Metabolic Myopathy
Pompe disease
McArdle disease
Tarui disease
- Fatty Acid Oxidation Disorders
Carnitine palmitroyltransferase II deficiency
Very long chain Acyl-coA dehydrogenase deficiency
Medium chain Acyl-coa dehydrogenase deficiency
MELAS
MERRF
Kearns Sayre Syndrome
- Disorders of purine nucleotide cycle
Myoadenylate deaminase deficiency
- Myopathy due to other mtabolic pathway disorder
Phosphoglycerate kinase deficiency
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Myopathy Due to Glycogen Storage Disease
Introduction
Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders characterized by defects in glycogen metabolism. Myopathy due to GSD primarily affects skeletal muscles, resulting in exercise intolerance, muscle weakness, and other related symptoms. These conditions are caused by enzymatic deficiencies that impair glycogen synthesis, breakdown, or utilization, leading to muscle glycogen accumulation or energy production deficits.
History
The first descriptions of GSD-related myopathies date back to the early 20th century. In 1928, von Gierke identified GSD type I, while McArdle described GSD type V in 1951, highlighting exercise-induced muscle symptoms. Advances in biochemical and genetic techniques have since allowed the classification of GSD into various subtypes based on the specific enzyme defect and clinical presentation.
Epidemiology
GSDs are rare disorders, with an estimated incidence of 1 in 20,000 to 25,000 live births. Some myopathic forms, such as GSD type V (McArdle disease) and GSD type VII (Tarui disease), represent a smaller fraction. GSDs display autosomal recessive inheritance patterns, with some mitochondrial and autosomal dominant exceptions.
Pathophysiology
GSD-related myopathies arise from enzymatic deficiencies in glycogen metabolism, resulting in impaired glycogen breakdown or utilization.
The underlying metabolic dysfunction results in muscle weakness, cramps, and fatigue due to insufficient available energy during exertion.
Clinical Manifestations
Exercise intolerance often presents with early fatigue. Muscle cramps and pain are common, especially during anaerobic exercise. Strenuous activity may lead to myoglobinuria, which causes dark urine. Muscle weakness can be proximal or generalized, with some cases showing progressive muscle atrophy. Certain conditions, like McArdle disease, exhibit a second wind phenomenon, while others, such as Pompe disease, may involve the cardiac and respiratory systems.
Diagnosis
Treatment
Prognosis
The prognosis of GSD-related myopathy varies depending on the subtype and severity of the enzyme deficiency. McArdle disease typically presents with a benign course, while Pompe disease can lead to life-threatening cardiopulmonary complications. Early diagnosis and appropriate management significantly improve the quality of life and reduce morbidity in affected individuals. Future advancements in gene therapy, enzyme replacement, and metabolic interventions hold promise for improving outcomes in patients with GSD-related myopathies.
Fatty Acid Oxidation Disorders
Carnitine Palmitroyltransferase II (CPT II) Deficiency
Introduction
Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inherited disorder of mitochondrial fatty acid oxidation, crucial for energy production, especially during prolonged fasting, stress, or exercise. It affects the enzyme CPT II, which is central in transporting long-chain fatty acids into the mitochondria for β-oxidation. CPT II deficiency can present at any age, with symptoms ranging from mild muscle weakness to life-threatening neonatal illness. It is inherited in an autosomal recessive pattern.
Epidemiology
CPT II deficiency is the most common inherited long-chain fatty acid oxidation disorder. The adult myopathic form is the most prevalent, particularly in people of Northern European descent. The estimated prevalence is 1 in 40,000 to 1 in 300,000, although the actual frequency may be underreported due to diagnostic challenges. Carrier frequency in some populations may be as high as 1:70.
Pathophysiology
CPT II is located on the inner mitochondrial membrane and is crucial in converting long-chain acylcarnitines to acyl-CoA within the mitochondrial matrix. In CPT II deficiency, long-chain fatty acids cannot efficiently enter the mitochondrial matrix. As a result, β-oxidation and energy production are reduced, particularly during catabolic stress. This energy deficit can impair cellular function. Additionally, the accumulation of toxic long-chain acylcarnitines may disrupt cellular membranes and contribute to organ dysfunction.
