lipid abnormalities. The dyslipidemia, together with elevated erythrocyte aggregation, could predispose these patients to atherosclerosis, but premature atherosclerosis has not yet been clearly documented except for rare cases. Impaired platelet aggregation and increased antioxidative defense to prevent lipid peroxidation may function as a protective mechanism to help reduce the risk of atherosclerosis. Frequent fractures and radiographic evidence of osteopenia are common; bone mineral content is reduced, even in prepubertal patients.

By the 2nd or 3rd decade of life, some patients with type I GSD develop hepatic adenomas that can hemorrhage and turn malignant in some cases. Pulmonary hypertension has been seen in some long-term survivors of the disease. Iron-refractory anemia and an increased prevalence of thyroid autoimmunity are also being recognized.

Renal disease is another late complication, and most patients with type I GSD >20 yr of age have proteinuria. Many also have hypertension, renal stones, nephrocalcinosis, and altered creatinine clearance. Glomerular hyperfiltration, increased renal plasma flow, and microalbuminuria are often found in the early stages of renal dysfunction and can occur before the onset of proteinuria. In younger patients, hyperfiltration and hyperperfusion may be the only signs of renal abnormalities. With the advancement of renal disease, focal segmental glomerulosclerosis and interstitial fibrosis become evident. In some patients, renal function has deteriorated and progressed to failure, requiring dialysis and transplantation. Other renal abnormalities include amyloidosis, a Fanconi-like syndrome, hypocitraturia, hypercalciuria, and a distal renal tubular acidification defect.

Patients with GSD Ib can have additional features of recurrent bacterial infections from neutropenia and impaired neutrophil function. Oral involvement including recurrent mucosal ulceration, gingivitis, and rapidly progressive periodontal disease may occur in type Ib. Intestinal mucosa ulceration culminating in GSD enterocolitis is also common. Type 1b is also associated with a chronic inflammatory bowel disease (IBD)–like picture involving the colon that may be associated with neutropenia and/or neutrophil dysfunction; it may resemble ulcerative colitis or Crohn disease.

Diagnosis

The clinical presentation and laboratory findings of hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia lead to a suspected diagnosis of type I GSD. Neutropenia is noted in GSD Ib patients, typically before 1 yr of age. Neutropenia has also been noted in some patients with GSD Ia, especially those with the p.G188A variant. Administration of glucagon or epinephrine leads to a negligible increase, if any, in blood glucose levels, but the lactate level rises significantly. Before the availability of genetic testing, a definitive diagnosis required a liver biopsy. Gene-based variant analysis by single-gene sequencing or gene panels provides a noninvasive way to diagnose most patients with GSD types Ia and Ib.

Treatment

Treatment focuses on maintaining normal blood glucose levels and is achieved by continuous nasogastric (NG) infusion of glucose or oral administration of uncooked cornstarch. In infancy, overnight NG drip feeding may be needed to maintain normoglycemia. NG feedings can consist of an elemental enteral formula or only glucose or a glucose polymer to provide sufficient glucose to maintain euglycemia. During the day, frequent feedings with high-carbohydrate content are typically sufficient.

Uncooked cornstarch acts as a slow-release form of glucose and can be introduced at a dose of 1.6 g/kg every 4 hr for children <2 yr of age. The response of young children is variable. For older children, the cornstarch regimen can be changed to every 6 hr at a dose of 1.6-2.5 g/kg body weight and can be given orally as a liquid. Newer starch products, such as extended-release waxy maize starch, are thought to be longer acting, better tolerated, and more palatable. Medium-chain triglyceride (MCT) supplementation improves metabolic control, leading to improved growth in children. Since fructose and galactose cannot be converted directly to glucose in GSD type I, these sugars should be restricted in the diet. Sucrose (table sugar, cane sugar, other ingredients), fructose (fruit, juice, high-fructose corn syrup), lactose (dairy foods), and sorbitol should be avoided or limited. As a result of these dietary restrictions, vitamins and minerals such as calcium and vitamin D may be deficient, and supplementation is required to prevent nutritional deficiencies.

