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:  

• McArdle (GSD V, myophosphorylase deficiency)

• Tarui (GSD VII, phosphofructokinase deficiency)

• GSD IX (phosphorylase b kinase deficiency)

• GSD X (phosphoglycerate mutase deficiency)

• GSD XI (lactate dehydrogenase deficiency)

• GSD XII (aldolase A deficiency)

• GSD XIII (β-enolase deficiency)

• Phosphoglucomutase deficiency

  • Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG.

  •  PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients’ symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. 

  • D-galactose

• Phosphoglycerate kinase 1 deficiency

Fatty acid oxidation defect:

• Carnitine palmitoyl transferase 2 deficiency

• Trifunctional protein deficiency

• Very-long-chain acyl-CoA dehydrogenase deficiency

Mitochondrial myopathy:

• mtDNA mutations (MELAS, cytochrome b, cytochrome c oxidase)

• nuclear DNA mutations (POLG, TK2)

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:

1. Determine whether it is a static vs dynamic process.  Fixed weakness may be absent in childhood but present in adulthood.

2. Muscle atrophy or hypertrophy may be seen in cases of muscular dystrophies associated with rhabdomyolysis.

3. If the patient has fixed or progressive weakness it is a static myopathy, Pompe disease needs to be considered, particularly if there is early respiratory failure.  A good test to do is the dried blood spot analysis.  A muscle bx may be needed, particularly if tests are negative. 

4. If the patient has exercise intolerance then it suggests a dynamic process.  An exercise forearm test can be done to determine if it is a disturbance in glycogen or fatty acid metabolism.  If exercise forearm test is abnormal (no rise in lactic acid despite rise in ammonia), then genetic testing for McArdle disease can be performed.  If this is negative, then do a muscle bx and metabolic assay to determine which enzyme is deficient.  

5. If the patient has myoglobinuria only after excessive exercise, fasting, or infection, then first step would be genetic testing for CPT2 deficiency.  If this is negative, proceed with a muscle biopsy and metabolic analysis. 

Disorders of carbohydrate metabolism

• • McArdle disease (myophosphorylase deficiency) or glycogensosis type V encoded by a gene on chromosome 11q12-q13.1.  It is the most common neuromuscular disorder of carbohydrate metabolism.   It is the most common glycogen storage disease affecting the skeletal muscle.  It is caused by autosomal recessive mutations in PYGM, encoding muscle glycogen phosphorylate which is an enzyme that catalyzes the first step of glycogenolysis to release glucose-1-phosphate (G1P) monomers from the intracellular glycogen polymers.  

    • Enzyme myophosphorylase catalyzes the conversion of glycogen into glucose-6-phosphate.  The enzyme is involved in the breakdown of glycogen to glucose for use in muscle.  Myophosphorylase removes 1,4 glycosyl residues from outer branches of glycogen and adds inorganic phosphate to form glucose-1 phosphate.  Deficiency of the enzyme results in the accumulation of glycogen.

  • Incidence: 1:100,000

  • Onset during the first 10 years of life.   Although its onset is at birth, it often goes undiagnosed until adulthood and well into the third and fourth decades.  History of exercise intolerance through childhood; complain of being tired and unable to keep up with their peers in physical activities and sports. 

  • Classic symptoms appear in the teenage years.  Fatigue and pain begin within the first few minutes of exercise (sprint, weight lifting, etc) particularly if it is strenuous and causes the person to slow down the intensity of exercise.  The person feels limited by a barrier to exert more and slows down.  The symptoms may be more in arms than in legs and can be asymmetric.  If exercise is continued, pain develops within the muscle, which at first is deep aching but then gives way to the rapid development of a painful tightening of muscles, becoming hard and contracted.  The muscle contracture may last for several hours and can be differentiated from a muscle cramp:  EMG is electrically silent, and the duration of the contracture is far longer than that of a physiological cramp, which usually disappears after a few minutes at most or by stretching the muscle.

  • It is a dynamic myopathy but with recurrent attacks of rhabdomyolysis, can result in a fixed weakness (static myopathy).  Myoglobulinuria occurs only about 50% of the time during physically strenuous exertional activity.  It may not be seen until the 2nd or 3rd decade of life.  ~10% of attacks are accompanied by renal failure.  Most patients have a normal motor exam in between (interictal) attacks.  Fixed contractures can develop with recurrent bouts of rhabdomyolysis and the condition turns from a dynamic to a static myopathy.  Rarely, do patients develop proximal muscle atrophy and weakness in late adult life rather than exercise intolerance.  Fixed weakness when it occurs has been described to involve proximal muscles of upper and lower limbs and can be asymmetric.  Isolated paraspinal involvement has rarely been reported.  MRI of skeletal muscles can reveal the involvement of paraspinal, semimembranosus, long-head of biceps femoris, moderate to severe fat replacement of subscapularis muscle, and involvement of tongue.  Some cases are reported with congenital weakness leading to rapidly progressive ventilatory failure within the first year of life.  

  • The second-wind phenomenon is seen as another aspect of the condition.  If, with the onset of fatigue, the patient slows down exercise but does not stop, the abnormal sensation of fatigue may disappear, 7 - 10 minutes later, and thereafter, the muscle may function more normally.  By gradually increasing the level of exercise, the patient may be able to break through the barrier and then may be able to perform exercise at an adequate level for longer periods.  The second-wind phenomenon is associated with a rise in fatty acid use as a substrate.  It is, however, the result of mobilization and use of blood-borne glucose.  Cardiac, neuronal, and metabolic adaptation occurs, presumably.  It results in a change in blood supply in the muscle from mobilization of blood-borne glucose.  There is an associated switch to fatty acid oxidation as the fuel substrate required for aerobic metabolism (usually after 10 minutes of exercise).

  • The second-wind phenomenon is not seen in patients with other disorders associated with exercise intolerance, such as glycogenosis types VII (phosphofructokinase deficiency, Tarui disease), VIII (phosphorylase b kinase deficiency), and X (phosphoglycerate mutase deficiency); acid maltase deficiency; mitochondrial myopathies; and disorders of lipid metabolism.

  • Pathological: Subsarcolemmal glycogen deposits (blebs) which are PAS positive. Intermyofibrillar vacuoles. Immunostain show absent staining for phosphorylase.

  • In patients with myophosphorylase deficiency (McArdle disease), serum CK is usually elevated even between episodes of myoglobinuria,

    • Exercise forearm test:

      • Given the very high sensitivity and specificity of the forearm ischemic test and nonischemic forearm exercise test, a normal test rules out every glycolytic and glycogenolytic defect with the possible exception of phosphorylase b kinase deficiency, which can be further evaluated with the aerobic cycling exercise test. There are many examples of aerobic cycling tests; however, a standard Bruce protocol test used for cardiac evaluation where the intensity/speed of either a cycle ergometer or treadmill is progressively increased until voluntary exhaustion with measurement of lactate and ammonia pre/post is sufficient.

      • A simple diagnostic clinical test is the non-ischemic exercise forearm test. 

        • A butterfly needle is inserted in the antecubital fossa, and baseline plasma lactate and ammonia are collected into wet ice-chilled tubes, followed by 1 minute of maximal handgrip dynamometry with a 9-second on, 1-second off ratio, and then blood samples after 1 minute.

        • Before the test used to have more blood draws.  Blood draws are obtained immediately, 1, 2, 4, 6, and 10 minutes post-exercise (serum lactic acid and ammonia and pyruvate concentrations should be measured). A single post exercise sample at 1 minute may be as sensitive as a standard 10-minute test. 

      • The normal response is a three- to fourfold rise in lactic acid and ammonia.

        • Sr. lactate is raised >20 mg/dL, and Sr. ammonia is raised >100 mcg/dL. 

      • If neither lactate nor ammmonia conc. increases during the test, the subject is not exercising strenuously and the test should be repeated.

