Metabolic myopathies

Introduction

Metabolic myopathies refer to genetic skeletal muscle disorders that impact enzymes and proteins involved in the intermediary metabolism of glucose and free fatty acids.  Although some drugs and hormones can affect metabolism in skeletal muscle, the disorders reviewed here relate to genetic defects in skeletal muscle substrate oxidation. 

Classification:  Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies.   Mitochondrial encephalomyelopathies do not cause defects in a specific biochemical pathway and are technically not considered as metabolic myopathies.

Physiological basis:   The immediate source of energy for muscles is derived from the hydrolysis of ATP.   At rest, the major substrate for muscle in terms of ATP production comes from the metabolism of long-chain fatty acids.  Therefore, any disorder impairing beta oxidation of long-chain fatty acids in the mitochondria can lead to a myopathy.  During exercise, ATP is derived from the metabolism of carbohydrates, fatty acids, and ketones.  Early in the course of exercise (up to 45 minutes), energy is derived mainly from free glucose or glucose made available through glycogenolysis.   Subsequently, there is a shift toward the metabolism of fatty acids such that after a few hours, 70% of energy is derived from lipid breakdown.

Overview of skeletal muscle metabolism:

The continual supply of ATP to the fundamental cellular processes that underpin skeletal muscle contraction during exercise is essential for physical exercise in events lasting seconds to several hours.  Because the muscle stores of ATP are small, metabolic pathways must be activated to maintain the required rates of ATP synthesis.  These pathways include phosphocreatine and muscle glycogen breakdown, thus enabling substrate-level phosphorylation (‘anaerobic’) and oxidative phosphorylation by reducing equivalents from carbohydrate and fat metabolism (‘aerobic’). The relative contribution of these metabolic pathways is primarily determined by the intensity and duration of exercise. 

At the onset of exercise, an immediate drop in adenosine triphosphate (ATP) occurs; this leads to an increased flux through the adenylate kinase (AK) enzyme (ADP + ADP > AK > ATP + AMP), which is maintained by the adenosine monophosphate deaminase 1 (AMPD1) pathway.  The AMPD1 enzyme catalyzes the deamination of adenosine monophosphate (AMP) to inosine monophosphate which, after several enzymatic steps, leads to the conversion of xanthine to uric acid. This pathway is active in muscle contraction in healthy people but is enhanced in those with glycogen storage diseases and can lead to gout through increased uric acid production (myogenic hyperuricemia).  Traditionally, myoadenylate deaminase deficiency was considered to be a metabolic myopathy; however, the AMPD1 enzyme is not directly involved in substrate metabolism and its role in metabolic myopathies has been called into question for several reasons:  (1) the prevalence of the most commonly reported “pathogenic” stop gain variant in AMPD1 (c.34C>T;p.Gln12Ter) was present in 8.7% of a random sample of 282,334 healthy people (gnomad.broadinstitute.org/gene/ENSG00000116748?dataset=gnomad_r2_1) with approximately 2% being homozygous; (2) muscle blood flow is increased with no significant power reduction in skeletal muscle; homozygous patients who are AMPD1 deficient do not have exercise impairment or any of the predicted deleterious metabolic consequences in skeletal muscle. Thus, AMPD1 deficiency is not a metabolic myopathy and humans appear to compensate well for complete AMPD1 deficiency.

The creatine-phosphocreatine system is also activated at the onset of exercise, and adenosine diphosphate (ADP) is rephosphorylated by phosphocreatine to produce ATP and free creatine (Cr) via the cytosolic CK enzyme. A proton (H+) is also part of the reaction (ADP + PCr + H+ > CK > ATP + Cr) and this reaction is driven by the H+ produced by anaerobic glycolysis and glycogenolysis.  Skeletal muscle phosphocreatine stores are depleted after approximately 10 seconds of muscle contraction and are restored about 2 minutes after stopping exercise by mitochondrially derived ATP.  The activation of the creatine-phosphocreatine system is also important in stimulating mitochondrial respiration.  Genetic defects occur in the creatine-phosphocreatine system, including creatine synthesis defects (eg, arginine: glycine aminotransferase deficiency) and creatine transporter defects; however, the impact on exercise is unclear as these disorders lead to severe infantile and childhood encephalopathic symptoms.  At the onset of exercise, glycogenolysis and glycolysis are activated and [lactate- + H +] are formed by lactate dehydrogenase. After the first few minutes of muscle contraction, an increase in aerobic respiration occurs through the tricarboxylic acid (TCA) cycle and the mitochondria. The generation of pyruvate increases the flux of acetyl coenzyme A (CoA) into the TCA cycle via the pyruvate dehydrogenase pathway to form citrate and increase TCA cycle flux/content via anaplerosis.  Reducing equivalents (NADH + H+ and FADH2) from the TCA cycle and fatty acid β-oxidation enter the mitochondria at complex I and II, respectively, and drive protons to the intermembrane space and build up the proton motive force. The electrons from the oxidation ofNADH+H+ and FADH2 are used to reduce molecular oxygen to water at complex IV. The proton motive force is used to drive ATP synthesis at complex V. 