Dietary therapy improves hyperuricemia, hyperlipidemia, and renal function, slowing the development of renal failure. This therapy fails, however, to normalize blood uric acid and lipid levels completely in some individuals, despite good metabolic control, especially after puberty. The control of hyperuricemia can be further augmented by the use of allopurinol, a xanthine oxidase inhibitor. The hyperlipidemia can be reduced with lipid-lowering drugs such as β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrate (see Chapter 104 ). Microalbuminuria , an early indicator of renal dysfunction in type I disease, is treated with angiotensin-converting enzyme (ACE) inhibitors. Citrate supplements can be beneficial for patients with hypocitraturia by preventing or ameliorating nephrocalcinosis and development of urinary calculi. Thiazide diuretics increase renal reabsorption of filtered calcium and decrease urinary calcium excretion, thereby preventing hypercalciuria and nephrocalcinosis. Growth hormone (GH) should be used with extreme caution and limited to only those with a documented GH deficiency. Even in those patients, there should be close monitoring of metabolic parameters and for the presence of adenomas.

In patients with type Ib GSD, granulocyte and granulocyte-macrophage colony-stimulating factors are successful in correcting the neutropenia, decreasing the number and severity of bacterial infections, and improving the chronic IBD. The minimum effective dose should be used because side effects are noted on these agents, including splenomegaly, hypersplenism, and bone pain. Bone marrow transplantation has been reported to correct the neutropenia of type Ib GSD.

Orthotopic liver transplantation is a potential cure of type I GSD, especially for patients with liver malignancy, multiple liver adenomas, metabolic derangements refractory to medical management, and liver failure. However, this should be considered as a last resort because of the inherent short- and long-term complications. Large adenomas (>2 cm) that are rapidly increasing in size and/or number may necessitate partial hepatic resection. Smaller adenomas (<2 cm) may be treated with percutaneous ethanol injection or transcatheter arterial embolization. Recurrence of liver adenomas is a challenge and may potentiate malignant transformation in these patients, ultimately requiring a liver transplant.

Before any surgical procedure, the bleeding status must be evaluated and good metabolic control established. Prolonged bleeding times can be normalized by the use of intensive intravenous (IV) glucose infusion for 24-48 hr before surgery. DDAVP (1-deamino-8- d -arginine vasopressin) can reduce bleeding complications, but it should be used with caution because of the risk of fluid overload and hyponatremia when administered as an IV infusion. Lactated Ringer solution should be avoided because it contains lactate and no glucose. Glucose levels should be maintained in the normal range throughout surgery with the use of 10% dextrose. Overall, metabolic control is assessed by growth, improvement, and correction of the metabolic abnormalities, such as elevated lactate, glucose, triglyceride, cholesterol, and uric acid levels.

Prognosis

Previously, type I GSD was associated with a high mortality at a young age, and even for those who survived, the prognosis was guarded. Inadequate metabolic control during childhood can lead to long-term complications in adults. Clinical outcomes have improved dramatically with early diagnosis and effective treatment. However, serious complications such as renal disease and formation of hepatic adenomas with potential risk for malignant transformation persist. The ability to identify transformation to hepatocellular carcinoma in the liver adenomas remains a challenge: α-fetoprotein (AFP) and carcinoembryonic antigen (CEA) levels often remain normal in the setting of hepatocellular carcinoma.

Clinical Manifestations

In infancy and childhood, GSD type III may be indistinguishable from type I GSD because of overlapping features such as hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation ( Fig. 105.2 ). Splenomegaly may be present, but the kidneys are typically not affected. Hepatomegaly in most patients with type III GSD improves with age; however, liver fibrosis, cirrhosis progressing to liver failure, and hepatocellular carcinoma (HCC) are noted in many in late adulthood. Hepatic adenomas occur less often in individuals with GSD III than those with GSD I. The relationship between hepatic adenomas and malignancy in GSD III remains unclear. AFP and CEA levels are not good predictors of the presence of hepatocellular adenomas or malignant transformation. A single case of malignant transformation at the site of adenomas has been noted.

