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Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 277-290
Approach to the diagnosis of metabolic myopathies

1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
2 Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

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Date of Submission08-Nov-2021
Date of Decision13-Dec-2021
Date of Acceptance23-Dec-2021
Date of Web Publication11-May-2022


Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan disorder' status. However, collectively they constitute a relatively common group of disorders that affect not only the skeletal muscle but also the heart, liver, and brain among others. Mitochondrial disorders, with a frequency of 1/8000 population, are the commonest cause of metabolic myopathies. Three main groups that cause metabolic myopathy are glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial myopathies. Clinically, patients present with varied ages at onset and neuromuscular features. While newborns and infants typically present with hypotonia and multisystem involvement chiefly affecting the liver, heart, kidney, and brain, patients with onset later in life present with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, GSDs result in high-intensity exercise intolerance while, FAODs, and mitochondrial myopathies predominantly manifest during endurance-type activity, fasting, or metabolically stressful conditions. Evaluation of these patients comprises a meticulous clinical examination and a battery of investigations which includes- exercise stress testing, metabolic and biochemical screening, electrophysiological studies, neuro-imaging, muscle biopsy, and molecular genetics. Accurate and early detection of metabolic myopathies allows timely counseling to prevent metabolic crises and helps in therapeutic interventions. This review summarizes the clinical features, diagnostic tests, pathological features, treatment and presents an algorithm to diagnose these three main groups of disorders.

Keywords: Glycogen storage disorders, lipid storage disorders, mitochondrial disorders

How to cite this article:
Nagappa M, Narayanappa G. Approach to the diagnosis of metabolic myopathies. Indian J Pathol Microbiol 2022;65, Suppl S1:277-90

How to cite this URL:
Nagappa M, Narayanappa G. Approach to the diagnosis of metabolic myopathies. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:277-90. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/277/345042

   Introduction Top

Metabolic myopathies are a rare group of phenotypically and genotypically heterogeneous disorders characterized by abnormalities in skeletal muscle bioenergetics leading to impaired adenosine triphosphate (ATP) production. These disorders are due to defect not only in glycogen, lipid, or purine metabolic pathways, but also in the mitochondrial electron transport chain, endocrine system, and electrolyte metabolism.[1],[2],[3] While muscle is primarily affected, other sites of the neuro-axis and other organ systems may also be affected.[1] Besides, certain drugs (eg., statins), that bring about alterations in the muscle metabolic pathways are classified under toxic myopathies.[4] Here we provide an overview of three major myopathies - Glycogen storage disorders (GSDs), lipid storage disorder (LSD), and mitochondrial disorders. Glycogen is metabolized to pyruvate in the cytoplasm and enters mitochondria. Short-and medium-chain fatty acids cross freely into the mitochondria, while, long chain fatty acids bind to carnitine for transport across the mitochondrial membrane, a process mediated by acylcarnitine translocase and carnitine palmitoyl transferases (CPTs) I and II. Once in the mitochondria, these substrates are converted into acetyl coenzyme A (CoA), which enters the Krebs cycle and delivers the electrons to the mitochondrial respiratory chain to produce ATP. Defects in any of these pathways, that is, glycogen catabolism (glycogenolysis and glycolysis), fatty acid oxidation, Krebs cycle, or mitochondrial respiratory chain (oxidative phosphorylation) cause metabolic myopathies.