      • In patients with glycolytic pathway disorders: myophosphorylase (McArdle disease), phosphorylase b kinase, phosphoglycerate mutase, phosphoglycerate kinase, phosphofructokinase, debranching enzyme, LDH, and enolase deficiencies, there in no rise in lactate. but there is normal rise in ammonia concentration. 

      • In myoadenylate deaminase deficiency there is a rise in lactate with no rise in ammonia concentration.

    • MRI of paraspinal and subscapularis muscles and tongue. 

    • EDX:  Usually normal.  Cramps/contracture is electrically silent.  Occasional myotonic discharges, fibrillation potentials, and PSW in some patients.  Early recruitment and myopathic potentials can also be seen. 

  • Management:

    • Diet: CHO diet, 75 gm of oral sucrose before exercise showed an improvement in exercise performance.  Benefits is short lasting, and repeated use may lead to weight gain.  High-protein diet  may be beneficial. 

    • Creatine: Low-dose creatine (60 mg/kg/d) showed an increase in exercise capacity. High-dose creatine (150 mg/kg/d) resulted in worsening of symptoms. 

    • Vit B6, 50 mg/day can enhance exercise tolerance. 

    • Ramipril 2.5 mg daily in ACE D/D genotype patients. 

    • Exercise: Avoid intense isometric exercises – e.g., weight-lifting. Avoid maximum aerobic exercises – e.g., sprinting. Warm-up for 15 minutes with low-level activity prior to moderate exercise promotes transition to 2nd wind phenomenon. Initial training done in Exercise Physiology Laboratory

  • Tarui disease (glycogenosis type VII) is caused by phosophofructokinase deficiency in muscle and erythrocytes.  PFK catalyzes the ATPase-dependent conversion of fructose 6 phosphate to fructose 1,6-diphosphate.  Human PFK comprises 3 distinct isoenzyme subunits (M-muscle, L-liver, and P-platelet).  Skeletal muscles have only the M isoform, while erythrocytes have a hybrid of M and L subunits.  PFK-M (muscle) is the gene on 12q13.  The symptoms in the disease are due to the inactivation of PFK on muscle and partial inactivation of PFK in RBC. 

    • It is less common than McArdle disease.  It has clinical features that are quite similar to McArdle disease:  Exercise intolerance, muscle pain, contractures, and relief from discomfort by rest.  However, PFK deficiency is not associated with the warm of phenomena and there is a lower incidence of myoglobinuria.  An inadequate increase of lactate on forearm exercise testing suggests a glycolytic defect. The hemolytic trait, as indicated by the reticulocytosis and increased bilirubin, and the elevated uric acid distinguish phosphofructokinase deficiency from McArdle disease.

    • Some individuals who are affected present with only hemolytic anemia without a myopathy.  

    • Positive ischemic exercise test, CK is elevated.

    • EMG is normal myopathic, or irritative.

    • Pathological: Subsarcolemmal glycogen deposits (blebs) which are PAS positive. Intermyofibrillar vacuoles. Immunohistochemical stains show absent staining for phosphofructokinase.

    • Treatment: Patients with PFK rely on free fatty acids as a fuel substrate during exercise.  If given glucose infusion or high -CHO meals they will experience increased exercise intolerance.  This is because the presence of glucose reduces the blood levels of free fatty acids.  

  • Cori's disease (glycogenosis type III) is caused by a deficiency in the debranching enzyme, leading to glycogen accumulation.  It accounts for ~25% of GSD.   The debranching enzyme has two separate catalytic functions: oligo-1,4-1,4-glucanotransferase activity and alpha-1,6 glucosidase activity.  Both the transferase and glucosidase activities are vital in breaking down glycogen into glucose, and a deficiency in either or both enzymatic functions leads to myopathy. 

    • Forms of GSD III: 

      • GSD IIIa, debranching enzyme is deficient in both liver and muscle.

      • GSD IIIb, the debranching enzyme is deficient only in the liver.

      • GSD IIIc, only the glucosidase function of the debranching enzyme is affected.

      • GSD IIId, only the transferase function of the debranching enzyme is affected. 

    • The onset of muscle weakness may be appreciated in infancy and childhood but usually does not manifest until adulthood, usually in the 3rd or 4th decade of life.  It presents often in adulthood with short stature, exercise intolerance, progressive distal weakness, peripheral neuropathy (sensorimotor), mild hepatomegaly, and cardiomyopathy.  Severe atrophy and weakness of muscles in the distal extremity (peroneal and calf muscles) occur in ~50% of cases. Tight heel cords are common and patients tend to toe-walk.  The distal involvement may be given an appearance of motor neuron disease or peripheral neuropathy.  They may be pseudohypertrophy of proximal muscle groups.  Some patients develop ventilatory muscle weakness with or without extremity weakness.  Ventilatory failure evolves fairly rapidly. Some patients develop cardiomyopathy.  

    • Serum CK levels are elevated (2-20 x ULN).  Deficiency of enzyme can be demonstrated with biochemical assay of muscle, fibroblasts, or lymphocytes.  Exercise forearm test: increased in ammonia without increase in lactate levels.  

    • PFTs are reduced, with restricted defects. 

    • TTE shows HOCM

    • ECG: conduction defects and arrhythmias. 

    • Electrodiagnostic studies demonstrate short polyphasic motor unit action potentials and fibrillation potentials.

    • Muscle biopsy reveals vacuolar myopathy with abnormal accumulation of glycogen in the subsarcolemmal and intermyofibrillar regions of muscle fibers.  These vacuoles stain intensely with PAS and are digested by diastase.  The do not stain with acid-phosphatase, unlike acid-maltase deficiency, suggesting that the glycogen does not primarily accumulate in lysosomes. On EM, free pools of glycogen are seen.  Although some glycogen appear in lysosomes they are not quite to the same extent as seen in acid-maltase deficiency.  Glycogen is found in heart, valves, smooth muscle of intramyocardial arteries, skin and peripheral nerves.  

    • Molecular Genetics and Pathogenesis:  Mutation in the gene AGL on 1p21.

    • Treatment: Low -CHO, high-protein diet.  Supportive therapy for CHF.  Liver transplantation in cirrhosis of liver and hepatocellular carcinoma.  

  • Andersen's disease (glycogenosis type IV) is caused by a deficiency of branching enzyme that helps make the branched glycogen molecule.  Several forms exist:

    • A classic and most common form of GSD IV known as Andersen disease, presents in infancy characterized by failure to thrive, hepatomegaly, and splenomegaly.  Muscular weakness and atrophy, hypotonia, hyporeflexia, and contractures may occur until these manifestations are overshadowed by the liver disease.  

    • There is an accumulation of amylopectin-like polysaccharide, also known as polyglucosan, in almost all tissues. Its clinical presentation is variable and involves the liver or the neuromuscular system.  

    • Mutations in the GBE1 gene, located on chromosome 3, have been identified in both phenotypes. Non-progressive hepatic form of the disorder is rarely reported. Neuromuscular forms are primarily seen and reported (3 variants) which should be viewed as a clinical continuum and not separate.

    • Neuromuscular forms: Either proximal or distal muscle groups are preferentially affected. 

    • Congenital phenotype can be subdivided into two clinical subgroups. 

      • The first is characterized by severe perinatal disorder presenting as fetal akinesia deformation sequence (FADS) with by multiple congenital contractures (arthrogryposis multiplex congenita), hydrops fetalis, and perinatal death. 

      • The second is characterized by severe congenital myopathy, inconsistently associated with cardiopathy, often simulating Werding-Hoffman disease

    • Juvenile form is dominated by myopathy or by cardiomyopathy.

    • Adult form presents with myopathic weakness

      • The adult form of branching enzyme deficiency can present as isolated myopathy or adult polyglucosan body disease, characterized by a combination of upper and lower motor neuron syndromes, sensory nerve involvement, ataxia, neurogenic bladder, cardiomyopathy and dementia.  There is predilection for polyglucosan body neuropathy in the Ashkenazi Jewish population.  