In patients with GSD type IIIa, the muscle weakness is slowly progressive and associated with wasting. The weakness is less remarkable in childhood but can become severe after the 3rd or 4th decade of life. Low bone mineral density in patients with GSD III put them at an increased risk of potential fractures. 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.

Although overt cardiac dysfunction is rare, ventricular hypertrophy is a frequent finding. Cardiac pathology has shown diffuse involvement of various cardiac structures, including vacuolation of myocytes, atrioventricular conduction, and hyperplasia of smooth muscles. Life-threatening arrhythmia and the need for heart transplant have been reported 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 (see Chapter 631.1 ). Polycystic ovaries are noted; some patients can develop hirsutism, irregular menstrual cycles, and other features of polycystic ovarian syndrome. Fertility does not appear to be affected; successful pregnancies have been reported.

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. Glucagon administration 2 hr after a carbohydrate meal provokes a normal increase in blood glucose; after an overnight fast, however, glucagon may provoke no change in blood glucose level. Serum creatine kinase levels can be useful to identify patients with muscle involvement, although normal levels do not rule out muscle enzyme deficiency.

Diagnosis

The histologic appearance of the liver is characterized by a universal distention of hepatocytes by glycogen and the presence of fibrous septa. The fibrosis and the paucity of fat distinguish type III glycogenosis from type I. The fibrosis, which ranges from minimal periportal fibrosis to micronodular cirrhosis, appears in most cases to be nonprogressive. Overt cirrhosis has been seen in some patients with GSD III.

Patients with myopathy and liver symptoms have a generalized enzyme defect (type IIIa). The deficient enzyme activity can be demonstrated not only in liver and muscle, but also in other tissues such as heart, erythrocytes, and cultured fibroblasts. Patients with hepatic symptoms without clinical or laboratory evidence of myopathy have debranching enzyme deficiency only in the liver, with enzyme activity retained in the muscle (type IIIb). Before the availability of genetic testing, a definitive diagnosis required enzyme assay in liver, muscle, or both. Gene sequencing now allows for diagnosis and subtype assignment in the majority of patients.

Treatment

The mainstay of treatment of GSD III is dietary management, as in GSD I, although it is less demanding. Patients do not need to restrict dietary intake of fructose and galactose, although simple sugars should be avoided to prevent sudden spikes in blood glucose levels. Hypoglycemia is treated with small, frequent meals high in complex carbohydrates, such as cornstarch supplements or nocturnal gastric drip feedings. Additionally, a high-protein diet during the daytime as well as overnight protein enteral infusion is effective in preventing hypoglycemia. The exogenous protein can be used as a substrate for gluconeogenesis which helps to meet energy needs and prevent endogenous protein breakdown. Protein in the diet also reduces the overall starch requirement. Overtreatment with cornstarch should be avoided as it can result in excessive glycogen buildup, which is detrimental and can lead to excessive weight gain. MCT supplementation is being considered as an alternative source of energy. There is no satisfactory treatment for the progressive myopathy other than recommending a high-protein diet and a submaximal exercise program. Close monitoring with abdominal MRI is needed to detect progression of liver fibrosis to cirrhosis and further to HCC. Liver transplantation has been performed in GSD III patients with progressive cirrhosis and/or HCC. There are reports of cardiac transplant in GSD III patients with end stage cardiac disease.

Clinical Manifestations

There is a high degree of clinical variability associated with type IV GSD. The most common and classic form is characterized by progressive cirrhosis of the liver and manifests in the 1st 18 mo of life as hepatosplenomegaly and failure to thrive. Cirrhosis may present with portal hypertension, ascites, and esophageal varices and may progress to liver failure, usually leading to death by 5 yr of age. Rare patients survive without progression of liver disease; they have a milder hepatic form and do not require a liver transplant. Extrahepatic involvement in some patients with GSD IV consists of musculoskeletal involvement, particularly cardiac and skeletal muscles, as well as central nervous system (CNS) involvement.