Clinically, metabolic myopathies usually cause dynamic and reversible skeletal muscle dysfunction related to exercise.[5] The age at onset range from infancy to adulthood and correlates with the residual enzyme activity. While onset in childhood is characterized by extra-muscular manifestations, sometimes severe and life threatening,[6] patients with late-onset complain of easy fatiguability related to exertion, pain, weakness, cramps, stiffness, and myoglobinuria. Symptoms may also develop after prolonged fasting, infection, cold exposure, and general anesthesia. Non-reversible changes/deficits leading to progressive limb girdle weakness mimicking limb girdle muscular dystrophy (LGMD) can occur.[7] The neurological deficits progress depending on the severity and type of metabolic defects. In general, disorders of glycogen metabolism manifest with symptoms following brief and high intensity exercise such as lifting heavy weights or less intense and sustained exercise such as running or swimming, while disorders of free fatty acid metabolism produce symptoms following prolonged low intensity activity and fasting.[8] Second wind phenomenon a feature of McArdle disease is characterized by symptoms of pain and weakness related to vigorous exercise which improves with brief rest; subsequently, resumption of exercise leads to improved exercise tolerance,[9] whereas out of wind phenomenon (administration of glucose reduces the exercise tolerance) is a feature of Tarui's disease due to phosphofructokinase M isoform deficiency.[10],[11],[12] Patients with GSD develop painful contractures related to continued exercise lasting for hours and worsen on stretching. Unlike cramps, they are electrically silent on needle electromyography (EMG). However, contractures are not a feature of LSD. Rhabdomyolysis and myoglobinuria during the episodes and consequent rise in serum creatine kinase (CK) levels are higher in LSD arising from fatty acid transport and beta-oxidation defects including carnitine palmitoyl transferase (CPT) II deficiency, mitochondrial trifunctional protein (MTP) deficiency, and very long chain acyl CoA dehydrogenase deficiency (VLCAD) as compared to GSDs.[13] Myoglobinuria and renal dysfunction may develop after exertion or after infection/fever and may be associated with Reye syndrome. Rhabdomyolysis and myoglobinuria are uncommon in the setting of progressive limb girdle weakness. Although clinical manifestations of certain GSDs (McArdle's disease, Tarui's disease, GSD XIII) and LSDs (primary muscle carnitine deficiency) are restricted to the muscle, other metabolic myopathies have additional variable involvement of other sites of neuraxis and other organ systems. Mitochondrial myopathies arising from mutations in the mitochondrial DNA manifest with progressive weakness and episodic worsening. Distal myopathy occurs in some patients with Cori/Forbes disease. Myoadenylate deaminase (MADA) is an enzyme that participates in the purine nucleotide cycle necessary for energy production in human skeletal muscle. Myoadenylate deaminase deficiency is usually asymptomatic but may cause exercise intolerance and myalgia in a subset of patients. Many of the patients with metabolic myopathies report being 'poor athletes' in childhood.[14] It is noteworthy that symptoms of metabolic myopathy can be present in other disorders such as fatigue in myasthenia, pain, and cramps in some LGMDs (“pseudometabolic myopathy”), chronic fatigue syndrome, etc., but can be differentiated by detailed and meticulous examination.


The diagnostic tests essential to recognize primary metabolic myopathies include exercise testing, metabolic and biochemical screening (serum biomarkers creatine kinase [CK], ammonia, lactate, acylcarnitine, and amino acids); determination of enzyme activity using blood spots by tandem mass spectroscopy (TMS); urine organic acids and myoglobin; CSF lactate/pyruvate ratio, electromyography, neuro-imaging (magnetic resonance imaging [MRI] and magnetic resonance spectroscopy), muscle biopsy, and genetics. A systematic clinical evaluation helps in selecting the tests as some of the tests are cumbersome; need expertise for interpretations and may have to be repeated based on the index of suspicion and clinical stage of the disease.

Metabolic and biochemical screening


A comprehensive metabolic profiling aids in identifying the site of the metabolic defects. Serum biomarkers have a crucial role in the diagnosis and follow-up. The yield is higher when the tests are carried out during the episodes of acute worsening. Hypoketotic hypoglycemia indicates an underlying lipid metabolism defect. Serum CK may be elevated in patients with progressive weakness, while elevated only during the acute episodes in those with intermittent symptoms. Normal serum lactate dehydrogenase (LDH) with elevated CK provides a clue for underlying LDH deficiency. Elevated serum lactate and pyruvate may be noted in mitochondrial myopathy. Acute rhabdomyolysis may be accompanied by myoglobinuria and consequent azotemia, increase levels of potassium, phosphate, uric acid, and reduced calcium. 'Myogenic' hyperuricemia is a feature of McArdle and Tarui's disease.[4] In Pompe disease, platelet-derived growth factor BB (PDGF-BB) and transforming growth factor 1 (TGF-1) concentrations are significantly lower, while, PDGF-AA and connective tissue growth factor values are significantly higher. PDGF-BB level differs between symptomatic and asymptomatic PD patients. GSD can be associated with hemolysis/hemolytic anemia (e.g., GSD7, phosphoglycerate kinase 1 deficiency, GSD12). Secondary deficiency of pyridoxine (vitamin B6) is reported in McArdle disease with R49 X mutation.[15] Total plasma carnitine is reduced in carnitine uptake defects, however, maybe normal or increased in CPT 1 deficiency. The ratio of free total carnitine levels may be normal or reduced in lipid storage myopathies but elevated in CPT 1 deficiency. An increase in the individual acyl carnitine levels points towards specific defects in the lipid metabolism pathway. Elevated plasma and CSF amino acids, and plasma acylcarnitine indicate underlying mitochondrial dysfunction. Thymidine phosphorylase (TP) enzyme deficiency resulting in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd) is noted in mitochondrial myopathy neurogastrointestional encephalopathy (MNGIE). Increased levels of serum neurofilament light chain and cytokines such as fibroblast growth factor 21 (FGF-21) and Growth and differentiation factor 15 (GDF-15) have been identified as potential biomarkers in primary mitochondrial disorders.