    • Serum CK may ben normal to slightly elevated.  EMG shows muscle membrane irritability and myopathic features, axonal sensorimotor neuropathy,  ECG shows conduction defects, complete AV block. Echocardiogram shows DCM.  

    • Treatment:  Liver transplantation in children has shown some beneficial results.  

  • Phosphoglycerate kinase deficiency. The gene for this disorder is on chromosome Xq13.

  • Phosphoglycerate mutase deficiency. The responsible gene is located at chromosome 7p12-13.

  • Lactate dehydrogenase deficiency.  11p15.4.

  • β-Enolase deficiency

    • A single patient has been reported with exercise intolerance, myalgias, and episodic hyper-CK-emia caused by a mutation in the gene encoding β-enolase.

  • Acid maltase deficiency, or Pompe's disease (glucogenosis type II), is an autosomal recessive disorder caused by a deficiency of lysosomal acid α-1,4 glucosidase in lysosomes on 17q21.23.  Missense, nonsense, and frame-shift mutations have been identified in the alpha-glucosidase gene. 

    • Lysosomal α-1,4 glucosidase breaks down glycogen to glucose.  It does so by cleaving 1,4 and 1,6 linkages in glycogen, maltose, and isomaltose.  Glycogen within lysosomes is degraded to glucose by alpa-glucosidase, and the deficiency of the enzyme results in glycogen accumulation.  It is hypothesized that the accumulating glycogen accumulates in the lysosomes and eventually rupture, thereby releasing proteases that degrade myofibrils and other important muscle proteins.  The accumulated glycogen may also displace  or replace important cellular organelles.   Patients do not exhibit exercise intolerance or myoglobinuria because metabolism of non-membrane-bound glycogen and glucose for energy metabolism is not impaired. 

    • Glycogen accumulation in tissues resulting in typical histopathologic findings on muscle biopsy, mainly type I muscle fibers, demonstrating vacuolated sarcoplasm with glycogen accumulation that stains strongly with acid phosphatase.  These vacuoles are prominent in muscles in infantile form, but not so apparent (25-75%) in childhood and adult forms.  The vacuoles stain intensely with PAS stain and are digested by diastase.  They stain intensely with acid phosphatase stain, confirming that the vacuoles are secondary lysosomes filled with glycogen.  On EM glycogen can be found free in the cytoplasm. There is necrotic and regenerating muscle fibers, variation in fiber size and fiber splitting.  In later stages, muscle fiber atrophy and increased endomysial connective tissue may be present.  Occasionally fiber type grouping and group atrophy may be seen due to motor neuron degeneration.  Glycogen accumulates in the AHC and bulbar nuclei as well as Schwann cells accounting of the superimposed neurogenic findings in some patients.  

    • Forms: 

      • Severe infantile form is called Pompe's disease

        • Infantile Pompe's disease, the classic form, is characterized by generalized weakness and hypotonia, cardiomegaly, macroglossia and mild to moderate hepatomegaly with onset in the first several months of life. The weakness and cardiomyopathy are progressive, and the disease is invariably fatal by 2 years of age, secondary to cardiorespiratory failure.  Feeding difficulties and ventilatory muscle weakness are common.

        • Incidence: 1:31,000 to 1 in 138,000.  CK levels are moderately elevated in infantile onset.

        • Dried blood spot test if positive > GAA genetic test.

        • Prenatal diagnosis is possible with amniocentesis or CVS.

          • Tx:  Intravenous recombinant α-glucosidase enzyme appears to be safe and beneficial for infants with Pompe disease

      • Childhood-onset type

        • Occurs by 1st decade of  life.  Mainly myopathic.  Manifests with proximal weakness, motor developmental delay, hypotonia, enlarged calves, waddling gait, and rarely with cardiomegaly, hepatomegaly, and mental retardation.  Significant lumbar lordosis may be present.  Children demonstrate a Gower maneuver to arise from the floor.  Affected children are commonly misdiagnosed with Duchenne or some other form of limb-girdle muscular dystrophy.  Rarely, acid maltase deficiency presents with rigidity of the spine.  Unlike infantile onset acid maltase deficiency, cardiomegaly, hepatomegaly, and macroglossia are uncommon.  Patients may die of pulmonary infections and respiratory failure.

        • Incidence: 1:53,000

      • Milder adult-onset variant

        • Mainly myopathic - Limb girdle type weakness.

        • Occurs in 3rd to 4th decades of life (upto 8th decade).

        • Manifests with slowly progressive proximal limb girdle weakness more than distal muscle weakness resembling polymyositis or LGMD, some have scapuloperoneal distribution of weakness.  Weakness can be sometime asymmetric, may involve face and tongue.  Patient complain of muscle pain, mostly in their thighs.  Shortness of breath, myalgia, axial weakness, trendelenburg gait, and typically weakness of the diaphragm, leading to neuromuscular respiratory problems.  MSR may be reduced.   16% to 33% of patients present with symptoms related to ventilatory insufficiency (dyspnea, frequent nocturnal arousals, morning headaches, and excessive daytime sleepiness). 

        • These patients do not typically have cardiomegaly, hepatomegaly, or mental retardation.

        • CK is normal, TTE. FVC (seated and supine shows restrictive defect with reduced FVC, reduced MIP and MEP, early fatigue of the diaphragm.) EMG (myotonia)

        • ,GAA enzyme activity (high sensitivity) correlates with disease severity.  Infantile onset disease is associated with a severe deficiency of alpha-glucosidase activity, while the less severe adult onset form has residual activity, upto 30% in muscle and 53% in lymphocytes.  A direct spot analysis of alpha-glucosidase activity is not the preferred initial screening test.  The activity level by this method does not correlate with disease severity.  If the dried blood spot test shows reduced enzyme activity, confirmatory testing may be performed using genetic testing of GAA gene.

        • Echocardiogram (septal hypertrophy).  MRI may show increased signal in tongue muscles (genioglossus). 

        • ECG abnormalities and arrhythmias can be seen.  

        • CT and MRI scans confirm the early and severe involvement of the abductor magnus and semimembranosus in the early stage of the disease and later fat infiltration of the long head of the biceps femoris, semitendinosus, and the anterior thigh muscles.  In advanced phases, selective sparing of the sartorius, rectus femoris, and gracilis muscles, and peripheral portions of the vastus lateralis are also evident.  Skeletal muscle MRI and CT also reveal early involvement of paravertebral and abdominal trunk muscles.

        • Motor and sensory nerve conduction studies are normal.  EMG revealed increased insertional and spontaneous activity in the form of fibrillation potentials, positive sharp waves, CRDs, and even myotonic discharges.  In mild forms of the disease these irritative discharges may be evident only in the paraspinal muscles.  Myopathic MUP are seen.

        • Lumizyme 20 mg/kg IV every 2 weeks.  A poor prognostic factor among infants is cross-reactive immunologic material (CRIM) status; CRIM-negative is strongly correlated with a poor outcome.  Although most CRIM-negative infants initially respond to continuous use of ERT, a resurgence of the natural progression of weakness subsequently ensues.   The CRIM negative infants develop antibodies directed against the infused recombinant alpha-glucosidase.  Presumably, those infants who do not produce even minute amount of alpha-glucosidase are at increased risk of mounting an antibody response against alpha-glucosidase, as it is seen to be foreign protein by the immune system.

        • Nexviazyme

        • Albuterol (8 mg bid): May improve response to enzyme replacement treatment  

        • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621909/

        • Review:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035871/

  • Danon disease, is an X-linked disorder caused by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The disorder is associated with early onset of proximal weakness and is usually associated with a cardiomyopathy and mental intellectual disability. Biopsies show non-rimmed, lysosomal vacuoles that do not immunostain with LAMP1 antibodies.

