α-Glucosidase Deficiency (Acid Maltase Deficiency, Pompe’s Disease, Type II Glycogenosis)

α-Glucosidase deficiency can manifest in three ways. In the neonatal period, it typically causes hypotonia, cardiomyopathy and, less frequently, hepatomegaly, and enlargement of the tongue. Cardiac and respiratory difficulties usually lead to death by 2 years of age.² The childhood manifestations are less dramatic, with progressive proximal weakness and no cardiac involvement. Adult patients usually present with a slowly progressive proximal myopathy, but up to one third of them may have respiratory failure.³

The serum creatine kinase level is typically raised, and electromyography reveals myopathic features, often in association with myotonic discharges. Muscle biopsy reveals a vacuolar myopathy: Vacuoles contain glycogen and show increased acid phosphatase activity. These features are nonspecific, and the diagnosis must be confirmed by enzyme assay either in muscle, fibroblasts, or lymphocytes. Genetic analysis of the α-glucosidase (GAA) gene often reveals the underlying mutation, and there is often a good relationship among type of mutation, biochemical defect, and clinical phenotype.⁴

Treatment is largely supportive, often involving nocturnal respiratory support after presentation in childhood or adulthood. Clinical trials of enzyme replacement therapy show promise, providing some hope for the future.^5,6

Debranching Enzyme Deficiency (Type III Glycogenosis)

Debranching enzyme deficiency can manifest in childhood or adulthood. Symptoms are more prominent in childhood and can include episodes of hypoglycemia. Manifestation in adulthood is usually with a slowly progressive distal myopathy without hepatosplenomegaly. The serum creatine kinase level is usually elevated, and electromyography demonstrates myopathy with occasional myotonic discharges.^l Muscle biopsy reveals a vacuolar myopathy, and the diagnosis is confirmed by biochemical assay in red or white blood cells or in muscle. Different clinical subtypes of debranching enzyme deficiency appear to be associated with different mutations in the AGL gene.⁷

Branching Enzyme Deficiency (Type IV Glycogenosis)

Branching enzyme deficiency can manifest in infants with muscle hypotonia and hepatosplenomegaly, leading to fatal liver cirrhosis. An infantile neuromuscular manifestation, often with cardiac or central nervous system involvement and sometimes simulating spinal muscular atrophy, is probably more common than previously suspected and should be considered in the differential diagnosis of the floppy infant syndrome.^8,9 The muscle biopsy reveals periodic acid–Schiff stain–positive, diastase-fast deposits. The diagnosis is confirmed by enzyme assay, and mutations may be found in the GBE gene.⁹ Treatment is supportive, including liver transplantation in early childhood.

Myophosphorylase Deficiency (McArdle’s Disease, Type V Glycogenosis)

Myophosphorylase deficiency typically manifests in late childhood or the early teenage years with muscle pain and weakness in the early stages of moderate exertion. Mild symptoms are rapidly relieved by rest, but after prolonged exercise, the symptoms may persist for days, accompanied by reversible painful contractures. Some patients are able to work through the initial symptoms and find that prolonged exercise becomes possible (the so-called “second wind” phenomenon), because of the mobilization of fatty acids as a fuel. By gradually “warming up” with light exercise, some patients reduce the intensity of their symptoms and increase exercise tolerance, presumably through the same mechanism. Myoglobinuria is common (often microscopic), and rhabdomyolysis may occur, even as a presenting feature.

The serum creatine kinase level is usually elevated between acute attacks but rises dramatically immediately after an episode of muscle pain. Electromyography may reveal nonspecific myopathic features, but the appearance is often normal. Forearm exercise testing characteristically reveals a high or even supranormal ammonia response, with a minimal or no increase in venous blood lactate levels during or immediately after exercise. This test is not without risk, inasmuch as it may provoke rhabdomyolysis or a forearm compartment syndrome. Skeletal muscle histochemistry study demonstrates glycogen storage and the absence of phosphorylase activity. Muscle phosphorylase deficiency can be confirmed biochemically (levels usually <5% of normal), but this is rarely necessary. In the majority of patients of European descent, molecular genetic analysis reveals the R49X mutation (>70%) in the PYGM gene,¹⁰ which is either homozygous or compound heterozygous, with another mutation in the coding region of the gene. Different common mutations are found in other populations.¹¹

Most patients adapt their lifestyles to avoid precipitating factors. There is evidence that an oral sucrose load before activity can increase exercise tolerance, but this may not be practical in every circumstance.¹² Myoglobinuria and rhabdomyolysis should be treated aggressively by increasing the fluid intake. Careful monitoring of the serum creatine kinase and phosphate levels is essential. Intravenous fluids, furosemide, and hemodialysis are sometimes required.

Phosphorylase b Kinase (Type VIII Glycogenosis)

Phosphorylase kinase is multimeric, with four subunits: α, β, γ, and δ. The enzyme is regulated by the α and β subunits, γ is the catalytic subunit, and δ regulates calcium sensitivity. The α subunit gene is on the X chromosome, and the other genes are on autosomes, which explains why phosphorylase b kinase deficiency can be either X-linked recessive or autosomal recessive.