Exercise-mediated substrate fuel selection is determined by a number of factors, including exercise intensity and duration, training status, habitual dietary intake, and biological sex. Aerobic exercise intensity is usually measured as a percentage of maximal oxygen consumption (VO2max). Most people will oxidize free fatty acids at exercise intensities less than 50% VO2max, with the carbohydrate contribution increasing at higher exercise intensities and free fatty acids being predominant with longer-duration endurance exercise.  Women oxidize proportionately more lipid at any relative exercise intensity as compared to men.

The main source of carbohydrates during exercise is intramuscular glycogen and muscle glycogen stores, and mitochondrial and free fatty acid metabolic enzymes are higher following endurance exercise training.   In addition, the depletion of glycogen during the same absolute exercise intensity is less than after endurance exercise training.  Muscle glycogen can also be manipulated by diet, with the short-term (3-day) consumption of a high-carbohydrate diet resulting in a significant increase in muscle glycogen, especially in men.

In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever).

Metabolic myopathies can also be viewed as static or dynamic disorders.  Static myopathies are defined by the presence of fixed or progressive weakness.  On the other hand, dynamic myopathies are associated with exercise intolerance (exertional myalgias, cramps, and myoglobinuria) as the dominant clinical features.  Some metabolic defects are associated with both dynamic and static myopathy.

There are 16+ recognized glycogen storage diseases also called glycogenoses which is somewhat of a misnomer because some of these glycogenoses do not result in accumulation of glycogen in the tissues.  The glycogenoses predominantly affect the liver and muscle.  Type I (glucose-6-phosphate deficiency) and type VI (liver phosphorylase deficiency) affect the liver only.   Type II (lysosomal alpha-glucosidase deficiency), type V (phosphorylase deficiency), type VII phosphofructokinase deficiency), type X (phosphoglycerate mutase deficiency), and type XI (lactate dehydrogenase deficiency) almost exclusively cause muscle disease.

Glycogen storage diseases:  

Fatty acid oxidation defect:

Mitochondrial myopathy:

The metabolic myopathies can present in the neonatal and infant period as part of more systemic involvement with hypotonia, hypoglycemia, and encephalopathy; however, most cases present in childhood or adulthood with exercise intolerance (often with rhabdomyolysis) and weakness. The glycogen-storage diseases present during brief bouts of high-intensity exercise, whereas fatty acid oxidation defects and mitochondrial myopathies present during a long-duration/low-intensity endurance-type activity or during fasting or another metabolically stressful event (eg, surgery, fever). The clinical examination is often normal between acute events, and evaluation involves exercise testing, blood testing (creatine kinase, acylcarnitine profile, lactate, amino acids), urine organic acids (ketones, dicarboxylic acids, 3-methylglutaconic acid), muscle biopsy (histology, ultrastructure, enzyme testing), MRI/spectroscopy, and targeted or untargeted genetic testing.

Approach to patient with metabolic myopathy:

Disorders of carbohydrate metabolism

Disorders of lipid metabolism

Biochemistry of fatty  acid oxidation (Text Video1  Video2)

https://www.youtube.com/watch?v=BtAt1VwRxuY

https://www.youtube.com/watch?v=nBFSz63T1c0

https://www.youtube.com/watch?v=iKcvb1IihcM

CPT2 Deficiency:  autosomal recessive.  2nd to 3rd decade of life.  Muscular pain and myoglobinuria followed by intense or prolonged exertion usually by 2nd or 3rd decade of life.  Prolonged fasting and infection are other precipitating factors.  Neuromuscular exam is normal in between bouts of rhabdomyolysis.  

Systemic primary Carnitine Deficiency (CDSP) results and defective fatty acid oxidation.  It encompasses a broad clinical spectrum including the following:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331364/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1226127/

https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-015-0199-5

https://medlineplus.gov/genetics/gene/acadm/#resources

Screening Laboratory Tests for Mitochondrial and Metabolic Myopathies

Blood

CSF: Lactic acid: elevated; folate: decreased (not specific)

Urine: Organic acids: elevated lactic acid, pyruvic acid, tricarboxylic acid cycle intermediates, dicarboxylic acids, 3-methylglutaconic acid in some primary mitochondrial diseases and disorders of lipid metabolism