  • Glycogneosis type 0 (Glycogen synthase 1 deficiency): 

    • Clinical features: Only few patients have been reported with this rare disorder.  Individuals present with childhood onset of exercise intolerance and recurrent attacks of syncope for presumed cardiac origin.  Prolonged QT syndrome and sudden cardiac death occurred.  Mild proximal weakness may be evident.

    • Laboratory features: Exercise foreram test shows failure of lactate elevation.  MRI of the skeletal muscles show fatty degeneration of the gluteal and flexor muscles of the thigh.  CK levels have not been reported.

    • Muscle biopsy shows depletion of glycogen and skeletal, cardiac muscle as well as skin fibroblasts.  Phosphorylase activity may also be deficient of muscle fibers.

    • Molecular genetics and pathogenesis: Synthesis of glycogen requires glycogen synthase 1 which catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages.  Mutations in the GYS1 gene that encode glycogen synthetase 1 results in deficiency of this enzyme leading to the depletion of glycogen in skeletal and cardiac muscles.

    • Treatment: No specific medical therapies are available.

Disorders of Fatty Oxidation

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

Mitochondrial fatty acid oxidation is a complex process involving the transport of activated acyl-CoA moieties into the mitochondria, and sequential removal of two carbon acetyl-CoA units.  It is the main energy source for many tissues including the heart and skeletal muscle and is critically important during fasting or physiologic stress.  When the body’s glycogen stores are depleted, long-chain fatty acids are mobilized from adipose tissue and taken up by liver and muscle cells.  While short-chain and medium-chain fatty acids (C4 to C12) diffuse freely across plasma and mitochondrial membranes, the transport of longer-chain species (C14 to C20) depends at least in part on active transport, a high-affinity mechanism of major physiological importance in skeletal muscle, liver, and adipocytes. Two additional enzymatic steps are necessary for the complete oxidation of mono- and diunsaturated fatty acids: 2,4 dienoyl-CoA reductase and an enoyl-CoA isomerase, which allow for the complete oxidation of physiologically abundant fatty acids such as linoleate (C18:2) and oleate (C18:1).  

Each pathway cycle produces a molecule of acetyl-CoA and a fatty acid with two fewer carbons.  Under physiological conditions, the latter reenters the cycle until completely consumed.  In peripheral tissues, the acetyl-CoA is terminally oxidized in the Krebs cycle for ATP production. in the liver, the acetyl-CoA from fatty acid oxidation can instead be utilized for the synthesis of ketones, 3-hydroxybutyrate,  and acetoacetate, which are then exported for final oxidation by brain, heart,  and other tissues.  At least 25 enzymes and specific transport proteins are responsible for carrying out the steps of mitochondrial fatty acid metabolism, some of which have only recently been recognized,   Of these, defects in at least 22 have been shown to cause disease in humans.

Most patients with fatty acid oxidation defects are now identified through newborn screening by Tandem mass spectroscopy (T-MS) of carnitine esters in blood spots.  Unscreened patients can present throughout life.  In the first week of life, cardiac arrhythmias, hypoglycemia, sudden death, and occasionally facial dysmorphism and malformations, including renal cystic dysplasia are seen.  Symptoms in later infancy and early childhood may relate to the liver or cardiac or skeletal muscle dysfunction and include fasting or stress-related hypoketotic hypoglycemia or Reye-like syndrome, conduction abnormalities, arrhythmias or dilated or hypertrophic cardiomyopathy, and muscle weakness or fasting- and exercise-induced rhabdomyolysis. Adolescent- or adult-onset muscular symptoms, including rhabdomyolysis, and cardiomyopathy predominate. Diagnosis can usually be established even when the patient is asymptomatic, although analysis of samples during acute illness can uncover some mild cases. The most important single diagnostic test is the analysis of acylcarnitine esters in serum, plasma, or dried blood spots by tandem MS, which will identify characteristic compounds in many of these conditions. Other tests that may be useful include urine organic acids and acylglycines, free and total carnitine in serum and urine, and enzyme assays or flux studies in leukocytes or fibroblasts. 

Treatment of the acute encephalopathy of hypoketotic hypoglycemia is by intravenous glucose and l-carnitine. Long-term therapy involves replenishing carnitine stores with l-carnitine, and preventing hypoglycemia. In some cases this can be done by providing a snack or glucose polymers before bedtime, but in others requires continuous intragastric feeding.  Supplementation with medium-chain triglyceride (MCT) oil provides a fat source that can be utilized by patients with long-chain defects.

Defects of the β-Oxidation Spiral

Once in the mitochondrial matrix, acyl-CoA esters enter the β-oxidation spiral in which a series of four reactions successively removes two-carbon fragments of acetyl-CoA.  FAD-dependent acyl-CoA dehydrogenases first oxidize the acyl-CoA to 2,3-unsaturated (enoyl-) derivatives, and these are hydrated to 3-hydroxy esters by hydratases.  Oxidation to 3-ketoacyl-CoAs by NAD-requiring hydroxyacyl-CoA dehydrogenases and removal of acetyl-CoA by 3-ketothiolases follow, and the acyl-CoA, now two carbons shorter, reenters the spiral.  The acyl-CoA dehydrogenases differ from most other dehydrogenases because they utilize electron transfer flavoprotein (ETF) as a final electron acceptor, and thus can channel electrons directly into the ubiquinone pool of the electron transport machinery by way of ETF: ubiquinone oxidoreductase (ETF dehydrogenase, ETF:QO)

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

Screening Laboratory Tests for Mitochondrial and Metabolic Myopathies

Blood

• Lactic acid: elevated values in resting subjects, best performed without a tourniquet

• Amino acids: elevated alanine in fasting sample or alanine-to-lysine ratio greater than 4:1; elevated proline or sarcosine, low arginine, taurine, or citrulline in some mitochondrial myopathies.

• Carnitine: low free carnitine (may be low in infants and vegetarians), as well as abnormal acylcarnitine intermediates in some primary mitochondrial diseases and lipid myopathies.

• Creatine kinase: nonspecific but elevated in some mitochondrial and metabolic myopathies

• Growth differentiating factor-15: elevated in mitochondrial myopathy, false elevation in diabetes mellitus, not elevated in nonmitochondrial myopathies

• 3-Methylglutaconic acid: elevated in some mitochondrial disease 

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

• Systemic Evaluation (As Deemed Necessary Based On Clinical Presentation)

• Brain: MRI, EEG

• Muscle: EMG, polysomnography

• Nerve: nerve conduction study

• Eyes: ophthalmologic evaluation, electroretinogram

• Ears: audiogram

• Gastroenterology: consultation, swallowing study, gastric emptying test, stool fat

• Heart: ECG, echocardiogram

• Lung: pulmonary function test, cardiopulmonary exercise testing

Other Laboratory Tests to Consider for Disease Mimicry

• Hemogram, iron, and ferritin

• Complete metabolic panel

• Vitamin B12 level and methylmalonic acid

• Thyroid-stimulating hormone (TSH), free T4

• Hemoglobin A1c

• Paraneoplastic/autoimmune panel

• Selective vitamin levels, vitamin deficiencies, including micronutrient disorders seen in patients who have undergone bariatric surgery, on chronic total parenteral nutrition, self-induced restrictive diets, inflammatory bowel disease, or short bowel syndrome.

• Genetics:  

  • Check for DOK-7 mutation (congenital MG)

  • MD1

  • PABPN1, MYH2, SLC25A4, TWNK, POLG1, POLG2, TYMP, OPA1, RRM2B, DNA2, MT-TL1, RNASEH1.

  • The SLC22A5 gene is associated with autosomal recessive primary carnitine deficiency 

  • Fatty acid oxidation defects Genetics. All three enzyme defects are inherited as autosomal recessive traits, and the genes CPTIA, CPT2, and SLC25A20 (the gene for the translocase) have been localized to chromosomes 11 (11q13), 1 (1p32), and 3 (3p31.21), respectively.

