There has been a dramatic increase in the understanding of disorders that affect the metabolism of muscle, particularly with regard to their biochemistry and molecular basis. A large number of clinical syndromes related to glycogen and lipid metabolism, mitochondrial function and ion channels are now known but only in some is muscle pathology helpful. In the following chapters we shall concentrate on conditions where pathological studies are helpful rather than attempting to give a detailed review of the biochemistry.
The breakdown of glycogen is an important source of energy in muscle ( ). Defects in any step in the glycolytic pathway can cause muscle fatigue, cramps or rhabdomyolysis, which is an important indicator of several metabolic problems ( ). The discovery by of deficient glucose-6-phosphatase in von Gierke’s disease opened the way for the recognition of a number of inborn errors of glycogen metabolism. The numerical classification suggested by Cori has found wide acceptance and they are numbered approximately in the order they were discovered (with some variation in the later forms) ( ). When the genetic defects have been identified, modifications of the nomenclature have been introduced ( ). Of the numerous established types to date, muscle symptoms are apparent in several, in particular exercise intolerance, cramps and fatigue, and other organs and tissues are also affected ( Table 17.1 ). Inheritance of glycogenoses is usually autosomal recessive.
| Type | Enzyme Deficiency /Gene | Common Clinical Features |
|---|---|---|
| Type 0, muscle | Glycogen synthase 1 GYS1 | Muscle weakness, exercise intolerance, cardiomyopathy |
| Type II Pompe disease | α-1,4-glucosidase (acid maltase) GAA | Severe infantile form: hypotonia, muscle weakness, cardiomyopathy, respiratory distress. May resemble SMA Milder forms: insidious onset in childhood or adolescence, hypotonia, progressive muscle weakness. May resemble LGMD |
| Type III Forbes disease Cori disease | Debrancher enzyme AGL | GSD IIIa: childhood reversible hepatomegaly and hypoglycaemia followed by distal or generalized progressive muscle weakness, exercise intolerance and cardiomyopathy |
| Type IV Andersen disease Amylopectinosis | Branching enzyme GBE1 | Typical form: early onset rapidly progressive and fatal liver disease. Later onset of myopathy if liver is transplanted Neuromuscular forms: Perinatal: polyhydramnios, arthrogryposis, fetal hydrops and early death Congenital/infantile: myopathy, hypotonia, muscle weakness, neuropathy, respiratory distress. May resemble SMA. Cardiomyopathy may occur Juvenile: myopathy with muscle weakness. Cardiomyopathy and nervous system involvement may occur Adult: isolated myopathy with muscle weakness or multiorgan polyglucosan body disease with nervous system involvement (adult polyglucosan body disease) |
| Type V McArdle disease | Myophosphorylase PYGM | Exercise intolerance, cramps, fatigue, myoglobinuria. Muscle weakness at increasing age |
| Type VII Tarui disease | Phosphofructokinase PFKM | Exercise intolerance, cramps, muscle weakness, fatigue, myoglobinuria and compensated haemolytic anemia. Neonatal arthrogryposis |
| Type IXb | Phosphorylase kinase PHKB | Liver disease, mild muscle involvement |
| Type IXd | Phosphorylase kinase PHKA1 (X-linked) | Exercise intolerance, muscle stiffness, cramps, myoglobinuria, muscle weakness |
| (Type IX) | Phosphoglycerate kinase PGK1 (X-linked) | Exercise intolerance, cramps, fatigue and myoglobinuria, haemolytic anemia and encephalopathy |
| Type X | Phosphoglycerate mutase PGAM2 | Exercise intolerance, cramps, fatigue, myoglobinuria |
| Type XI | Lactate dehydrogenase LDHA | Exercise intolerance, cramps, fatigue, myoglobinuria Skin lesions |
| Type XII | Aldolase A ALDOA | Exercise intolerance with episodes of rhabdomyolysis. Haemolytic anaemia |
| Type XIII | β-Enolase ENO3 | Exercise intolerance with myalgia, myoglobinuria |
| Type XIV | Phosphoglucomutase 1 PGM1 | Exercise intolerance, cramps, myoglobinuria CDG syndrome with congenital malformations, hormone deficiencies, dilated cardiomyopathy and hepatopathy. Abnormal transferrin isoforms |
| Type XV PGBM2 | Glygogenin-1 GYG1 | Muscle weakness and/or cardiomyopathy, exercise intolerance |
| PGBM1 | Haem-oxidized IRP2 ubiquitin ligase 1 ( HOIL-1 ) RBCK1 | Muscle weakness, cardiomyopathy Immunodeficiency in some cases |
| Glycogen storage disease of heart CMH6 | γ2 Subunit of AMP-activated protein kinase PRKAG2 (AD) | Cardiomyopathy. No skeletal muscle symptoms, but glycogen storage may occur |
On muscle biopsy there will often be an excessive deposition of glycogen, sometimes in vacuoles, but glycogen can easily be lost from the fibres and excess may not always be apparent. The degree of pathological change can vary considerably from a striking vacuolar myopathy with marked disruption of the muscle structure, as shown in many cases of type II glycogenosis, to a fairly normal histological pattern with very little structural change, as seen in some cases of types II, III and V glycogenosis. In phosphorylase (type V) and phosphofructokinase (type VII) deficiency the absence of the enzyme can readily be demonstrated histochemically ( ). The confirmation of the specific enzyme deficiency rests on an accurate biochemical study of the muscle biopsy, in addition to genetic investigations. Some lysosomal diseases of muscle, such as Danon disease, may have features similar to glycogenosis with vacuolization of muscle fibres (See Ch. 16 ) ( ).