A neuromuscular form of type IV GSD has been reported, with 4 main variants recognized based on age at presentation. The perinatal form is characterized by a fetal akinesia deformation sequence (FADS) and death in the perinatal period. The congenital form presents at birth with severe hypotonia, muscle atrophy, and neuronal involvement, with death in the neonatal period; some patients have cardiomyopathy. The childhood form presents primarily with myopathy or cardiomyopathy. The adult form, adult polyglucosan body disease (APBD), presents as an isolated myopathy or with diffuse CNS and peripheral nervous system dysfunction, accompanied by accumulation of polyglucosan material in the nervous system. Symptoms of neuronal involvement include peripheral neuropathy, neurogenic bladder, and leukodystrophy, as well as mild cognitive decline in some patients. For APBD, a leukocyte or nerve biopsy is needed to establish the diagnosis because branching enzyme deficiency is limited to those tissues.

Diagnosis

Deposition of amylopectin-like materials can be demonstrated in liver, heart, muscle, skin, intestine, brain, spinal cord, and peripheral nerve in type IV GSD. Liver histology shows micronodular cirrhosis and faintly stained basophilic inclusions in the hepatocytes. The inclusions are composed of coarsely clumped, stored material that is PAS positive and partially resistant to diastase digestion. Electron microscopy (EM) shows, in addition to the conventional α and β glycogen particles, accumulation of the fibrillar aggregations that are typical of amylopectin. The distinct staining properties of the cytoplasmic inclusions, as well as EM findings, could be diagnostic. However, polysaccharides with histologic features reminiscent of type IV disease, but without enzymatic correlation, have been observed. The definitive diagnosis rests on the demonstration of the deficient branching enzyme activity in liver, muscle, cultured skin fibroblasts, or leukocytes, or on the identification of pathogenic variants in the GBE gene. Prenatal diagnosis is possible by measuring enzyme activity in cultured amniocytes, chorionic villi, or DNA-based methodologies.

Treatment

There is no specific treatment for type IV GSD. Nervous system involvement, such as gait problems and bladder involvement, requires supportive, symptomatic management. Unlike patients with the other liver GSDs (I, III, VI, IX), those with GSD IV do not have hypoglycemia, which is only seen when there is overt liver cirrhosis. Liver transplantation has been performed for patients with progressive liver disease, but patients must be carefully selected as this is a multisystem disease, and in some patients, extrahepatic involvement may manifest after transplant. The long-term success of liver transplantation is unknown. Individuals with significant diffuse reticuloendothelial involvement may have greater risk for morbidity and mortality, which may impact the success rate for liver transplant.

X-Linked Liver Phosphorylase Kinase Deficiency (From PHKA2 Variants)

X-linked liver PhK deficiency is one of the most common forms of liver glycogenosis in males. 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 boy 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, but can be severe. 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 PhK deficiency. It is increasingly being recognized that this disorder is not benign as previously thought, and there are patients with severe disease and long-term hepatic sequelae. In rare cases, liver fibrosis can occur and progress to cirrhosis.

Liver histology shows glycogen-distended hepatocytes, steatosis, and potentially mild periportal fibrosis. 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 III GSD. Fibrous septal formation and low-grade inflammatory changes may be seen.

The gene for the common liver isoform of the PhK α subunit, PHKA2, is located on the X chromosome (αL at Xp22.2). Mutations in the PHKA2 gene account for 75% of all PhK cases. X-linked liver PhK deficiency is further subdivided into 2 biochemical subtypes: XLG1, with measurable deficiency of PhK activity in both blood cells and liver, and XLG2, with normal in vitro PhK activity in blood cells and variable activity in liver. It is suspected that XLG2 may be caused by missense variants that affect enzyme regulation, whereas nonsense variants affecting the amount of protein result in XLG1. Female carriers are unaffected.

Autosomal Liver and Muscle Phosphorylase Kinase Deficiency (From PHKB Variants)

PhK deficiency in liver and blood cells with an autosomal recessive mode of inheritance has been reported. Similar to the X-linked form, chief symptoms in early childhood include hepatomegaly and growth retardation. Some patients also exhibit muscle hypotonia. In a few cases where enzyme activity has been measured, reduced PhK activity has been demonstrated in muscle. Mutations are found in PHKB (chromosome 16q12-q13), which encodes the β subunit, and result in liver and muscle PhK deficiency. Several nonsense variants, a single-base insertion, a splice-site mutation, and a large intragenic mutation have been identified. In addition, a missense variant was discovered in an atypical patient with normal blood cell PhK activity.