  • LPIN-1 deficiency - recurrent rhabdomyolysis.  Lipin-1. Mutations in the lipin-1 gene (LPIN1) have been described recently in pediatric patients with recurrent rhabdomyolysis.  LPIN1 Deficiency - Metabolic Support UK 

Carnitine and Acylcarnitine Profile

The most sensitive and specific test for a fatty acid oxidation defect is the carnitine - acylcarnitine profile performed by liquid chromatography-tandem mass spectrometry.  This test may be abnormal between acute events; however, a false-negative test can occur in a non-stressed situation.  Patients should come fasting in the morning, which tends to increase the diagnostic yield.  Additionally, this test should be sent if a fatty acid oxidation defect is suspected during an acute metabolic crisis.

Carnitine plays a role in the transportation of fatty acids into the mitochondria and the catabolism of branched-chain amino acids, and it also assists in the excretion of organic acids in some IEMs.  Carnitine is mostly made in the liver by conjugation of lysine and methionine (essential amino acids).  Carnitine is found in meat.  An acyl group from many organic acids can be esterified to carnitine to form acylcarnitine. Accumulation of the different acylcarnitines can occur in IEM, and the distinct pattern of the types of acylcarnitines observed indicates where the enzyme deficiency occurs. Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common disorder of fatty acid β-oxidation,

Total and Free Carnitine levels:  This test measures the amount of carnitine in the blood.  It looks at how much usable or "free" carnitine is available.  It compares that with the total amount available in blood.  Carnitine is a compound that is present in nearly every part of the body.  Cells normally use fats (fatty acids) for energy.  Without carnitine, the body has trouble using fatty acids for energy, especially in periods of stress, illness, or fasting.  It uses sugar in the blood for energy instead.  Some people have a carnitine deficiency. If the body cannot use carnitine and there is a state of low blood sugar, the person feels weak, tired, and anemic. Some people even get symptoms of progressive weakness.

Primary Carnitine Deficiency (CDSP)

Primary carnitine deficiency is caused by a defect in the sodium-dependent high-affinity carnitine transporter which is encoded by the OCTN2 (SLC22A5) gene located on chromosome 5q31.1.  The incidence of CDSP is 1 in 50,000.

Carnitine is present in the plasma membrane of muscle and kidney (but not liver) cells, which ultimately limits β-oxidation by reducing the entry of acyl-CoA esters into mitochondria.  Free fatty acids are transported through the blood after intestinal absorption or mobilization from endogenous stores by the use of albumin as a carrier protein or in the form of triacylglycerols in lipoprotein complexes . Transport of free fatty acids intracellularly and through the cytoplasm is probably accomplished by a specific transport process; however, the mechanism of this step is not well characterized.  Before undergoing β-oxidation, free fatty acids must be activated to their corresponding acyl-CoA thioesters.  Long chain-specific acyl-CoA synthetases can be found in various subcellular locations but are thought to arise from a single gene product. Short- and medium-chain carboxylic acids directly enter the mitochondrial matrix where they are activated.  In contrast, long-chain fats are activated in the cytoplasm and require active transport into mitochondria.  Transport of long-chain acyl-CoAs requires at least two enzymes, a transporter protein, and the use of carnitine as an intermediate carrier molecule.  Carnitine is itself transported intracellularly by a specific transporter protein. Two carnitine transporters have been described, one specific to the liver and a second with a more ubiquitous distribution including kidney, muscle, and fibroblasts.  

Long-chain acyl-CoAs are conjugated to carnitine by carnitine palmitoyl transferase I (CPT I).  This enzyme is located on the inner aspect of the outer mitochondrial membrane. Tissue-specific isoforms of this enzyme exist for muscle, liver, and brain.  Long-chain acylcarnitines are then passed to carnitine palmitoyl transferase II (CPT II) in the inner mitochondrial membrane by a translocase.  Carnitine is freely filtered by the kidney and must be reabsorbed from the proximal tubules to preserve plasma levels.  Lack of carnitine uptake in the kidney and gut causes severe hypocarnitinemia, which responds dramatically to l-carnitine.

Clinical Course.  Patients with carnitine transporter deficiency can present with severe hypoglycemia (hypoketotic hypoglycemia), dilated cardiomyopathy, heart arrhythmias leading to sudden infant death, myopathy and rhabdomyolysis. in infancy or childhood. Alternatively, they may show onset of hypertrophic cardiomyopathy, progressive muscle weakness, and muscle lipid storage with mild elevations of creatine kinase.  Carriers of OCTN2 mutations are usually asymptomatic, but hypertrophic cardiomyopathy has been reported in middle-aged individuals.  Fetal hydrops secondary to this disorder have been reported.  Multiple reports of asymptomatic, affected mothers have been identified when newborn screening of their affected or carrier offspring has been positive for severely low free carnitine levels

• • Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis.  

  • Childhood myopathy involving heart and skeletal muscle with onset between age two and four years.

  • Pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia

  • Fatigability in adulthood

  • Absence of symptoms

  • The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants

  • The systemic manifestations tend to overshadow the myopathy.  Rhabdomyolysis and respiratory weakness can occur.  

Secondary carnitine deficiency can result from a variety of disorders, including respiratory defects, organic aciduria, endocrinopathies, dystrophies, and renal and liver failure, malnutrition (carnitine poor diets) and as a toxic effect of certain medications especially valproic acid.  It is not known if the secondary deficiency of carnitine can in and of itself cause a myopathy.

Diagnosis.  Acylcarnitine and organic acid analysis are usually normal, and diagnosis is suggested by finding extremely low levels of carnitine in serum and tissues.  In fact, serum carnitine may be 1 μmol/L or undetectable (normal = 30–70).  If necessary, deficient carnitine uptake by tissues such as cultured fibroblasts can also be demonstrated.  Molecular testing of the OCTN2 (SLC22A5) gene is clinically available.  

• Plasma carnitine levels are extremely reduced or absent in primary carnitine deficiency.   This differentiates it from CP2 deficiency where carnitine level is normal or low. 

•  Plasma and tissue (including muscle) carnitine levels are markedly diminished in primary carnitine deficiency, and the levels are only moderately reduced (25 to 50% of normal) in secondary forms of carnitine deficiency.  

• Serum acylcarnitine levels are also reduced.  

• Increased urinary carnitine.

• Increased blood levels of LCFA and long-chain dicarboxylic acids.  

• Serum CK levels are normal in approximately 50% of patients with a myopathic form of the disease but can be elevated to as much as 15 times normal. 

•  In primary system accounting deficiency, liver enzymes are also elevated.  

• Fasting individuals with carnitine deficiency may develop hypoglycemia, acidosis, elevated CK levels, and liver function tests.  However, ketones are not elevated in the urine during fasting (hypoketotic hypoglycemia).  

• EMG may reveal increased insertional activity with positive sharp waves, fibrillation potentials, and CRDs.  Early recruitment of short duration, small amplitude, and polyphasic motor unit action potentials can be observed.   An echocardiogram can demonstrate dilated or hypertrophic cardiomyopathy.

  • The diagnosis is established by identification of biallelic pathogenic variants in SLC22A5 (a.k.a OCTN2) on 5q33.1 or demonstration of reduced fibroblast carnitine transport.

Treatment.  The response to l-carnitine supplementation is dramatic and life-saving; 100 mg/kg/day can be given intravenously in emergency situations, and then administered orally on a long-term basis.  

• • Treatment of manifestations: Metabolic decompensation and skeletal and cardiac muscle function improve with 100-200-400 mg/kg/day oral levocarnitine (L-carnitine) if it is started before irreversible organ damage occurs.  Hypoglycemic episodes are treated with intravenous dextrose infusion; cardiomyopathy requires management by specialists in cardiology. 