Urine analysis

Increased urinary di-carboxylic acid (DCA) may be present in beta-oxidation defects and in conditions of prolonged fasting, disease states such as diabetic ketoacidosis, and intake of drugs like sodium valproate but is absent in fatty acid transport disorders such as CPT I, CPT II, and carnitine acylcarnitine translocase deficiency.[14] Increased urinary acyl glycines such as short-chain and medium-chain acyl-CoA dehydrogenase, electron transfer flavoprotein, and electron transfer flavoprotein-coenzyme Q oxidoreductase deficiencies may be noted in fatty acid oxidation defects.[16] Elevated urine organic acids indicate underlying mitochondrial dysfunction.


EMG shows a myopathic pattern in subjects with progressive muscle weakness. Myotonic discharges may be seen in patients with acid maltase deficiency, debrancher enzyme deficiency, and myophosphorylase deficiency.[5],[17]

Exercise testing

Forearm exercise test is used to record lactate, pyruvate, and ammonia levels in venous blood at 1, 2, 3, 5, and 10 min after exercise. The normal rise in lactate and ammonia by three to four times the pre-exercise values in the first few minutes fails to occur in metabolic myopathies.[5],[18],[19] Specialised laboratories perform isometric hand grip, cycle ergometry, and treadmill exercise to diagnose and differentiate the various metabolic myopathies as well as to assess response to treatment.

Muscle biopsy

Muscle biopsy subjected to histological and enzyme histochemical stains [Table 1], and electron-microscopy has a important role in the diagnostic process.[20]
Table 1: Histological, histochemical stains and morphological features

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Molecular genetics

Genetic abnormalities can be detected in a reliable and efficient manner by next-generation sequencing technology.[14]

Several flow charts for an approach to the diagnosis and treatment including a three-tier system of investigations have been suggested.[21],[22] We propose a simplified algorithm for the diagnosis of metabolic myopathies [Figure 1].
Figure 1: Algorithm

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In recent years, there is a remarkable understanding of disorders affecting muscle metabolism with respect to their biochemistry and molecular basis. A large number of clinical syndromes related to glycogen and lipid metabolism and mitochondrial function are known. However, only in a few, the muscle pathology is supportive. Hence, metabolic conditions where myopathological studies are helpful are detailed.

Glycogen storage disorders (GSDs)

Defects in any step in the glycolytic pathway can result in myopathy. The overall incidence is estimated to be 1/20000-43000 live births. To date, 15 types of GSDs have been reported and numerically classified based on the order of discovery. Subsequently, identification of enzyme deficiency and mutations in genes encoding individual enzymes in the glycogen metabolic pathway lead to modification of the nomenclature.[23] All GSDs are inherited by an autosomal recessive trait except phosphorylase b kinase (GSDVIII) and phosphoglycerate kinase (GSD IX) deficiency which is X-linked recessive. The clinical manifestations of GSDs vary depending on the residual enzyme activity, its relative expression in the liver, kidney, skeletal muscle, or heart, and molecular genetic defects.[24],[25] As a general rule, liver GSDs commonly present with fasting hypoglycemia ± hepatomegaly, while muscle GSDs present either with exercise intolerance and rhabdomyolysis as seen in dynamic disorders like McArdle (GSDV), and Tarui (GSDVII) diseases or fixed muscle weakness without rhabdomyolysis as seen in cytoplasmic disorders associated with glycogenolysis defects such as debrancher defect (GSDIIIa) or lysosomal glycogen breakdown defects (Pompe disease -GSDII)[26] [Table 2].
Table 2: Summary - disorders due to defect in glycogen metabolism

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GSD: I GSD 1a (Von Gierke's disease) and GSD Ib

Muscle is not the primary target in GSD1.