Autosomal Liver Phosphorylase Kinase Deficiency (From PHKG2 Variants)

This form of PhK deficiency is caused by pathogenic variants in the testis/liver isoform (TL) of the γ subunit gene (PHKG2). In contrast to X-linked PhK deficiency, patients with variants in PHKG2 typically have more severe phenotypes, with recurrent hypoglycemia, prominent hepatomegaly, significant liver fibrosis, and progressive cirrhosis. Liver involvement may present with cholestasis, bile duct proliferation, esophageal varices, and splenomegaly. Other reported presentations include delayed motor milestones, muscle weakness, and renal tubular damage. The spectrum of involvement continues to evolve as more cases are recognized. PHKG2 maps to chromosome 16p12.1-p11.2; many pathogenic variants are known for this gene.

Phosphorylase Kinase Deficiency Limited to Heart

These patients have been reported with cardiomyopathy in infancy and rapidly progress to heart failure and death. Recent studies have shown that this is not a case of cardiac-specific primary PhK deficiency as suspected previously, but rather linked to the γ ₂ subunit of adenosine monophosphate (AMP)–activated protein kinase (see later). The γ ₂ subunit is encoded by the PRKAG2 gene.

Diagnosis

PhK deficiency may be diagnosed by demonstration of the enzymatic defect in affected tissues. PhK can be measured in leukocytes and erythrocytes, but because the enzyme has many isozymes, the diagnosis can be easily missed without studies of liver, muscle, or heart. Individuals with liver PhK deficiency also usually have elevated transaminases, mildly elevated triglycerides and cholesterol, normal uric acid and lactic acid concentrations, and normal glucagon responses. Gene sequencing is used for diagnostic confirmation and subtyping of GSD IX.

The PHKA2 gene encoding the α subunit is most frequently involved, followed by the PHKB gene encoding the β subunit. Variants in the PHKG2 gene underlying γ-subunit deficiency are typically associated with severe liver involvement with recurrent hypoglycemia and liver fibrosis.

Treatment and Prognosis

The treatment for liver PhK deficiency is symptomatic. It includes a diet high in complex carbohydrates and proteins and small, frequent feedings to prevent hypoglycemia. Cornstarch can be administered with symptom-dependent dosage and timing (0.6-2.5 g/kg every 6 hr). Oral intake of glucose, if tolerated, should be used to treat hypoglycemia. If not, IV glucose should be given.

Prognosis for the X-linked and certain autosomal forms is typically good; however, long term complications are being recognized. Patients with mutations in the γ subunit typically have a more severe clinical course with progressive liver disease. Liver involvement needs to be monitored in all patients with GSD IX by periodic imaging (abdominal ultrasound or MRI every 6-12 mo) and serial hepatic function tests.

Clinical Manifestations

Pompe disease is broadly classified into infantile and late-onset forms. Infantile Pompe disease (IPD) is uniformly lethal without enzyme replacement therapy (ERT) with alglucosidase alfa. Affected infants present in the 1st day to weeks of life with hypotonia, generalized muscle weakness with a floppy infant appearance, neuropathic bulbar weakness, feeding difficulties, macroglossia, hepatomegaly, and hypertrophic cardiomyopathy, which if untreated leads to death from cardiorespiratory failure or respiratory infection, usually by 1 yr of age.

