Treatment and Management of Hereditary Metabolic Myopathies

Glycogen Storage Disease Ii (Pompe Disease)

GSD type II (Pompe disease) is an autosomal recessive disorder caused by a lack of the lysosomal enzyme acid α-glucosidase, also called acid maltase . Acid α-glucosidase catalyzes the hydrolysis of glycogen to glucose within the acidic milieu of lysosomes. In acid α-glucosidase deficiency, the pool of glycogen that enters the lysosomes via autophagy is poorly degraded and overloads the lysosomal system. This leads to a progressive and irreversible cellular damage, mostly of the skeletal and cardiac muscle fibers.

The number of individuals born with GSD II is estimated to be 1 in 40,000. GSD II patients present with a continuous spectrum of phenotypes, with variable age at onset, variable severity, and variable rate of progression. A registry for confirmed GSD II patients has been established ( https://clinicaltrials.gov/ct2/show/NCT00231400 ) to understand the clinical course of the disease and to evaluate long-term treatment effectiveness in Pompe disease. Although there is a wide continuum, three forms have been described in more detail in the literature: (1) infantile GSD II (“classic” Pompe disease) presents in the first few months of life, and most infants die within 12 months from cardiorespiratory insufficiency; (2) “nonclassic” GSD II begins between ages 1 and 2 years; and (3) late-onset GSD has the onset of symptoms at any time after age 2 years, including GSD II presenting in childhood, adolescence, and adulthood ( Fig. 23.3 ). The natural course of late-onset GSD II was studied in detail in 54 Dutch patients from 45 families. In this large group of patients, the first complaints started at a mean age of 28 ± 14.3 years and were mostly related to mobility problems and limb-girdle weakness. Problems in running and playing sports were reported in approximately 70%, climbing stairs in about 30%, rising from an armchair in 20%, walking in 17%, and rising from a lying position in about 10% of the patients. Fatigue and muscle cramps were frequent first complaints. Approximately 60% of the adult patients had mild muscular symptoms during childhood, such as running more slowly than other children, being unable to keep up with other children during physical exercise or when playing games, as well as frequent falls or gait disturbance. In 28% of the patients, the final diagnosis was made more than 5 years after the first visit to a physician for disease-related symptoms. Some patients were initially diagnosed as having spinal muscular atrophy, Duchenne muscular dystrophy, or Becker muscular dystrophy. Nearly all patients experienced problems walking, varying from imbalance or a waddling gait to a complete inability to walk. About 50% of the group used a wheelchair, and the mean age at which patients started using a wheelchair was 46.1 ± 12.4 years. Approximately 40% required artificial ventilation at the time of investigation, either noninvasively by nose hood or facemask or invasively by tracheal cannula. The mean age at the start of artificial ventilation was 48.6 ± 16.3 years. The course of the late-onset GSD II form was shown to be quite variable between patients with respect to age at onset and rate of disease progression. There was also variability regarding the time at which patients first needed wheelchairs or artificial ventilation.

More than 500 different mutations within the GAA gene have been identified so far ( www.pompecenter.nl ). Approximately 63% of these lead to total loss of acid α-glucosidase, 12% to partial deficiency, and 25% are nonpathogenic. In general, there is good correlation among the nature of the mutation, the degree of residual enzyme activity, and the severity of the clinical presentation. Many patients with the late-onset form carry the c.-32-13T>G mutation on one allele with another GAA mutation on the second allele. Some of the mutations are found more frequently in different ethnic groups ( ). In the Netherlands, where extended molecular studies have been undertaken, a deletion at nucleotide 525 in exon 2 (del525T) leading to a frameshift (p.Glu176fsX45) and a large deletion of exon 18 (c.2481+102_2646+31del) are frequent. The p.R854X (c.2560C>T) mutation was frequently found among Blacks, and the p.D645E (c.1935C>A) mutation, among Asians.