GSD II (Pompe disease/acid α-1,4-glucosidase (acid maltase) deficiency)

Clinically, there are three forms- (i) Classical infantile form presents with floppiness, delayed motor milestones, fatal hypertrophic cardiomyopathy, macroglossia, hepatomegaly, failure to thrive due to respiratory insufficiency, and death before 2 years of age. In the 'non-classical' form, the cardiomyopathy is less severe and survival is longer.[24] (ii) Childhood form presents with delayed motor milestones and limb girdle weakness, which may progress to respiratory muscle weakness. Severe scoliosis exaggerated lumbar lordosis, rigid spine, dysphagia and dysarthria may also occur.[27],[28] (iii) Adult-onset form predominantly presents with proximal muscle weakness with elevated CK values mimicking limb girdle muscular dystrophy. Cardiac and hepatic involvement does not occur.[24],[25],[29] Ptosis, scapular winging, and paraspinal muscle wasting have been described.[30] In a large study of 3,076 subjects with unclassified limb girdle weakness and asymptomatic hyper-CK-emia, acid maltase deficiency was detected in 2.4%. Among these, 85.3% had limb girdle weakness, 61% had limb girdle and respiratory muscle weakness, 2.7% had isolated respiratory muscle weakness and 12% had isolated hyper-CK-emia.[31] Cardiac arrhythmias and intracranial vascular abnormalities such as aneurysms and basilar artery dolichoectasia have also been described.[32],[33],[34] Muscle biopsy reveals large vacuoles with basophilic granular material positive to periodic acid Schiff (PAS), diastase sensitive, and elicits a positive reaction to acid phosphatase [Figure 2]a, [Figure 2]b, [Figure 2]c. These vacuoles are more pronounced in the infantile form and lesser degree in the late onset forms. The presence of reducing body-like inclusions has been reported in the late onset form.[35] The vacuoles in addition are positive to sarcolemmal proteins dystrophin and spectrin and not to laminins and help distinguish vacuoles noted in Danon disease due to mutation in gene encoding LAMP-2 (lysosomal associated membrane protein)[36] and X-linked myopathy with excessive autophagy.[37] Electron microscopically (EM), glycogen granules are typically seen within membrane-bound vacuoles as well as large lakes of freely dispersed granules.[38]
Figure 2: Glycogen storage disorders. (a-c) (A case of GSD II): Biopsy from a 43/M showing (a) large vacuoles with basophilic granular material (H&E), (b) intense PAS staining suggesting glycogen aggregation, and (c) positive reaction to acid phosphatase suggesting lysosomal vacuoles. ×400 (d-g) (A case of GSD IV): Biopsy from 5 days baby showing (d) presence of polyglucosan bodies (↑)(H&E) intensely Logol's iodine (e) and PAS-positive (f) and (g) diastase resistance. ×400 (h-l) (A case of GSD-VII): Biceps muscle from a 19/M showing (h) mild variation in fiber size with subsarcolemmal vacuole (HE), (i) vacuole intensely stained with PAS (∗), (j) total absence of phosphofructokinase as against normal positive control (k). (l) Electron micrograph showing aggregation of glycogen (∗) in the subsarcolemmal and intermyofibrillar region. Bar 1 μm

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GSD III (Cori-Forbes disease/Debrancher enzyme deficiency)

Clinically, two types, type IIIa (childhood and adult onset forms) noted in 85% of the cases affects both liver and muscle and rarely cardiac involvement, while the less frequent type IIIb predominantly affects the liver.[6]

Type IIIa: Children with debrancher enzyme deficiency develop hepatomegaly, failure to thrive, short stature, hypoglycemia, and hyperlipidemia. Symptoms improve with age. Sometimes, cirrhosis, hepatic adenoma, or hepatocellular carcinoma may occur.[39] Cardiac involvement in the form of hypertrophic cardiomyopathy, arrhythmias, and sudden cardiac death has been reported.[39],[40] Neurological manifestations include hypotonia, weakness, motor delay, and hypoglycemia-induced seizures. Adults manifest with proximal or distal weakness. As the disease evolves, 2/3 of the patients develop distal muscle weakness and wasting, mimicking motor neuron disease or Charcot Marie Tooth disease.[39] Exercise intolerance may also be superimposed. A mild sensory axonal polyneuropathy may also be present.[41] Muscle biopsy shows mild variation in fiber size. Moth-eaten appearance may be noted on hematoxylin eosin (HE) stained sections due to disruption of myofibrils by a large accumulation of glycogen. In some cases, subsarcolemmal vacuoles positive to PAS are reported.[42]

GSD IV (Andersen disease/brancher enzyme deficiency/amylopectinosis)