Late-onset Pompe disease (LOPD; juvenile-, childhood-, and adult-onset disease) is characterized by proximal limb girdle muscle weakness and early involvement of respiratory muscles, especially the diaphragm. Cardiac involvement ranges from cardiac rhythm disturbances to cardiomyopathy and a less severe, short-term prognosis. Symptoms related to progressive dysfunction of skeletal muscles can start as early as within 1 yr of age to as late as the 6th decade of life. The clinical picture is dominated by slowly progressive proximal muscle weakness with truncal involvement and greater involvement of the lower limbs than the upper limbs. The pelvic girdle, paraspinal muscles, and diaphragm are the muscle groups most seriously affected in patients with LOPD. Other symptoms may include lingual weakness, ptosis, and dilation of blood vessels (e.g., basilar artery, ascending aorta). With disease progression, patients become confined to a wheelchair and require artificial ventilation. The initial symptoms in some patients may be respiratory insufficiency manifested by somnolence, morning headache, orthopnea, and exertional dyspnea, which eventually lead to sleep-disordered breathing and respiratory failure. Respiratory failure is the cause of significant morbidity and mortality in LOPD. Basilar artery aneurysms with rupture also contribute to mortality in some cases. Small-fiber neuropathy presenting as painful paresthesia has been identified in some LOPD patients. Gastrointestinal disturbances such as postprandial bloating, dysphagia, early satiety, diarrhea, chronic constipation, and irritable bowel disease have been reported. Genitourinary tract involvement is not uncommon and may present as bladder and bowel incontinence, weak urine stream or dribbling. If untreated, the age of death varies from early childhood to late adulthood, depending on the rate of disease progression and the extent of respiratory muscle involvement. With the advent of ERT, a new natural history is emerging for both survivors of infantile and LOPD.

Laboratory Findings

These include elevated levels of serum creatine kinase (CK), aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH). Urine glucose tetrasaccharide, a glycogen breakdown metabolite, is a reliable biomarker for disease severity and treatment response. In the infantile form a chest x-ray film showing massive cardiomegaly is frequently the first symptom detected. Electrocardiographic findings include a high-voltage QRS complex, Wolff-Parkinson-White (WPW) syndrome, and a shortened PR interval. Echocardiography reveals thickening of both ventricles and/or the intraventricular septum and/or left ventricular outflow tract obstruction. Muscle biopsy shows the presence of vacuoles that stain positively for glycogen; acid phosphatase is increased, presumably from a compensatory increase of lysosomal enzymes. EM reveals glycogen accumulation within a membranous sac and in the cytoplasm. Electromyography reveals myopathic features with excessive electrical irritability of muscle fibers and pseudomyotonic discharges. Serum CK is not always elevated in adult patients. Depending on the muscle sampled or tested, the muscle histologic appearance and electromyography may not be abnormal.

Some patients with infantile Pompe disease who had peripheral nerve biopsies demonstrated glycogen accumulation in the neurons and Schwann cells.

Diagnosis

Diagnosis of Pompe disease can be made by enzyme assay in dried blood spots, leukocytes, blood mononuclear cells, muscle, or cultured skin fibroblasts demonstrating deficient acid α-glucosidase activity. Gene sequencing showing 2 pathogenic variants in the GAA gene is confirmatory. The enzyme assay should be done in a laboratory with experience using maltose, glycogen, or 4-methylumbelliferyl-α- d -glucopyranoside (4MUG) as a substrate. The infantile form has a more severe enzyme deficiency than the late-onset forms. Detection of percent residual enzyme activity is captured in skin fibroblasts and muscle. Blood-based assays, especially dried blood spots, have the advantage of a rapid turnaround time and are being increasingly used as the first-line tissue to make a diagnosis. A muscle biopsy is often done with suspected muscle disease and a broad differential; it yields faster results and provides additional information about glycogen content and site of glycogen storage within and outside the lysosomes of muscle cells. However, a normal muscle biopsy does not exclude a diagnosis of Pompe disease. Late-onset patients show variability in glycogen accumulation in different muscles and within muscle fibers; muscle histology and glycogen content can vary depending on the site of muscle biopsy. There is also a high risk from anesthesia in infantile patients. An electrocardiogram can be helpful in making the diagnosis in suspected cases of the infantile form and should be done for patients suspected of having Pompe disease before any procedure requiring anesthesia, including muscle biopsy, is performed. Urinary glucose tetrasaccharides can be elevated in the urine of affected patients, and levels are extremely high in infantile patients. Availability of next-generation sequencing panels and whole exome sequencing allows for identification of additional patients with Pompe disease, especially when the diagnosis is ambiguous. Prenatal diagnosis using amniocytes or chorionic villi is available.