Glycogen Storage Disease Iii

Glycogen-debranching enzyme plays an important role in the degradation of glycogen and has two independent catalytic activities, oligo-1,4→1,4-glucanotransferase and amylo-1,6-glucosidase, on a single 160-kDa protein. Both activities and glycogen binding are required for complete function. In GSD III, debrancher activities are virtually absent in affected organs; the deficiency causes excessive accumulation of abnormal glycogen with truncated outer chains. Most patients (GSD IIIa) have liver and muscle involvement of variable severity and clinical onset. Typical symptoms include fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy, and cardiomyopathy. Some patients have only liver involvement without evidence of a myopathy (GSD IIIb).

Glycogen Storage Disease Iv (Andersen Disease)

Andersen disease (GSD IV, or amylopectinosis) is an autosomal recessive disease caused by mutations in the glycogen branching enzyme 1 ( GBE1 ) gene, resulting in deficiency of the glycogen branching enzyme (GBE). GBE participates with glycogen synthase in the synthesis of glycogen by transferring a minimum of six α-1,4-linked glycosyl units into an α-1,6 position. The human GBE1 gene is located on chromosome 3p12.3 and has a coding sequence of 2.106 bp with 16 exons encoding a 702–amino acid GBE protein, which is ubiquitously expressed.

Deficiency of GBE results in the accumulation of abnormal, amylopectin-like polysaccharide with fewer branching points, more 1,4-linked units, and longer outer branches than normal glycogen. These are called polyglucosans , and they accumulate in all tissues to various degrees. The typical clinical phenotype of GSD IV as originally described is characterized by failure to thrive, hepatosplenomegaly, and progressive liver cirrhosis leading to death in early childhood. The neuromuscular presentation of GSD IV is remarkably heterogeneous, with four main variants. The perinatal form presents as fetal akinesia deformation sequence and is characterized by multiple congenital contractures (arthrogryposis multiplex congenita), hydrops fetalis, and perinatal death. The congenital form includes hypotonia, muscle wasting, neuronal involvement, inconsistent cardiomyopathy, and death in early infancy. The childhood form is dominated by myopathy, a neuromuscular form, or cardiomyopathy. The adult form can present as an isolated myopathy or as a multisystem disorder with central and peripheral nervous system involvement (adult polyglucosan body disease).

Glycogen Storage Disease V (Mcardle Disease)

Glycogenosis type V (GSD V), also known as myophosphorylase deficiency or McArdle disease , is the most common disorder of muscle carbohydrate metabolism with an estimated prevalence of 1 in 140,000 people ( ). GSD V is inherited in an autosomal recessive manner; patients have mutations in both alleles of the PYGM gene, which encodes myophosphorylase, the skeletal muscle isoform of glycogen phosphorylase. Myophosphorylase initiates the breakdown of muscle glycogen by removing α-1,4-linked glycosyl units from the outer branches of glycogen, which leads to the liberation of glucose-1-phosphate. Glucose-1-phosphate is normally converted to glucose-6-phosphate, which subsequently undergoes glycolysis, resulting in pyruvate production. Muscle pyruvate can be converted to lactate in anaerobic conditions, which is then released to the blood. Most of the pyruvate crosses the mitochondrial membrane, where it is converted to acetyl coenzyme A (acetyl-CoA) and further metabolized in the citric acid cycle. GSD V patients have absent myophosphorylase activity and are unable to mobilize muscle glycogen stores during exercise. However, they can take up glucose from the blood, which is converted to glucose-6-phosphate and metabolized via the intact glycolytic pathway.

GSD V typically presents with symptoms of exercise intolerance, such as myalgia, painful cramps, muscle contractures, premature fatigue, and episodic myoglobinuria during static or dynamic exercise. In most patients, a few minutes of rest relieves these symptoms. The onset of exercise intolerance usually occurs in childhood; fixed weakness and severe limitations of daily life activities may occur with increasing age.