The most common is the infantile onset form with hepatic fibrosis and early death. Onset in the prenatal period is characterized by polyhydramnios, fetal hydrops, multiple contractures, and early death. The infantile onset presents as floppy babies with severe hypotonia, respiratory insufficiency resembling spinal muscular atrophy.[43] Isolated myopathy may occur with or without cardiomyopathy,[39] dilated cardiomyopathy, and neuronal involvement resulting in neonatal death. The childhood onset to date reported in Ashkenazi Jews presents with cardiomegaly. The adult onset form has progressive upper and lower motor involvement, sensory loss, dementia or mental retardation, axonal neuropathy, pyramidal signs neurogenic bladder, and elevated CK levels.[39],[27],[44] Muscle biopsy is characterized by the presence of intensely PAS and Logol's iodine positive and diastase resistance polyglucosan bodies [Figure 2]d, [Figure 2]e, [Figure 2]f, [Figure 2]g. Electron microscopy reveals filamentous/fibrillar glycogen resembling amylopectin. In the perinatal form, the bodies are pleomorphic, some are birefringent while some PAS negative. Ultrastructurally, most inclusions in the perinatal form are granular and membrane-bound. While others have irregular contours, are more electron-dense and not membrane-bound, or are homogenous resembling the 'hyaline'bodies. A paracrystalline pattern of granules showing periodicity of 10 nm is also seen.[45]

GSD V (McArdle disease/Myophosphorylase deficiency)

Unlike other forms described above, GSD V involves the skeletal muscle with onset in childhood and adulthood. The major clinical features include cramps, pain, edema, and muscle weakness following high-intensity activity (sprinting, sit-ups, lifting heavy objects) leading to myoglobinuria.[9],[46] A subset of patients (50%) with myoglobinuria develop acute renal failure. Muscle contractures (muscle is 'locked') are common in the exercising muscle, for example, in the finger flexors after lifting heavy weights. Sustained submaximal activity such as walking uphill may lead to fatigue and dyspnea. Typically, all patients develop a second wind phenomenon 6 to 8 min into exercise.[7] Progressive predominant proximal weakness can occur, particularly in individuals older than 40 years of age.[47] CK levels are elevated. In the severe form, generalized hypotonia, weakness, and respiratory muscle weakness are noted at birth which may be fatal. Atypical phenotypes may mimic polymyositis or LGMD.[48] Histopathological features are variable from mild variation in myofiber diameter to nonspecific myopathic features (few degenerating or necrotic and regenerating fibers) and subsarcolemmal vacuoles/blebs positive to PAS. Enzyme activity for myophosphophorylase shows complete absence/marked reduction in staining. On EM, vacuoles are more evident with glycogen in the subsarcolemmal region, between myofilaments and myofibrils, the plasma membrane, and basement membrane besides dilatation of sarcoplasmic reticulum.[49]

GSD VII (Tarui disease/Phosphofructokinase [PFK] deficiency)

This is the most common disorder of the glycolytic pathway manifesting with exercise-induced myalgia and cramps.[14] Similar to McArdle's disease, contractures, rhabdomyolysis, and myoglobinuria with high intensity exercise and fatigue, dyspnea, and nausea triggered by modest exercise is reported. Out of wind phenomenon may occur. Other features include hemolytic anemia, mild jaundice, gout, cardiomyopathy, and central nervous system involvement.[50] Muscle biopsy may be normal, show nonspecific myopathic features, or may reveal multiple subsarcolemmal vacuoles positive to PAS and aggregation of glycogen granules in the subsarcolemmal and intermyofibrillar region. Histochemical staining to PFK shows total absence [Figure 2h, [Figure 2]i, [Figure 2]j, [Figure 2]k, [Figure 2]l. Marked reduction in PFK activity is also noted in the erythrocytes.[11] Additionally, diastase resistant polyglucosan body is reported.[51]

GSD IX (Phosphoglycerate kinase [PGK] deficiency)

The enzyme PhK comprises four subunits (α, β, γ, and δ). Different phenotypic manifestations are recognized. Infantile onset with severe hemolytic anemia, seizures, tremor and mental retardation. A myopathic form with mild hemolytic anemia has been reported. A rare patient with a pure myopathic form with intolerance to brief intense exercise, exertional myoglobinuria, and contractures are documented.[52] Being an X-linked disorder, males are predominantly affected.[5] Muscle morphology shows diffuse increase of PAS positivity within the myofibers. EM shows accumulations of glycogen in the myofibers, in the mitochondria as large matrix granules, and the endothelial cells. Large hypomyelinated axons without demyelination and remyelination is noted in the sural nerve biopsy.

GSD X (Phosphoglycerate mutase [PGAM] deficiency)

Reported predominantly in Afro-Americans, the symptoms include exercise induced contractures, pain, and episodic myoglobinuira following vigorous exercise and absence of second wind-phenomenon.[5] The striking feature on muscle biopsy is the presence of tubular aggregates as evidenced on NADH-tr and modified Gomori trichrome (MGT) staining in one third of the patients reported to date, suggesting high calcium release from the sarcoplasmic reticulum relative to calcium reuptake capacity as the cause of cramps.[53],[54]

GSD XI (Lactate dehydrogenase (LDH) deficiency)

Seen mostly in patients of Japanese descent, this rare disorder is clinically characterized by erythematous skin rash in addition to uterine stiffness during parturition, exercise-induced myoglobinuria, high CK levels, and low plasma LDH levels.[5],[55] Muscle biopsy shows normal or nonspecific features.