Clinical Manifestations
- Neonatal: The neonatal form appears within the first days of life, with symptoms including hypoglycemia, cardiomyopathy, seizures, hepatomegaly, dysmorphic features, and respiratory distress; it is often fatal despite intensive care.
- Infantile: The infantile form typically begins between 6 and 24 months of age and is characterized by hepatomegaly, liver failure, hypoketotic hypoglycemia, muscle weakness, and cardiomyopathy, often triggered by fasting, infection, or stress.
- Adult Myopathic: The adult myopathic form has onset in adolescence or adulthood. It presents with exercise-induced myalgia, muscle stiffness, rhabdomyolysis, myoglobinuria (dark urine), and elevated creatine kinase levels. This form is triggered by prolonged exercise, fasting, cold exposure, fever, or infection and does not involve the heart or liver.
Diagnosis
Treatment
Acute Management
Prognosis
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
Introduction
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive disorder of mitochondrial β-oxidation. It impairs the body’s ability to metabolize long-chain fatty acids, critical for energy production during fasting, illness, or prolonged exercise. VLCAD is one of the most common long-chain fatty acid oxidation disorders and can present with a broad clinical spectrum, from life-threatening cardiomyopathy in infancy to exercise-induced muscle symptoms in adolescence or adulthood.
Epidemiology
VLCAD deficiency affects approximately 1 in 30,000 to 1 in 100,000 live births. It is more commonly detected in regions with expanded newborn screening (NBS) programs, which can identify asymptomatic cases early. No apparent ethnic or geographic predilection has been identified, though incidence may vary by population.
Pathophysiology
VLCAD is a mitochondrial enzyme responsible for the first step in the β-oxidation of very long-chain fatty acids (C14–C20). In VLCAD deficiency fatty acid oxidation is impaired, especially during metabolic stress. Energy production from fats is reduced, leading to hypoglycemia and energy deficit. Accumulation of toxic long-chain acyl-CoAs and acylcarnitines can damage the liver, heart, and muscle tissue.
Clinical Manifestations
- Severe early-onset form: The condition typically presents in the neonatal period or early infancy with features such as hypertrophic or dilated cardiomyopathy, pericardial effusion, hypoketotic hypoglycemia, hepatomegaly, and arrhythmias. If left untreated, it carries a high risk of mortality.
- Childhood hepatic form: The condition typically begins in infancy to early childhood, presenting with recurrent episodes of fasting-induced hypoketotic hypoglycemia, along with hepatomegaly, vomiting, and lethargy. Episodes are often triggered by infections or prolonged fasting, and cardiomyopathy is usually absent.
- Adolescent/Adult myopathic form: The condition typically presents in later childhood, adolescence, or adulthood with exercise-induced muscle pain, weakness, rhabdomyolysis, and myoglobinuria. There is no significant involvement of the liver or heart.
Diagnosis
Treatment
Acute Management
Prognosis
Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
Introduction
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation. It impairs the body's ability to break down medium-chain fatty acids into acetyl-CoA, particularly during fasting or increased energy demand. This leads to energy deficiency and accumulation of toxic metabolites.
Epidemiology
MCAD deficiency occurs in approximately 1 in 10,000 to 20,000 live births, with higher prevalence among individuals of Northern European descent. It is inherited in an autosomal recessive manner. The condition is most often caused by mutations in the ACADM gene on chromosome 1p31.3, with the c.985A>G (K304E) mutation being the most common.