  • Prevention of primary manifestations:  Maintain appropriate plasma carnitine concentrations with oral L-carnitine supplementation; prevent hypoglycemia with frequent feeding and avoiding fasting.  Hospitalization for intravenous glucose administration for individuals who are required to fast for a procedure or who cannot tolerate oral intake due to illness such as gastroenteritis.  

  • Prevention of secondary complications: Oral metronidazole and/or decreasing the carnitine dose usually results in the resolution of the fishy odor due to L-carnitine supplementation. 

  • Surveillance: Echocardiogram and electrocardiogram: annually during childhood and less frequently in adulthood; monitor plasma carnitine concentration frequently until levels reach the normal range, then, measure three times a year during infancy and early childhood, twice a year in older children, and annually in adults; evaluate serum creatine kinase concentration and liver transaminases during acute illnesses. 

  • Agents/circumstances to avoid: Fasting longer than age-appropriate periods. 

  • Evaluation of relatives at risk: Measure plasma carnitine levels in sibs of an affected individual. 

  • Pregnancy management: Pregnant women with Primary carnitine deficiency require close monitoring of plasma carnitine levels and increased carnitine supplementation as needed to maintain normal plasma carnitine levels. 

Genetics.  The carnitine uptake defect is inherited as an autosomal recessive trait.  The OCTN2 (SLC22A5) gene encoding the carnitine transporter is on chromosome 5q31.1, and numerous disease-causing mutations have been described,.  No single prominent mutation has been identified.  Prenatal diagnosis can be accomplished by showing deficient carnitine uptake in cultured amniocytes or molecular testing when mutations in the proband are known.

• Genetic counseling CDSP is inherited in an autosomal recessive manner.  At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.  Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the SLC22A5  (OCTN3) pathogenic variants in the family are known. 

• https://www.dojolvihcp.com/

• https://www.ultragenyx.com/wp-content/uploads/2023/10/DOJOLVI-USPI.pdf

CPT1 Deficiency

Genetic: CPTIA, localized to chromosomes 11 (11q13),

Clinical Course:

• Severe deficiency of liver CPT I is rare but more frequent milder variants have been identified in geographically restricted populations.  Severe symptoms include episodic hypoketotic hypoglycemia beginning in infancy and multiorgan system failure . Cardiac symptoms are not present.  

• Creatine kinase levels in blood are elevated in acute episodes.  Organic aciduria is not prominent in this disorder, but hyperammonemia may be present.  Mild CPT1 deficiency is found in high frequency in First Nation populations in Canada and Alaska where it is most frequently identified through newborn screening.

• Carnitine levels in serum is high.

• Increase in LCFA blood.

• Increase in long-chain dicarboxylic acids in blood. 

• Hypoketotic hypoglycemia

• High ratio of free carnitine (C0) to the sum of palmitoylcarnitine (C16) plus stearoylcarnitine (C18).

  • C0/ (C16 + C18) is elevated as a direct result of a decreased ability to make acylcarnitines. 

CPT2 Deficiency

CPT II deficiency is the most common of this group of disorders of fatty acid entry into mitochondria.   It is autosomal recessive.  It classically presents in late childhood or early adulthood as episodes of recurrent exercise- or stress-induced myoglobinuria.  Episodes can be severe enough to lead to acute renal failure.  Patients are typically well between episodes.  There is no tendency to develop hypoglycemia.  Weakness and muscle pain are reported.  The characteristic diagnostic finding in these patients is a low total plasma carnitine level with an increased acylcarnitine fraction and no dicarboxylic aciduria.  Long-chain acylcarnitines may be elevated.  A more severe variant of CPT II deficiency presenting symptoms similar to severe CACT deficiency has been described.  In these patients, the presenting symptoms were neonatal hypoglycemia, hepatomegaly, and cardiomyopathy. Several polymorphic variants in the CPT gene have been associated with an adverse neurologic outcome in influenza encephalitis in Japan.

• • The neuromuscular exam is normal in between bouts of rhabdomyolysis.  

  • In adults, carnitine palmitoyltransferase II deficiency is the most common cause of recurrent myoglobinuria

  • Rare cases of CPT2 deficiency cause a fatal CM in infancy or early childhood.  

Diagnosis. 

• • • CK is normal, except when a patient does intense physical activities or fasts.  

    • Exercise forearm test is normal, which helps distinguish CPT2 deficiency from glycogen storage disorders which can also cause exercise-induced rhabdomyolysis.

    • The acylcarnitine profile may be normal in mild disease. 

    • Increased blood levels of long-chain fatty acylcarnitine.  

    • Increased blood levels of long-chain dicarboxylic acid.

    • Urine organic acids either are normal or show mild dicarboxylic aciduria.

    • Decreased blood levels of carnitine.

    • Hypoketotic hypoglycemia.

    • Blood amino acids are usually normal. 

    • Free carnitine in serum is two to three times normal in CPT I deficiency and is very low in CPT II and translocase deficiency (distinguishing features). 

    • All three enzymes can be assayed in fibroblasts and leukocytes.

    • Acylcarnitine profile by HPLC-TMS: C12, C14, C16, C18, & C18.1 elevations in serum.   Acylcarnitine/Free carnitine (AC/FC) ratio is high..  DDx of C12 to C18 acylcarnitines elevations includes glutaric acidemia type II and carnitine acylcarnitine translocase deficiency, which can be excluded by additional screening of urinary metabolites such as glutaric and 3-OH-glutaric acids.

    •  Muscle biopsy is performed 6 weeks after an episode.  It may show mild fiber type 2 predominance and marked reduction in CPT II activity (less than 10% of normal levels).

    • Histopathology: No gross abnormality on light microscopy exam of muscle tissue.  However, an increase in the lipid content of muscle may be apparent on EM.

    • Molecular genetics:  CP2 mutations located on 1p32.  Deficiency of CP2 impairs transport of acylcarnitine across the inner mitochondrial membrane.  Thus, the generation of ATP from fatty acid metabolism is diminished.  

    • Tx: High protein, low-fat diet with frequent meals should be advised. Avoid prolonged strenuous activity, cold temperatures, and fasting may prevent episodes of rhabdomyolysis.  During febrile illness, patients should be instructed to increase the intake of complex carbohydrates and again avoid fasting. 

    • Treatment of manifestations: 

      • Multidisciplinary approach

      • Dietary restriction of lipid intake

        • High-carbohydrate (70%) and low-fat (<20%) diet (MCFA) + L-carnitine.

      • Avoidance of known triggers

      • Infusions of glucose during intercurrent infections to prevent catabolism

      • Avoiding extended fasting and prolonged exercise

      • Avoid:  Valproic acid, anesthetic agents, ibuprofen, and diazepam in high doses.

      • Triheptanoin (anaplerotic) diet

      • Bezafibrate has been shown to induce fatty acid oxidation in cells and improve flux through fatty acid oxidation in cells from patients with residual CPT2 activity.

      • Adequate hydration to prevent renal failure during episodes of myoglobinuria.

      • Genetic counseling of patient and family members. 

MCAD 

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

 (MCAD) 

 MCAD 

The most common of the fatty acid oxidation disorders, MCAD deficiency, historically most frequently presented during the first 2 years of life with episodes of fasting-induced vomiting, hepatomegaly, hypoketotic hypoglycemia, and lethargy progressing to coma and seizures.  Blood levels of ammonia, uric acid, liver transaminases, and creatine phosphokinase may be elevated during acute episodes, and liver biopsy shows microvesicular steatosis.  Autopsy shows fatty infiltration of the liver, renal tubules, and heart and skeletal muscle.  The disorder was often misdiagnosed as Reye syndrome or sudden infant death syndrome, because the initial episode was fatal in about 25% of cases.  Diagnosis through clinical symptoms is now rare as the disorder is readily identified through newborn screening by tandem MS.  Patients thus identified are typically well, although at risk for hypoglycemia with intercurrent illness, and fatalities are a rarity.  A few enzyme-deficient individuals born prior to newborn screening have had their first presentation in adolescence or adult life and some have remained asymptomatic.