Type II Glycogenosis (Pompe Disease, Acid Maltase Deficiency)
In type II glycogenosis the accumulation of glycogen is due to a deficiency of lysosomal acid maltase (α-1,4-glucosidase), which hydrolyzes maltose, linear oligosaccharides and the outer chains of glycogen to glucose. More than 200 different mutations have been described in the corresponding gene, GAA .
Clinical features
There are three main clinical types associated with acid maltase deficiency: a severe infantile form (Pompe disease), a juvenile form and adult-onset form ( ). Pompe disease is the most severe form of glycogenosis and is usually fatal in infancy. It is a generalized disease, with involvement not only of liver, heart and skeletal muscle but also many other tissues such as the central nervous system (CNS) and kidneys. Affected infants present either with severe hypotonia and weakness or with symptoms of cardiac or respiratory failure. The muscle weakness is due either to direct involvement of the muscle itself or to the involvement of the anterior horn cells of the spinal cord. These severely affected infants may look very similar clinically to cases of infantile spinal muscular atrophy (SMA) but can be distinguished by the associated diaphragmatic and cardiac involvement, which does not occur in SMA. The clinical picture in the milder cases is variable. Some cases may present with respiratory failure, and some may resemble a limb-girdle dystrophy. Cardiac involvement is a less consistent feature. By the currently used enzyme replacement treatment (ERT), the disease course is modified ( ).
Pathology
The amount of glycogen deposition in different tissues may vary considerably, and in some cases in cardiac muscle it may be minimal or completely absent. Muscle biopsies have a pronounced vacuolar appearance and periodic acid–Schiff (PAS) staining shows large deposits of glycogen in most fibres ( Fig. 17.1 ). The glycogen is digested by α-amylase, but some resistant material remains. The enzyme is present in lysosomes and there is, consequently, abundant acid phosphatase activity ( Fig. 17.2 ). Ultrastructurally, glycogen is characteristically seen in membrane-bound areas in muscle fibres, as well as in large lakes of freely dispersed granules ( Fig. 17.3 ; and see Fig. 5.70 ). In some cases very few myofibrils remain and the fibres are so disrupted that only the sarcolemma is left (see Fig. 17.1 ). Glycogen may be lost during processing for microscopy, and the excessive amount is therefore not always apparent. Although overall a biopsy may look disrupted and abnormal, sarcolemmal labelling of proteins such as dystrophin and β-spectrin is preserved.
The muscle pathology in milder cases is variable. The vacuolation may be extensive, or minimal, or may only be apparent in some fibres, mainly type 1 fibres ( Figs. 17.4 and 17.5 ) or, sometimes, both fibre types. Increased areas of acid phosphatase activity, however, are always apparent, and this is one of the most useful applications of the technique (see Figs. 17.4 and 17.5 ). Increased glycogen is also usually apparent (see Fig. 17.5 ).