Other glycogen storage disorders

GSD XII (Aldolase A deficiency)

The clinical features include hemolyticanemia, jaundice, myopathy, and fever-triggered rhabdomyolysis.[5]

GSD XIII (β-enolase deficiency) and GSD XIV (Phosphoglucomutase 1 deficiency) are characterized by exercise-induced fatigue, cramps, pain, and myoglobinuria.

Muscle histology in both is either normal or show non-specific features

GSD 0 and GSD XV (Glycogenin 1 deficiency)

GSD 0 is due to deficiency of glycogen synthase, an enzyme responsible for glycogen synthesis, while GSD XV is due to impaired autoglucosylation of glycogenin-1, an enzyme involved in the biosynthesis of glycogen, and capable of self-glucosylation, forming an oligosaccharide primer that serves as a substrate for glycogen synthase. Clinically, patients present with exercise intolerance due to myopathy and cardiomyopathy. Unlike other GSDs, muscle biopsy shows depletion of glycogen, mitochondrial proliferation, and type 1 fiber predominance.[56]

Lipid storage myopathy

Lipid storage myopathies are a heterogeneous group of genetic disorders due to failure to transport long chain fatty acids into mitochondria secondary to carnitine or CPT I or II deficiencies or due to defects in intramitochondrial β-oxidation resulting in a variable degree of lipid accumulation in muscle as well as in other tissues [Table 3].
Table 3: Summary - disorders due to defect in lipid metabolism

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Carnitine deficiency

This may manifest with primary muscle carnitine deficiency, primary systemic carnitine deficiency with hepatic encephalopathy and myopathy, and primary systemic carnitine deficiency with progressive cardiomyopathy. Primary muscle carnitine deficiency is caused by impaired function of the plasma membrane sodium dependant carnitine transporter (OCTN2).[57] Several mutations in SLC22A5 encoding OCTN2 have been reported in primary carnitine deficiency (PCD) patients. Clinically there is progressive limb weakness that improves after replenishing carnitine. Exercise intolerance, fatigue, and myoglobinuria may also occur. In primary systemic carnitine deficiency with hepatic involvement, a Reye-like syndrome with hepatomegaly, elevated liver enzymes, increased ammonia, metabolic acidosis, and hypoketotic hypoglycemia is seen in infancy.[39] Mild hypotonia and weakness may occur. Overt myopathy does not occur. In primary systemic carnitine deficiency with cardiac involvement, there is progressive dilated cardiomyopathy leading to death. Ventricular fibrillation without cardiomyopathy may be present. Other manifestations include hypoketotic hypoglycemia and peripheral neuropathy.[58] Asymptomatic PCD is also recognized [7],[13] or affected adults may complain only of easy fatiguability, although decompensation during pregnancy may occur.[39] The muscle biopsy shows polygonal to round fibers and a vacuolar myopathy on the HE stain [Figure 3]a. The vacuoles are fine and demonstrate large and small lipid droplets when stained with oil-red-O/Sudan black within type 1 fibers [Figure 3]b. Ragged red fibers (RRF) are visualized on cryosections stained with MGT having ragged edges and appear as a bright red accumulation of staining [Figure 3]c and intense enzyme activity on succinic dehydrogenase (SDH) reaction. Under an electron microscope, lipid droplets appear as empty rounded spaces of uniform diameter between the myofibrils and in the subsarcolemmal region adjacent to increased number, size, and abnormal (altered cristae) mitochondria.
Figure 3: Lipid storage disorder. Quadriceps biopsy from a 37/M: showing (a) fine vacuoles (HE), (b) large and small lipid droplets stained with oil-red-O, and (c) Ragged red fibers on MGT. ×400

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Carnitine palmitoyl transferase (CPT) II deficiency

Patients develop intermittent symptoms of cramps, myalgia, and weakness with or without myoglobinuria after prolonged exertion, fasting, exposure to cold, fever, infection, emotional stress, general anesthesia, and drugs.[59],[60] Repeated episodes of rhabdomyolysis lead to persistent proximal weakness of limbs. CPT II deficiency is the commonest cause of recurrent rhabdomyolysis. Patients with CPT II deficiency adapt to their illness by consciously avoiding the triggering factors.[6] A Reye-like syndrome may be noted in infants. In the neonatal form, which constitutes the most severe phenotype, congenital malformations, hepatomegaly, cardiomegaly, and encephalopathy are noted.[39] Muscle biopsy rarely shows pathological changes. However, lipid storage, less marked than in carnitine deficiency is noted when the biopsy is performed during the attack. Biopsy soon after an episode of myoglobinuria shows necrosis and regenerating fibers, while it appears normal during the quiescent phase between attacks.