Treatment

Enzyme replacement therapy with recombinant human acid α-glucosidase (alglucosidase alfa) 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. 105.3 ). ERT should be initiated as soon as possible across the disease spectrum, especially for babies with the infantile form, because the disease is rapidly progressive. Infants who are negative for cross-reacting immunologic material (CRIM) develop a high-titer antibody against the infused enzyme and respond to the ERT less favorably. Treatment using immunomodulating agents such as methotrexate, rituximab, and intravenous immune globulin (IVIG) have demonstrated efficacy in preventing the development of an immune response to ERT and immune tolerance. 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.

In addition to ERT, other adjunctive therapies have demonstrated benefit in Pompe patients. For patients with the late-onset disease, a high-protein diet may be beneficial. Respiratory muscle strength training has demonstrated improvements in respiratory parameters when combined with ERT. Submaximal exercise regimens are of assistance to improve muscle strength, pain, and fatigue. Other approaches are under clinical development to improve the safety and efficacy of enzyme delivery to affected tissues. These include use of chaperone molecules to enhance rhGAA delivery, and neoGAA, which is a second-generation ERT with a high number of mannose-6-phosphate (M6P) tags that enhances M6P receptor targeting and enzyme uptake. Gene therapy studies to correct the endogenous enzyme production pathways have shown promise.

Early diagnosis and treatment are necessary for optimal outcomes. Newborn screening using blood-based assays in Taiwan has resulted in early identification of Pompe cases and thus improved disease outcomes through the early initiation of ERT.

Clinical Manifestations

Symptoms usually first develop in late childhood or in the 2nd decade of life. Clinical heterogeneity is uncommon, but cases suggesting otherwise have been documented. Studies have shown that McArdle disease can manifest in individuals as old as 74, as well as in infancy in a fatal, early-onset form characterized by hypotonia, generalized muscle weakness, and respiratory complication. Symptoms are generally characterized by exercise intolerance with muscle cramps and pain. Symptoms are precipitated by 2 types of activity: brief, high-intensity exercise, such as sprinting or carrying heavy loads, and less intense but sustained activity, such as climbing stairs or walking uphill. Most patients can perform moderate exercise, such as walking on level ground, for long periods. Many patients experience a characteristic “second wind” phenomenon, with relief of muscle pain and fatigue after a brief period of rest. As a result of the underlying myopathy, these patients may be at risk for statin-induced myopathy and rhabdomyolysis. While patients typically experience episodic muscle pain and cramping from exercise, 35% of patients with McArdle disease report permanent pain that has a serious impact on sleep and other activities. Studies also suggest that there may also be a link between GSD V and variable cognitive impairment.

Approximately 50% of patients report burgundy-colored urine after exercise as a result of exercise-induced myoglobinuria secondary to rhabdomyolysis . Excessive myoglobinuria after intense exercise may precipitate acute renal failure.

Lab findings show elevated levels of serum CK at rest, which further increases after exercise. Exercise also elevates the levels of blood ammonia, inosine, hypoxanthine, and uric acid, which may be attributed to accelerated recycling of muscle purine nucleotides caused by insufficient ATP production. Type V GSD is an autosomal recessive disorder. The gene for muscle phosphorylase (PYGM) has been mapped to chromosome 11q13.

Diagnosis

The standard diagnosis for GSD V includes a muscle biopsy to measure glycogen content as well as enzyme and sequencing of PYGM . An ischemic exercise test offers a rapid diagnostic screening for patients with a metabolic myopathy. Lack of an increase in blood lactate levels and exaggerated blood ammonia elevations indicate muscle glycogenosis and suggest a defect in the conversion of muscle glycogen or glucose to lactate. The abnormal ischemic exercise response is not limited to type V GSD. Other muscle defects in glycogenolysis or glycolysis produce similar results (deficiencies of muscle phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, or LDH). An ischemic exercise test was once used to be a rapid diagnostic screening for suspected patients but was associated with severe complications and false-positive results. A nonischemic forearm exercise test with high sensitivity that is easy to perform and cost-effective has been determined to be indicative of muscle glycogenosis. However, as with the ischemic test, it cannot differentiate between abnormal exercise responses due to type V disease versus other defects in glycogenolysis or glycolysis or debranching enzyme (noted when the test is done after fasting).