The vacuoles may be surrounded by dystrophin and spectrin but not by laminins, although indentations of the sarcolemma show laminins and may appear like vacuoles in transverse section. There is also abundant major histocompatibility complex I (MHC-I) labelling associated with the vacuoles, on the sarcolemma of some fibres and also internally within them ( Fig. 17.6 ). Vacuoles without sarcolemmal proteins and the absence of labelling of certain lectins help to distinguishing vacuoles caused by defects in the gene for the lysosomal associated membrane protein 2 ( LAMP2 ), responsible for Danon disease ( ), and those seen in X-linked myopathy with excessive autophagy (XMEA; see Chapter 16, Chapter 6 ). In Pompe disease there is increased immunoreactivity to LAMP2 because of lysosomal proliferation.
Type III Glycogenosis (Debrancher Enzyme Deficiency)
discovered an abnormal glycogen with very short side chains (limit dextrin) in the liver and muscle of the 12-year-old girl recorded by . They postulated that the deficient enzyme was probably amylo-1,6-glucosidase (the debrancher enzyme), and this was subsequently confirmed ( ).
Clinical features
Type III glycogenosis is more benign than early-onset type II (Pompe) but affects both liver and skeletal muscle, and sometimes cardiac muscle ( ). Typical features include failure to thrive, hepatomegaly and episodes of hypoglycaemia at fasting from early childhood. Cardiomyopathy appears later in childhood, and skeletal muscle symptoms occur in childhood or adulthood. Liver cirrhosis may appear later. Skeletal muscle is often mildly affected in type III glycogenosis, which can present with hypotonia and proximal or distal weakness as well as exercise intolerance with pain. Some patients may develop severe muscle weakness affecting ambulation. A proportion of cases show only liver involvement with no muscle-specific symptoms (GSDIIIb). This may relate to differential expression of the six spliced forms produced from the single gene. The enzyme, in concert with phosphorylase, influences the number of glucose molecules of the glycogen, and the enzyme deficiency results in glycogen with short side chains (limit dextrin). This contrasts with the structurally abnormal glycogen (amylopectin) that occurs in type IV glycogenosis (branching enzyme deficiency).
Pathology
Muscle biopsies in type III glycogenosis show a vacuolar change with glycogen accumulation often at the periphery of fibres ( ) ( Fig. 17.7 ). At a later stage, the muscle may appear dystrophic with atrophy and connective tissue infiltration and no apparent glycogen storage ( Fig. 17.8 ).
Type IV Glycogenosis (Branching Enzyme Deficiency)
Branching enzyme deficiency was first described as a liver disease by . The enzyme is encoded by GBE1 and the clinical presentation may be extremely heterogeneous with variable tissue involvement possibly due to tissue-specific splice variants ( ).
Clinical features
The typical presentation is rapidly progressive liver disease with cirrhosis and death in early childhood ( ). However, several neuromuscular forms have been described (see Table 17.1 ), with perinatal, congenital/infantile, juvenile and adult-onset forms ( ). Pure myopathic forms have also been described ( ). The perinatal form is characterized by polyhydramnios, fetal hydrops, fetal akinesia deformation sequence (FADS), multiple contractures and early death. The congenital variant is a severe infantile disease that resembles infantile SMA. Patients present at birth with severe hypotonia, respiratory insufficiency and, sometimes, dilated cardiomyopathy generally without hepatic failure. The juvenile and adult forms generally present as an isolated myopathy, but cardiac or nervous system involvement may occur.
A special form first described by is known as adult polyglucosan body disease (APBD) and manifests as a chronic neurological disease with neurogenic bladder, spastic gate and peripheral neuropathy. Most but not all patients reported are of Ashkenazi Jewish background ( ), but there are exceptions ( ). Age at onset is usually 40–60 years, and the progressive course may eventually lead to wheelchair dependency. Mild cognitive impairment is common, and brain magnetic resonance imaging (MRI) shows features of leucoencephalopathy and atrophy of the medulla oblongata and spinal cord ( ). Polyglucosan bodies are widely distributed in the central and peripheral nervous system. Most patients with Ashkenazi Jewish background are homozygous for the c.986A>C (p.Y329S) variant.
Pathology
When muscle is affected, there is accumulation of PAS-positive material, some of which appears as polyglucosan ( Figs. 17.9 and 17.10 ), which may look filamentous or amorphous in comparison to normal glycogen particles (see Fig. 17.9c, d ). These polyglucosan bodies are to some extent resistant to α-amylase digestion ( Fig. 17.10c ). In the perinatal form some of the inclusions are birefringent ( Fig. 17.10d ) and the polyglucosan bodies are pleomorphic ( Fig. 17.11 ). Some of the inclusions may not even be PAS positive ( ).