Other Laboratory Tests to Consider for Disease Mimicry

Pseudometabolic Myopathies

Pseudometabolic myopathies are structural myopathies that mimic metabolic myopathies by initially presenting as exercise-induced rhabdomyolysis.  Although energy depletion during exercise is a trigger, these disorders are structural or calcium dysregulation myopathies and are not directly involved in substrate metabolism per se.  The most common disorders with a pseudometabolic presentation are limb-girdle muscular dystrophies (TTN, SGCA, SGCB, SGCD, ANO5, and DYS gene mutations) and Becker muscular dystrophy (DMD gene mutation).   Exercise induces sarcolemmal damage, excessive calcium influx, or both resulting in rhabdomyolysis in these disorders.  Even before fixed proximal weakness occurs, a clue to their existence is a CK elevation persisting for more than 10 days following a bout of rhabdomyolysis.  

HyperCKemia has not been seen with the excitation-contraction coupling associated mutations (RYR1 and CACNA1S) seen in malignant hyperthermia susceptibility myopathies.  Exercise-induced rhabdomyolysis with autosomal dominant mutations in the RYR1 or CACNA1S gene has been reported.  These proteins link depolarization of the transverse tubule (dihydropyridine receptor, CACNA1S gene) to calcium release from the sarcoplasmic reticulum (ryanodine receptor, RYR1 gene) with mutations leading to isolated malignant hyperthermia, core myopathy, or exercise-induced rhabdomyolysis.   A correlation between RYR1 mutation phenotype and rhabdomyolysis does not seem to exist, although biallelic RYR1 variants are usually associated with a more severe fixed weakness phenotype/core myopathy.   Practically, patients with malignant hyperthermia should avoid exercise in the heat or when dehydrated and should wear a medical alert bracelet.  In addition, it is important to recognize that several acquired disorders can lead to exercise-induced rhabdomyolysis.  

Statins are one of the most commonly prescribed medications in the world and are a well-known trigger of rhabdomyolysis; they can even trigger an autoimmune process mediated by anti–3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies.  Statins result in a higher CK response to standardized exercise, can lead to myalgia in approximately 10% of individuals, and may unmask an underlying genetic metabolic myopathy.  

Vitamin D deficiency (<30 nmol/L) can lead to exercise intolerance, rhabdomyolysis, and persistent hyperCKemia, with a good clinical and laboratory response to vitamin D supplementation.  A reduction in or resolution of statin-associated myalgia was reported in vitamin D-deficient patients following supplementation.  Consequently, it is reasonable to measure vitamin D levels in all cases of exertional rhabdomyolysis or statin-associated myalgia/myopathy and replace them to achieve sufficient levels (typically >75 nmol/L).

Hypothyroidism can lead to a fixed myopathy with hyperCKemia and weakness but predisposes to exertional rhabdomyolysis.  Hypothyroidism can lead to mitochondrial dysfunction and carnitine depletion, which likely explains the relationship to exercise-induced rhabdomyolysis.  Although less common, hyperthyroidism can also lead to rhabdomyolysis.  It is therefore reasonable to check plasma thyroid-stimulating hormone (TSH) and thyroxine levels in cases of exertional rhabdomyolysis.

I usually check CK, serum lactate, pyruvate, total and free plasma carnitine, acylcarnitine/free carnitine ratio, amino acids, urine organic acids.  GDF-15 (growth differentiating factor – 15 from Mayo). EMG/NCS, ophthalmologic evaluation, GI (if MNGIE suspected), PFT, ECG, echocardiogram.  In my opinion EMG, genetics and muscle biopsy have been helpful. 

Case Vignettes

A 23-year-old woman presented to the emergency department with rhabdomyolysis following a 30-minute spin class.  Her creatine kinase (CK) peaked at 56,000 U/L (normal <220 U/L) during 2 days of in-hospital IV fluids, and she was discharged home with a requisition to measure CK 2 weeks later.  The CK 2 weeks later was still at 1200 U/L and remained at 1100 U/L 4 weeks after the initial event.  She was referred to the neuromuscular clinic as her CK did not normalize.  Her neurologic examination was normal except for hypertrophic calf muscles.  A dystrophin genetic test for deletions and duplications was normal, her DMD gene was sequenced, and a known pathogenic stop codon at c.6118-3C>A in IVS 42 was found.

COMMENT This is a typical case of a pseudo-metabolic myopathy and provided the patient with an accurate diagnosis of manifesting carrier state for Duchenne muscular dystrophy and allowed for appropriate genetic counseling given that she was engaged and planning a family.  Echocardiogram was normal, but echocardiography was recommended every 5 years or if she developed any cardiac symptoms.  The patient was able to slowly work up to cardiovascular exercise four times a week for 30 to 45 minutes, with no further rise of CK and no further bouts of rhabdomyolysis.