Neutral lipid storage disease (NLSD)

NLSD, a rare LSD is caused by the defect in adipose triglyceride lipase and α/β hydrolase domain containing protein 5 (ABHD5). The two well recognized NLSDs include: (i) NSLDI- NLSD with ichthyosis presenting in childhood or adolescence is characterized by nonbullos congenital ichthyosiform erythroderma, neurosensory defects, microcephaly, cataract, mental retardation, slowly progressive predominantly distal muscle weakness, and cardiomyopathy and (ii) NLSDM - NLSD with myopathy presents with slowly progressive proximal or distal muscle weakness, cardiomyopathy with mild to moderate elevated CK levels. Muscle biopsy is critical as it shows massive lipid accumulation even in the presymptomatic period. In addition, rimmed vacuoles (vacuoles rimmed by red granular material when stained with MGT) have been reported.[61] Lipid vacuoles are also seen in leuckocytes in peripheral blood smears and fibroblasts. EM shows lipid droplets and shrunken mitochondria.

Phosphatidic acid phosphatase (LIPIN)-1 deficiency

Deficiency in LIPIN 1 causes recurrent acute myoglobinuria in childhood, generalized weakness, and myalgia following febrile illness, anesthesia, and fasting. Encephalopathy, cardiomegaly, and hepatomegaly may also occur during the episode.[62] Muscle biopsy is either normal or shows lipid accumulation, type 1 fiber predominance, type 2 fiber atrophy, and rarely RRF.

Beta oxidation enzyme deficiencies

These include the short-chain, medium-chain, long-chain, and VLCAD, short chain 3-hydroxy acyl coA dehydrogenase (SCAD), CoQ oxidoreductase, mitochondrial tri-functional protein (MTP), and hydroxy methyl glutaryl coA lyase. Clinical manifestations include varying combinations of myopathy, myoglobinuria, cardiomyopathy, and hepatic dysfunction or Reye-like syndrome during times of catabolic crisis. Among the various enzymes, medium-chain acyl coA dehydrogenase (MCAD) deficiency is the commonest and manifests with non-ketotic hypoglycemia and encephalopathy triggered by fasting and catabolic stresses.[59],[63] SCAD deficiency may be asymptomatic or manifest with episodic hypoglycemia, developmental delay, failure to thrive, seizures, vomiting, and weakness.[7],[59] VLCAD deficiency manifests with a fatal infantile onset multi-system disorder to recurrent rhabdomyolysis and myoglobinuria mimicking CPT II deficiency.[59],[64] MTP deficiency manifests with recurrent rhabdomyolysis in addition to pigmentary retinopathy and axonal neuropathy.[39],[65] Muscle biopsy in SCAD deficiency may show lipid storage and multicore (multiple small areas devoid of oxidative reaction).[66] While muscle pathology in VLCAD deficiency shows variation in fiber size and a mild increase in lipid. Immunohistochemical staining using an antibody to VLCAD shows absent or markedly reduced activity.[67] In cases with MTP deficiency, muscle exhibits non-specific changes, rarely show mild lipid accumulation and mitochondrial proliferation.

Multiple Acyl-CoA dehydrogenase deficiency (MADD)

MADD are heterogeneous with neonatal-onset forms with or without renal cystic dysplasia, congenital anomalies, and death in the first few weeks. While late- onset forms have proximal muscle weakness, hepatomegaly, and episodic hypoglycemia. Cardiomyopathy is seen in all forms. Muscle pathology is characterized by increased lipid droplets as seen in PCD.

Mitochondrial myopathies

Mitochondrial disorders are the commonest cause of metabolic myopathies[68] and arise from mutations in mitochondrial or nuclear DNA or intergenomic communication that impact the synthesis, assembly, and maintenance of the respiratory chain.[2],[69] The clinical features may be dynamic ranging from exercise induced myalgias to rhabdomyolysis and myoglobinuria, leading to progressive weakness of proximal or distal muscles or both.[7] The well-recognised phenotypes include chronic progressive external ophthalmoplegia (CPEO) and Kearns- Sayre syndrome (KSS). The latter is a multi-system disorder where CPEO is associated with cardiac conduction defects, pigmentary retinopathy and extensive white matter changes in the brain.[39] Myopathy is a part of various mitochondrial syndromes such as MELAS, MERRF, and MNGIE.[4] Electron transfer flavoprotein (ETF) dehydrogenase deficiency, a riboflavin responsive myopathy that manifests with weakness and exercises intolerance, and elevated CK, with evidence of lipid accumulation and secondary CoQ deficiency in muscle has been described.[6],[39] The infantile onset is fatal and manifests with multisystem involvement and congenital malformations such as dysmorphic face and dysplastic kidneys. Onset at a later age is characterized by a milder disease with limb-girdle and axial muscle weakness, though episodic encephalopathy may also occur.[13],[39] Exercise induced fatigue, dyspnoea, and myoglobinuria have been described in iron-sulphur cluster scaffold (ISCU) deficiency.[39]