In infancy, the disorder typically manifests with hepatosplenomegaly, hypotonia, and hypoglycemia or with cardiomyopathy. In later life, myopathic features are more prominent, including exercise intolerance, muscle stiffness, and weakness. Respiratory failure and cardiomyopathy can occur.

The serum creatine kinase level is often elevated. Glycogen is deposited within muscle fibers (typically type II), but with normal muscle phosphorylase activity. The diagnosis is confirmed by enzyme assay. Genetic analysis is complex because of the many subunits, and even with exhaustive sequencing of known genes, the results are often negative.¹³ Management is essentially supportive.

Phosphofructokinase Deficiency (Tarui’s Disease, Type VII Glycogenosis)

Approximately 90 cases of phosphofructokinase deficiency have been described in the literature.^13a The disorder has a clinical manifestation similar to that of myophosphorylase deficiency (McArdle’s disease, type V glycogenosis). In both disorders, the forearm ischemic exercise test produces a flat lactate response and a marked rise in ammonia levels. In myophosphorylase deficiency, the rise in venous ammonia can be abolished by infusing 5% dextrose, but in phosphofructokinase deficiency, this causes an even more dramatic rise in the ammonia level. Both disorders show a similar pattern of subsarcolemmal glycogen storage, but pockets of polyglucosan deposits are present in phosphofructokinase deficiency. The diagnosis is confirmed by biochemical assay of the muscle specific isoform of phosphofructokinase, followed by PFK-M gene analysis.¹⁴ Management is largely supportive. A high-protein diet may help, and rhabdomyolysis must be treated vigorously.

Disorders of the Distal Glycolytic Pathway

These disorders share similar clinical features, related to residual enzyme activity in skeletal muscle. Attacks of muscle pain and weakness are provoked by severe exercise, histochemical accumulation of glycogen may be scant or absent, and forearm exercise testing often yields a mildly positive result.

Phosphoglycerate Kinase Deficiency (Type IX Glycogenosis)

Phosphoglycerate kinase deficiency is an X-linked disorder that can manifest with either prominent myopathic or hemolytic features. A mixed phenotype has been observed, and central nervous system features may include mental retardation and epilepsy. A range of different mutations have been found in the PGK gene.¹⁵

Phosphoglycerate Mutase Deficiency (Type X Glycogenosis)

Phosphoglycerate mutase deficiency typically causes prominent exercise intolerance and is associated with a moderate rise in lactate level with a massive increase in ammonia on forearm exercise testing. This disorder has been associated with mutations in the PGAMM gene, which encodes the muscle-specific subunit of this dimeric enzyme.

Lactate Dehydrogenase Deficiency (Type XI Glycogenosis)

Lactate dehydrogenase deficiency typically manifests with exercise intolerance, myalgia, and, sometimes, a nonitchy erythematous rash on the extensor surfaces of the ankles and feet. The disorder is diagnosed by a biochemical assay of muscle lactate dehydrogenase activity and by mutation analysis of the LDH gene.¹⁶

Aldolase Deficiency (Type XII Glycogenosis)

Aldolase deficiency 2004 was described for the first time in one child. It is characterized by rhabdomyolysis, often linked to fever and associated with viral infection, leading to fixed weakness. The diagnosis is confirmed by measuring aldolase activity in skeletal muscle and by mutation analysis of the ALDOA gene.¹⁷

β-Enolase Deficiency (Type XIII Glycogenosis)

This enzyme defect has also been described in a single patient, a man with adult-onset exercise intolerance and chronically increased serum creatine kinase.^17a The patient was a compound heterozygote for mutations in the ENO3 gene, which encodes β-enolase, the isoform expressed predominantly in skeletal muscle.

Carnitine Uptake Defect

A genetic defect of the carnitine transporter typically manifests early in life with hypoglycemia and sudden death. In older patients, progressive myopathy and cardiomyopathy are present. The cardiomyopathy can be fatal; timely diagnosis is crucial because carnitine supplementation is curative.

Carnitine Palmitoyltransferase I Defect

There are three tissue-specific isoforms of CPT-I: the so-called liver (CPT-IA), muscle (CPT-IB), and brain (CPT-IC) isoforms. At present, only patients with deficiency of the liver enzyme have been well documented; they have severe hepatic encephalopathy.²¹

Carnitine: Acylcarnitine Translocase Defect

These patients usually have severe liver and cardiac problems early in life, but a milder form in which muscle weakness is common has been described.²²

Carnitine Palmitoyltransferase II Defect

The myopathic form of this deficiency usually manifests with exercise-induced muscle pain and no involvement of other tissues. A neonatal form is severe and often associated with neonatal death. The difference between the two forms of the disease is related to the degree of residual enzyme activity.²¹

Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Defect

Severe VLCAD manifests in newborns, but milder defects of this enzyme mimic CPT-II deficiency, with exercise-induced muscle pain.^23,24

Trifunctional Protein Deficiency and Isolated Long-Chain L-3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency

Although LCHAD is part of the TFP complex, isolated deficiencies of LCHAD and deficiencies of the whole TFP have been described. LCHAD deficiency tends to manifest with profound liver disease and death in infancy. Clinical features may also include cardiomyopathy, myopathy, pigmentary retinopathy, peripheral neuropathy, and sudden death.²⁵