We examined the muscle pain characteristics in 24 German GSD V patients using detailed pain questionnaires ( ); 23 patients complained of intermittent pain, and it was exercise induced in 15. Eight patients reported a more permanent muscle pain, and seven of those had superimposed exercise-induced myalgia. The patients with permanent pain were more often female, and they experienced more problems during higher-impact general activities, resulting in decreased sleep and more fatigue. This study showed that a substantial number of McArdle patients have permanent pain as a major complaint. Because this permanent pain is not related to age or disease duration, it might represent a clinically relevant subgroup of GSD V, differing from those with “pure” exercise-induced symptoms.

A specific feature of GSD V is the “second-wind” phenomenon, which denotes a sudden improvement in exercise capacity after a few minutes of sustained exercise or when resuming exercise after a brief rest. This second wind is produced by an exercise-related increase in the capacity for muscle oxidative phosphorylation, which correlates with increased availability of blood-borne fuels such as glucose and free fatty acids. It was recently shown that fat oxidation is augmented with the onset of second wind in GSD V patients during a prolonged, low-intensity exercise of 50% to 60% of maximal oxygen uptake capacity ( ). These results support the theory that the energy deficit in GSD V may be compensated by trials of moderate aerobic exercise to enhance fat oxidation.

In rare cases, GSD V may present with a severe generalized weakness at birth and death in childhood or with late-onset permanent muscle atrophy and weakness not preceded by symptoms of exercise intolerance.

Heterozygous individuals carrying one mutation in the PYGM gene may develop muscle symptoms that are considered to be caused by a critically low residual level (30%–40%) of myophosphorylase activity in muscle. A few GSD V families with an apparent autosomal dominant transmission have been reported. Molecular genetic analysis in such “pseudo-dominant” families identified either symptomatic heterozygous carriers in one parent or “true” recessive GSD V in one parent and heterozygosity in the other.

The most common mutation in European and North American GSD V patients is the nonsense mutation at p.R50X (previously referred to as p.R49X). More than 60 different mutations located throughout the entire PYGM gene on chromosome 11q13 have been reported. We performed molecular genetic analysis in a large cohort of 56 GSD V patients from Germany, the United Kingdom, and several other European countries. Allele frequency of the p.R50X mutation was 58%, and 71% of the McArdle disease patients carried this mutation on at least one allele. This study also detected 26 other less common mutations, with no clear genotype-phenotype correlation with respect to age of onset or severity ( ). A European Registry for GSD V patients and other rare muscle GSD forms was recently established to collect clinical and epidemiological data for future clinical trials ( http://www.euromacregistry.eu ).

Glycogen Storage Disease Vii (Tarui Disease)

Tarui disease (GSD VII) is caused by an inherited deficiency of muscle phosphofructokinase (PFK) and manifests with the combination of myopathy and hemolysis. Typically, GSD VII begins in early childhood and causes painful cramps or contractures on exercise, limitation of vigorous activity, hyperuricemia, a compensated hemolytic anemia, and, less frequently, myoglobinuria. The disease seems to be prevalent among people of Jewish-Russian ancestry, and the transmission is autosomal recessive. The clinical phenotype of GSD VII is similar to that of McArdle disease, so definitive diagnosis requires biochemical demonstration of the enzyme defect.

Glycogen Storage Disease

Phosphorylase kinase (Phk) is a regulatory protein kinase that stimulates glycogen breakdown. It receives input from hormonal and neuronal signals transmitted through the second messengers Ca ²⁺ and adenosine 3’,5’-cyclic monophosphate and responds by phosphorylating and thus activating glycogen phosphorylase. Phk deficiency alone accounts for approximately 25% of all cases of GSDs. Phk consists of four subunits in a hexadecameric complex (αβγδ) ₄ , and each of these subunits has isoforms or splice variants differentially expressed in different tissues. Consequently, Phk deficiency occurs in several subtypes that differ in mode of inheritance and tissue involvement.