The diagnosis is confirmed by molecular genetic testing of PYGM. A common nonsense variant, p.R49X in exon 1, is found in 90% of Caucasian patients, and a deletion of a single codon in exon 17 is found in 61% of Japanese patients. The p.R49X variant represents 55% of alleles in Spanish patients, whereas the p.W797R variant represents 14% and the p.G204S 9% of pathogenic alleles in the Spanish population. There seems to be an association between clinical severity of GSD V and presence of the D allele of the ACE insertion/deletion polymorphism. This may help explain the spectrum of phenotypic variability manifested in this disorder.

Treatment

Avoidance of strenuous exercise prevents the symptoms; regular and moderate exercise is recommended to improve exercise capacity. Glucose or sucrose given before exercise or injection of glucagon can greatly improve tolerance in these patients. A high-protein diet may increase muscle endurance, and low-dose creatine supplement has been shown to improve muscle function in some patients. The clinical response to creatine is dose dependent; muscle pain may increase on high doses of creatine supplementation. Vitamin B ₆ supplementation reduces exercise intolerance and muscle cramps. Longevity is not generally affected.

Clinical Manifestations

Although the clinical picture is similar to that of type V GSD, the following features of type VII GSD are distinctive:

• 1

  Exercise intolerance, which usually commences in childhood, is more severe than in type V disease and may be associated with nausea, vomiting, and severe muscle pain; vigorous exercise causes severe muscle cramps and myoglobinuria.

• 2

  Compensatory hemolysis occurs, as indicated by an increased level of serum bilirubin and an elevated reticulocyte count.

• 3

  Hyperuricemia is common and exaggerated by muscle exercise to a greater degree than that observed in type V or III GSD.

• 4

  An abnormal polysaccharide is present in muscle fibers; it is PAS positive but resistant to diastase digestion.

• 5

  Exercise intolerance is especially worse after carbohydrate-rich meals because the ingested glucose prevents lipolysis, thereby depriving muscle of fatty acid and ketone substrates. This is in contrast to patients with type V disease, who can metabolize blood borne glucose derived from either endogenous liver glycogenolysis or exogenous glucose; indeed, glucose infusion improves exercise tolerance in type V patients.

• 6

  The “second wind” phenomenon is absent because of the inability to break down blood glucose.

Several rare type VII variants occur. One variant presents in infancy with hypotonia and limb weakness and proceeds to a rapidly progressive myopathy that leads to death by 4 yr of age. A 2nd variant occurs in infancy and results in congenital myopathy and arthrogryposis with a fatal outcome. A 3rd variant presents in infancy with hypotonia, mild developmental delay, and seizures. An additional presentation is hereditary nonspherocytic hemolytic anemia . Although these patients do not experience muscle symptoms, it remains unclear whether these symptoms will develop later in life. One variant presents in adults and is characterized by a slowly progressive, fixed muscle weakness rather than cramps and myoglobinuria. It may also cause mitral valve thickening from glycogen buildup.

Diagnosis

To establish a diagnosis, a biochemical or histochemical demonstration of the enzymatic defect in the muscle is required. The absence of the M isoenzyme of phosphofructokinase can also be demonstrated in muscle, blood cells, and fibroblasts. Gene sequencing can identify pathogenic variants for the phosphofructokinase gene.

Treatment

There is no specific treatment. Strenuous exercise should be avoided to prevent acute episodes of muscle cramps and myoglobinuria. Consuming simple carbohydrates before strenuous exercise may benefit by improving exercise tolerance. A ketogenic diet has been reported to show clinical improvement in a patient with infantile GSD VII. Drugs such as statins should be avoided. Precautionary measures should be taken to avoid hyperthermia while undergoing anesthesia. Carbohydrate meals and glucose infusions have demonstrated worsening symptoms because of the body's inability to utilize glucose. The administered glucose tends to lower the levels of fatty acids in the blood, a primary source of muscle fuel.