MCAD is a defect of beta oxidation and CPT is a problem in LCFAD.  In MCAD there is the presence of acylcarnitines in serum and if it is CPT there is the presence of Long-chain fatty acids (C16) such as palmitoyl.  

MCAD, secondary to bi-allelic variants in the ACADM gene, is the most common fatty acid oxidation disorder (FAOD) with an overall prevalence of 5.3/100 000 births. 

Clinical findings:

•  MCAD deficiency is historically most frequently presented during the first 2 years of life with episodes of fasting-induced vomiting, hepatomegaly, hypoketotic hypoglycemia, and lethargy progressing to coma and seizures. 

• Blood levels of ammonia, uric acid, liver transaminases, and creatine phosphokinase may be elevated during acute episodes, and liver biopsy shows microvesicular steatosis.

• Autopsy shows fatty infiltration of the liver, renal tubules, and heart and skeletal muscle. The disorder was often misdiagnosed as Reye syndrome or sudden infant death syndrome, because the initial episode was fatal in about 25% of cases. 

Diagnosis:

• Through clinical symptoms is now rare as the disorder is readily identified through newborn screening by tandem MS.  Patients thus identified are typically well, although at risk for hypoglycemia with intercurrent illness, and fatalities are a rarity.  A few enzyme-deficient individuals born prior to newborn screening have had their first presentation in adolescence or adult life and some have remained asymptomatic.

• Analysis of serum acylcarnitines by tandem MS shows elevations of C6, C8, C8:1, and C10:1 esters even between episodes. The same abnormalities are identified through newborn screening. The C6, C8, and C10 dicarboxylic aciduria that occurs during acute episodes often should raise suspicion of the disease and biochemical confirmation can be obtained by measurement of hexanoylglycine and suberylglycine in urine.  Phenylpropionylglycine in urine will be elevated if the gut has been colonized by adult-type flora, but can be missed by all but the most sensitive techniques.  Free carnitine in serum is usually low.  Enzyme deficiency can be shown in fibroblasts or leukocytes, but molecular diagnosis is more readily available and often faster.

• Normalization of the ACP during intravenous dextrose administration has been observed in patients with long-chain FAODs and is thought to be related to the anabolic state and flushing of acylcarnitines from circulation by IV fluids.  

• Urine hexanoylglycine and suberylglycine are sensitive and specific markers and observed with variable genotype and phenotype severity, and in asymptomatic patients. 

• The c.199T>C/c.985A>G genotype has been associated with a mild clinical and biochemical phenotype, but increased urinary excretion of hexanoylglycine is typically present and moderately high on quantitative analysis.  However, undetectable urinary hexanoylglycine at time of diagnosis was reported in 2 cases identified by NBS. Interestingly, patient’s biochemical profile including urinary acylglycines normalizes after receiving high dextrose-containing IVF.  This unreported observation in MCADD highlights the importance of molecular testing and repeat biochemical screening if the diagnosis is highly suspected, despite normal initial workup under supportive care; it could also be of particular concern when confirming NBS results.

• Virtually all laboratories providing this analysis as a clinical service do so using tandem spectrometry (TMS) as the analytical platform.  Less frequently employed methodologies include gas chromatography-mass spectrometry, high-performance liquid chromatography, and capillary electrophoresis.

Treatment:

• Treatment of acute episodes in MCAD deficiency is primarily supportive and aimed at quickly reversing the catabolic state that is responsible for stimulating the pathways of lipolysis and fatty acid oxidation.  Hypoglycemia should be corrected with bolus administration of intravenous dextrose.  Continuous infusion of dextrose should then be given at a rate that maintains plasma glucose levels at, or slightly above, the normal range in order to stimulate insulin secretion and suppress adipose tissue lipolysis.  

• Specific therapy for the mild hyperammonemia that may be present during acute illness has not usually been required. Cerebral edema has occurred during treatment in some patients with severe coma, possibly as a late reflection of acute brain injury from hypoglycemia, toxic effects of fatty acids, or ischemia. Recovery from the acute metabolic derangements associated with coma may require more than a few hours, but is usually complete within 12–24 h, except where serious injury to the brain has occurred.  

• Long-term management consists of dietary therapy to prevent excessive periods of fasting that can lead to coma. Overnight fasting in infants should be limited to no more than 8 h.  A duration of 12 h is probably safe in children >1 year of age.  Home blood glucose monitoring is not useful because symptomatic illness can begin before hypoglycemia has occurred.  Although it is reasonable to modestly reduce dietary fat, because this fuel cannot be used efficiently in MCAD deficiency, patients appear to tolerate normal diets without difficulty, and severe restriction of fat intake may be unnecessary.  Formulas containing MCT oil should be avoided.  Although patients with MCAD deficiency and other acyl-CoA oxidation defects have secondary carnitine deficiency, the use of carnitine supplementation in these disorders is controversial.  Some investigators suggest 50–100 mg/day of oral carnitine but its utility is unproven.

MCADD workup

https://onlinelibrary.wiley.com/doi/full/10.1002/edm2.385

Genetics. 

• The ACADM gene is on chromosome 1 (1p31), and MCAD deficiency is inherited as a recessive trait.  The vast majority of patients with MCAD deficiency have a single common missense mutation: an A-to-G transition at cDNA position 985, which changes a lysine residue to glutamate at amino acid 329 of the MCAD precursor protein.  The mutated amino acid is far removed from the catalytic site of the enzyme but appears to make the protein unstable by interfering with intramitochondrial folding and assembly of the nascent peptide.  Preventing this misfolding offers an opportunity for development of new therapeutic agents for MCAD deficiency.  The A985G mutation accounts for approximately 90% of the mutant alleles in MCAD deficiency.  Approximately 70% of patients are homozygous for the A985G mutation. Most of the remaining patients are compound heterozygotes for the A985G allele in combination with one of several rarer mutations. Thus, only a small percentage of MCAD patients do not have at least one A985G allele. The unusually high frequency of a single common mutation has made molecular diagnosis especially valuable in MCAD deficiency. As more information accumulates from patients identified through newborn screening, correlation of phenotype with genotype is becoming clearer. Patients with the common mutation accumulate the highest levels of metabolites in the newborn period and are probably at risk for more severe disease than are many other mutations

SCAD

Short-Chain Acyl-CoA Dehydrogenase Deficiency Clinical Findings has clinical findings from episodes of intermittent metabolic acidosis, neonatal hyperammonemic coma, neonatal acidosis with hyperreflexia, multicore myopathy, and infantile-onset lipid storage myopathy with failure to thrive, and hypotonia. Hypoglycemia is a rare finding in this disorder. The characteristic metabolites of ethylmalonic and methylsuccinic acids of SCAD deficiency were also detected in individuals with normal SCAD activity in fibroblasts. Subsequently, it was demonstrated that the presence of one of two relatively common variants of SCAD (625 G>A and 511 C>T) predisposes to excessive ethylmalonic acid production. In general, it is clear that the vast majority of patients with complete SCAD deficiency identified through newborn screening have been well, while a variety of symptoms continue to be ascribed to the deficiency in patients identified through clinical testing later in life. The full clinical spectrum of this deficiency, and the clinical relevance of the common polymorphisms, remains to be defined.

Diagnosis:  Butyrylcarnitine in blood is elevated in complete SCAD deficiency and less reliably so in the presence of the common polymorphism. Urine ethylmalonic acid can be elevated in both clinical settings but is not specific for SCAD deficiency. Fibroblast enzyme analysis and acylcarnitine profile will identify the deficiency but may be normal in the presence of just the common polymorphisms. Molecular testing is clinically available.