Muscle-specific glycogenosis due to Phk deficiency can manifest in three different clinical forms. Frequently, the disorder becomes clinically apparent at a juvenile or early adult age, presenting with exercise intolerance, which includes pain, cramps, early fatigue, and sometimes myoglobinuria, resembling GSD V. A late-adult-onset form, manifesting with slowly progressive atrophy and weakness, and a neonatal form with generalized muscle hypotonia and respiratory insufficiency have also been described. Most patients with muscle-specific Phk deficiency are male, and mutations in the X-chromosomal gene of the muscle isoform of the Phkα subunit ( PHKA1 ) have been identified in a mouse mutant and in two male human patients ( ).

Other Muscle Glycogenoses

A family with cardiomyopathy and exercise intolerance caused by mutations in the muscle glycogen synthase gene ( GYS1 ) was reported by . Glycogen synthase catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of α-1,4-glycoside linkages (see Fig. 23.2 ). Although this autosomal recessive metabolic myopathy showed a lack of glycogen deposition in muscle biopsy specimens, it has been classified as muscle GSD type 0 (GSD 0) because of its enzyme defect within the first step of muscle glycogen synthesis.

Phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency (GSD X), lactate dehydrogenase (LDH) deficiency (GSD XI), and β-enolase deficiency (GSD XIII) are rare disorders that present mainly with symptoms of exercise intolerance. In addition to muscle symptoms, most of the glycolytic defects may produce signs of chronic hemolytic anemia. Phosphoglycerate kinase deficency and a subform of GSD IX are inherited in an X-chromosomal recessive manner and only males are reported to be affected, whereas the other muscle GSDs are autosomal recessive disorders. In aldolase A deficiency (GSD XII), muscle atrophy and weakness were associated with symptoms of exercise intolerance. Triosephosphate isomerase deficiency was described in a young girl with chronic hemolytic anemia and myopathy, and her muscle biopsy revealed elevated glycogen and mitochondrial alterations ( ). GSD XV is caused by digenic mutations in the glycogenin-1 gene (GYG1), the crucial primer enzyme of glycogen synthesis in muscle. GSD XV presents with predominant skeletal muscle symptoms (mainly adult onset limb-girdle muscle weakness) or cardiomyopathy ( ). Abnormally structured PAS-positive glycogen, partially resistant to α-amylase, accumulates as polyglucosan bodies in striated muscle or cardiac tissue.

An additional group of patients present with neuromuscular symptoms and periodic acid–Schiff (PAS)–positive vacuolar changes on muscle biopsy with increased glycogen concentration and without a definite enzymatic defect. These patients should be classified as having a muscle GSD with an unclear primary defect and should be further studied on a molecular level when we have more knowledge of the complex regulation and fine-tuning of glycogen metabolism in muscle.

Glycogen Storage Disease II

Enzyme replacement therapy (ERT) with recombinant alglucosidase alfa (Myozyme, Genzyme Corp., Framingham, MA) became available in 2006 for all forms of GSD II; this represents the first effective, disease-specific treatment for Pompe disease patients. It has been demonstrated that ERT improves cardiorespiratory and motor functions and prolongs survival in infantile GSD II patients ( ; , ; ; ; , ). In older children and adults, ERT improves or stabilizes skeletal muscle strength, muscle function, respiratory function, and also life expectancy ( ). However, the magnitude of the therapeutic responses varies considerably among individual patients. In a prospective multicenter study in GSD II adults, the majority benefit from long-term ERT, but many patients experience some secondary deterioration in muscle strength, walking ability, and/or pulmonary function after 3–5 years ( ).

Recommendations on starting and stopping the expensive ERT in adult patients were developed, based on experience of experts and evidence reported in the literature ( ). Patients receiving this treatment must have a confirmed diagnosis and presence of symptoms to start ERT. The commonly used treatment protocol consists of alglucosidase alfa 20 mg/kg body weight infusion every other week, although doses as high as 40 mg/kg per infusion have been used in individual patients. Regular 6-minute walking tests and forced vital capacity should be performed to follow the individual disease course and evaluate the treatment effects in late-onset GSD II patients receiving ERT. Stopping ERT should be considered in patients suffering from severe infusion-associated reactions or in patients with high antibody titers that significantly counteract the ERT effect. ERT continuation can be considered during pregnancy and lactation ( ).