Pathophysiology
MCAD is a key enzyme in the mitochondrial β-oxidation pathway, responsible for dehydrogenating medium-chain fatty acids (6–12 carbon atoms). In MCAD deficiency, this process is disrupted, leading to impaired breakdown of these fatty acids. As a result, the body cannot produce sufficient energy, especially during fasting or illness. Toxic metabolites such as medium-chain acylcarnitines and dicarboxylic acids accumulate. This leads to hypoketotic hypoglycemia, liver dysfunction, and, in severe cases, a risk of sudden death during metabolic stress.
Pathology
On macroscopic examination, the liver may appear enlarged and pale due to fatty infiltration. Histological findings typically show microvesicular steatosis in the liver and sometimes in the kidney and heart. Structural abnormalities in muscle or other tissues are generally absent unless significant metabolic decompensation exists.
Clinical Manifestations
MCAD deficiency typically presents between 3 months and 2 years of age, though it can also be detected before symptoms appear through newborn screening. Prolonged fasting, infections, or increased metabolic demand often trigger symptoms. Affected children may develop lethargy, vomiting, and hypoketotic hypoglycemia, often accompanied by hepatomegaly and liver dysfunction. In severe cases, seizures, coma, or sudden unexpected death may occur, especially if the condition is undiagnosed. Some adults may remain asymptomatic or experience only mild symptoms during periods of metabolic stress.
Diagnosis
Treatment
Prognosis
The prognosis is excellent with early diagnosis and management. Children diagnosed through newborn screening and managed properly can live normal lives with normal development. The risk of sudden death remains in undiagnosed or non-compliant individuals, particularly during illness or fasting.
Mitochondrial Myopathy
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes)
Introduction
MELAS is a progressive multisystem mitochondrial disorder primarily affecting the nervous system and muscles. It is characterized by a combination of encephalopathy, lactic acidosis, and recurrent stroke-like episodes, often beginning in childhood or adolescence. MELAS is caused by mutations in mitochondrial DNA (mtDNA), leading to impaired oxidative phosphorylation and deficient cellular energy production.
Epidemiology
MELAS is estimated to affect between 1 in 4,000 and 1 in 25,000 individuals. It is maternally inherited due to mutations in mitochondrial DNA. The most common genetic cause is the m.3243A>G mutation in the MT-TL1 gene, though other mtDNA mutations may also be responsible.
Pathophysiology
Mitochondria are critical for energy production via oxidative phosphorylation. Mutations in mtDNA impair this process, leading to decreased ATP production and increased reliance on anaerobic metabolism, resulting in lactic acidosis. Neurons and muscle cells, which are highly energy-dependent, are particularly vulnerable. The “stroke-like episodes” are not true vascular strokes but are believed to be due to mitochondrial energy failure in cerebral tissues, leading to neuronal injury and dysfunction.
Pathology
Clinical Manifestations
MELAS usually begins in childhood or adolescence, though symptoms may also appear in adulthood. A hallmark of the condition is stroke-like episodes before the age of 40, which can present with seizures, hemiparesis, cortical blindness, or altered consciousness. Encephalopathy with seizures and progressive cognitive decline or dementia is also common. Lactic acidosis or elevated lactate levels in blood and cerebrospinal fluid are key biochemical findings.
Other frequent symptoms include muscle weakness, exercise intolerance, hearing loss, migraines, and short stature. Additional complications may involve diabetes mellitus, gastrointestinal dysmotility, and cardiac problems such as cardiomyopathy or conduction defects.
Diagnosis
Treatment
No curative treatment exists, but management focuses on symptom relief and supportive care.
Prognosis
MELAS is a progressive disorder, and prognosis depends on mutation load, organs affected, and severity of complications. Most individuals experience gradual neurological decline, and many become wheelchair-dependent. Life expectancy is often reduced, with death commonly occurring in early adulthood, though milder cases can live into middle age or beyond with appropriate care.
MERRF (Myoclonic Epilepsy with Ragged Red Fibers)
Introduction
MERRF is a rare, progressive mitochondrial disease affecting multiple organ systems, particularly the nervous and muscles. It is characterized by myoclonus (involuntary muscle jerks), epileptic seizures, ataxia, and muscle weakness. The disease is caused by mutations in mitochondrial DNA (mtDNA), leading to impaired oxidative phosphorylation and reduced cellular energy.