Treatment: The need for specific dietary or supplement therapy is not supported by current literature.  Since ethylmalonic and butyric acids are organic acids, it seems prudent to caution parents to be alert for the development of signs of acidosis during intercurrent illness and seek emergency care if they develop.

Genetics. The ACADS gene is located at chromosome 12q24.31. The two common variants G>A and 511 C>T) can be present in as many as 35% of Caucasians.  A common inactivating mutation has been described in the Ashkenazi Jewish population. Multiple other private inactivating mutations have been reported, as have combinations of an inactivating mutation with one of the polymorphisms in trans.

VLCAD

Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency VLCAD is an enzyme encoded by the ACADVL  (otherwise know as: ACAD6) gene on chromosome 17p13.1.  It is autosomal recessive.  Deficiency is due to homozygous or compound heterozygous ACADVL mutations. More severe presentations are due to null mutations; less severe mutations with residual enzyme activity are associated with a milder phenotype; affected individuals may even be asymptomatic. ACADVL is reported to have a second function as a complex 1 assembly or stability factor in the respiratory chain complex. 

Incidence in the United States is suspected to be 1/30,000 live births. The clinical presentation of VLCAD deficiency clinical presentation is somewhat variable:

• Severe early-onset cardiac and multiorgan failure VLCAD deficiency: Manifests within the first few months of life with hypertrophic or dilated cardiomyopathy, arrhythmias, pericardial effusions, and hypotonia and hepatomegaly along with intermittent episodes of hypoglycemia. The arrhythmias may be life-threatening – atrioventricular block, ventricular tachycardia, and fibrillation have all been reported. Cardiomyopathies may be reversible if treated early.

• Hepatic or hypoketotic hypoglycemic VLCAD deficiency: Typically presents similarly to MCAD deficiency, with episodes of hypoketotic hypoglycemia; cardiomyopathy is typically absent in these individuals.  The hepatic presentation is characterized by fasting-induced hypoketotic hypoglycemia, encephalopathy, and mild hepatomegaly, often with mild acidosis, hyperammonemia, and elevated liver transaminases.

• Late-onset episodic myopathic VLCAD deficiency: Typically presents with intermittent muscular pain/cramps, exercise intolerance, and at the extreme, rhabdomyolysis. Hypoglycemia is typically not seen. This may be the most common phenotype.

Diagnosis:  

• Analysis of serum acylcarnitines by tandem MS usually shows elevations of saturated and unsaturated C14–18 esters in VLCAD deficiency, even between episodes.  

• Organic acid analysis during acute episodes often shows C6, C8, and C10 dicarboxylic aciduria, but because these acids can also be seen when physiological ketosis is resolving, or following the intake of MCTs, this will not raise suspicion of disease unless C12 and C14 dicarboxylic acids are also present.

• Free carnitine in serum is usually low.

• If necessary, enzyme deficiency can be demonstrated in fibroblasts or leukocytes.

• Elevations of 12- and 14-hydrocarbon fatty acids (C14:1, C14:2, C14, and C12:1) on acylcarnitine profile on tandem mass spectrometry of plasma or on dried blood spot on filter paper, especially if collected during periods of fasting or metabolic stress, should raise suspicion for VLCAD deficiency.  Diagnosis rests on molecular genetic testing for ACADVL mutations/deletions, though functional analysis of VLCAD activity in lymphocytes or cultured fibroblasts can also be performed.  Fasting individuals with suspected VLCAD deficiency should not be done. 

Treatment:

• Acute management of VLCAD deficiency involves administration of high infusion of high rates of glucose-containing intravenous fluids to give 8–10 mg/kg/min of glucose. 

• Chronic management is somewhat controversial.  

• Avoiding fasting and maintaining a high carbohydrate intake are clearly indicated, and continuous intragastric feeding may be necessary to achieve this goal, especially overnight. 

• MCTs, whose oxidation does not involve VLCAD, can be administered to provide calories but should not be used until a diagnosis of MCAD deficiency has been excluded.  

• Safe fasting intervals, the use of oral carnitine, and substitution in the diet of the experimental medium-chain oil triheptanoin are more controversial.

• As with CPT2 deficiency, bezafibrate has been suggested as a possible means of increasing activity in patients with partially stable mutations and residual enzyme activity). 

• Institution of high glucose infusion is warranted if hypoglycemia or elevated liver enzymes are elevated, but the need for chronic management when well has not been demonstrated.

• Acute rhabdomyolysis should be treated with fluid and urine alkalinization. Acute metabolic decompensation episodes should be treated with intravenous dextrose at high rates to switch the individual from a catabolic to an anabolic state. Arrhythmias, should they occur, should be treated appropriately; cardiac dysfunction should be treated with intensive supportive care and dietary modification and is often reversible. First-degree relatives of affected probands should be screened.

LCHADD and Trifunctional Protein Deficiency

Several chain length-specific NAD-dependent 3-hydroxyacyl-CoA dehydrogenases catalyze the oxidation of 3-hydroxyacyl-CoA esters to 3-ketoacyl esters. LCHAD acts on hydroxyacyl-CoAs longer than C8.  

LCHAD and long-chain enoyl-CoA hydratase activities are carried out on the α-subunit of the mitochondrial trifunctional protein, and long-chain β-ketothiolase activity is carried out on the β-subunit. 

LCHAD deficiency can exist alone, or together with deficiency of the other two

Clinical Findings: 

• Patients with a deficiency of this enzyme tend to fall into two clinical subclasses  

• One group presents primarily with symptoms of cardiomyopathy, myopathy, and hypoglycemia. Peripheral neuropathy and recurrent myoglobinuria may be present. These patients are deficient in all three enzymatic activities of the trifunctional protein. 

• The other group, deficient only in LCHAD activity, has hepatocellular disease with hypoglycemia with or without pigmentary retinopathy.  Cholestasis and fibrosis may also be present. 

• Considerable overlap in these groups has been described, however, and LCHAD deficiency has also been reported in patients with recurrent Reye syndrome-like symptoms and in sudden infant death.  

• Milder cases with adolescent onset of recurrent rhabdomyolysis have been reported.  

• Fetal LCHAD deficiency frequently causes acute fatty liver or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) in the (heterozygous) mother during pregnancy, especially when one or both mutant alleles in the fetus is E474Q enzymes.

Diagnosis:

• Acylcarnitine analysis by tandem MS is usually diagnostic including in the newborn period, and shows elevated saturated and unsaturated C16 and C18 hydroxyacylcarnitines (C14-OH, C18:01-OH, and C16-OH). Organic acid analysis often shows elevated C6–14 3-hydroxydicarboxylic acids, but the same abnormalities have been seen in patients with respiratory chain defects and glycogenoses, and are not specific. The enzyme defect can be demonstrated in fibroblasts and leukocytes and, for prenatal diagnosis, in amniocytes.

• C14-OH, C18:01-OH and C16-OH are elevated

Genetics:

• LCHAD deficiency, whether isolated or part of trifunctional protein deficiency, is inherited as an autosomal recessive trait, as the genes for both subunits (HADHA and HADHB) are located on chromosome 2 (2p24.1–23.3).  

• Several disease-causing mutations have been identified, and most affect the α-subunit.  One of these, E510Q (E474Q in the mature subunit), accounts for nearly 90% of mutant alleles in patients of European extraction with isolated LCHAD deficiency.  

• Defects in the β-subunit tend to destabilize the trifunctional protein resulting in the multiple enzymatic deficiencies seen in some patients. Prenatal diagnosis can be made by enzyme assay in amniocytes or chorionic villus samples or, when appropriate, by mutation analysis, and on occasion will be indicated to avoid the complications of pregnancy.

Treatment:

Therapeutic options and controversies parallel those for VLCAD deficiency.  In addition, docosahexaenoic acid, a polyunsaturated C20 acid, has been proposed to slow down the development of retinitis but remains under investigation.

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.