The hallmark pathological feature is the presence of RRF seen on the MGT stain [Figure 4]b. The red zone can be identified on HE stained sections as subsarcolemmal areas of amorphous, basophilic staining [Figure 4]a. In addition, enzyme stains for SDH and cytochrome C oxidase (COX) demonstrate ragged blue fibers (RBF), and COX deficient fibers respectively.[70] Combined SDH - COX staining displays COX deficient fibers which are blue in contrast to normal brown stain. [Figure 4]c. It is noteworthy that a mosaic pattern of COX-negative fibers and COX positive fibers is a marker of heteroplasmic mtDNA mutations affecting mitochondrial protein synthesis, ribosomal RNA genes, or affecting one of the three mtDNA encoded CIV sub-units. Diffuse COX deficiency is noted in Leigh syndrome due to SURF1 mutations, while cases with a homoplasmic mutation in mitochondrial tRNAGlu are associated with a severe but reversible infantile mitochondrial myopathy and biochemical and histochemical COX deficiency, often accompanied by RRF in skeletal muscle. Increased lipid may be seen in fibers with or without ragged red change and COX deficiency in KSS and PEO due to rearrangements in mtDNA and in mtDNA depletion syndrome due to mutations in TK2, RRM2B, SUCLA2 and SUCLG1, and CoQ2. In addition, extensive dystrophic features with necrosis, fibrofatty infiltration are reported in the TK2-related myopathic form of mtDNA depletion syndrome. RRF on EM shows proliferation of subsarcolemmal and intermyofibrillar mitochondria that are structurally abnormal and often contain paracrystalline inclusions. Readers are referred to detailed clinical features and pathological changes of mitochondrial disorders published elsewhere.[71]
Figure 4: Mitochondrial disorder. Biopsy from a 15/M, a case of CPEO: (a) HE stained sections showing amorphous, basophilic stained fibers (∗), (b) ragged red fibers (∗) (MGT) and (c) Combined COX - SDH staining displays COX deficient fibers (∗)

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   Treatment Top

Enzyme replacement therapy has been successful in Pompe disease with improvement in skeletal muscle and cardiac function.[72],[73] In patients with McArdle disease, progressive aerobic conditioning, and strategies to bypass or compensate for the glycogenolytic defect such as administration of oral sucrose, carbohydrate consumption before exercise, protein-rich diet, pyridoxine supplementation, and creatine monophosphate have been studied.[8],[74],[75],[76],[77] In fatty acid oxidation defects, dietary therapy involves the administration of carbohydrate rich diet to avoid hypoglycemia and increase muscle glycogen content and improve exogenous glucose oxidation. Administration of nocturnal corn starch and continuous high dose carbohydrate infusion is particularly useful in CPT II deficiency. Anaplerotic diet (supplementation with medium chain triglycerides) has also been recommended in CPT II deficiency.[74] Several patients adapt and adopt to their illness by avoiding physical activity during times of metabolic stress such as fever or fasting and further by voluntarily reducing physical activity in case myalgias develop during exercise.[8] Rhabdomyolysis and myoglobinuria are managed by fluids, correction or prevention of electrolyte abnormalities, and dialysis depending upon the requirement.[71] In the case of mitochondrial disorders, agents that ameliorate free radical production and anaerobic energy transduction including anti-oxidants such as vitamins C and E and alpha-lipoic acid, coenzyme Q10, riboflavin, thiamine, and alternative energy substrates such as creatine monophosphate administered in the form of a 'cocktail', as well as endurance exercise, have variable efficacy.[4],[8]

   Conclusion Top

The complex clinical phenotypes coupled with limited experience and expertise due to the uncommon nature of these disorders make the diagnosis a great challenge. A high index of suspicion and judicious use of various biochemical, histological, and other molecular diagnostic tests is essential to make an accurate and timely diagnosis.

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Correspondence Address:
Gayathri Narayanappa
Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_1088_21

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