Epidemiology
MERRF is rare, with an estimated prevalence of less than 1 in 100,000 individuals. It is maternally inherited, as mitochondrial DNA is passed only from the mother. The most common genetic cause is the m.8344A>G mutation in the MT-TK gene, which encodes tRNA^Lys. Other mtDNA mutations can also cause similar clinical presentations.
Pathophysiology
Mitochondria are essential for cellular energy production via oxidative phosphorylation. Mutations in mtDNA affect mitochondrial protein synthesis, leading to dysfunction in the respiratory chain complexes. This decreases ATP production, especially in energy-demanding tissues such as muscles and neurons. The increased reliance on anaerobic metabolism leads to lactic acidosis. Neurological symptoms arise from energy deficiency in both the central and peripheral nervous systems.
Pathology
Muscle biopsy is central to diagnosis: Ragged red fibers (abnormal accumulation of mitochondria in muscle cells, visible with Gomori trichrome staining) COX-negative fibers Reduced activity in the respiratory chain enzyme complexes Brain pathology may show neuronal degeneration and gliosis in the brainstem and cerebellum.
Clinical Manifestations
MERRF typically begins in childhood or early adolescence, with hallmark symptoms such as myoclonus, generalized epileptic seizures, ataxia, muscle weakness, and hypotonia. Patients often develop slowly progressive dementia, sensorineural hearing loss, and lactic acidosis. Other possible symptoms include short stature, peripheral neuropathy, scoliosis, cardiomyopathy, and respiratory problems.
Diagnosis
Treatment
Prognosis
MERRF is a progressive disorder, and its course varies depending on the mutation and the proportion of mutated DNA in different tissues (heteroplasmy). Many patients experience increasing neurological disability, and the disease can result in significant functional impairment. Life expectancy is often reduced, but some individuals can live into adulthood with a good quality of life if symptoms are managed effectively.
Kearns-Sayre Syndrome (KSS)
Introduction
Kearns-Sayre Syndrome (KSS) is a rare, progressive mitochondrial disorder primarily affecting the eyes, muscles, and other organ systems. It is characterized by a triad of chronic progressive external ophthalmoplegia (CPEO), pigmentary retinopathy, and onset before age 20. The condition is caused by large-scale deletions in mitochondrial DNA (mtDNA), leading to impaired oxidative phosphorylation and deficient cellular energy production.
Epidemiology
KSS is rare, with an estimated prevalence of 1 to 3 per 100,000 individuals. It is not inherited in a typical Mendelian pattern but arises from sporadic mutations in mtDNA. In most cases, the deletion is present in a heteroplasmic state, meaning only some of the mitochondria carry the mutation.
Pathophysiology
Mitochondria generate cellular energy via oxidative phosphorylation. Large deletions in mtDNA affect genes critical for the function of the respiratory chain complexes. This disrupts ATP production, especially in high-energy-demand tissues such as muscles, the brain, the heart, and the eyes. The resulting energy deficit underlies the multisystem manifestations of KSS.
Pathology
Muscle biopsy findings: Ragged red fibers (accumulation of abnormal mitochondria, seen with Gomori trichrome staining) COX-negative fibers (deficient cytochrome c oxidase activity) Decreased activity of mitochondrial respiratory chain complexes Cardiac and neural tissues may show degenerative changes on histological examination.
Clinical Manifestations
Kearns-Sayre Syndrome (KSS) typically begins before age 20, often during adolescence. The classic triad consists of chronic progressive external ophthalmoplegia with bilateral ptosis, pigmentary retinopathy causing visual disturbances, and early disease onset. Other common features include cardiac conduction defects, cerebellar ataxia, short stature, hearing loss, diabetes mellitus, and proximal muscle weakness. Endocrine abnormalities such as hypoparathyroidism and growth hormone deficiency may also occur.
Diagnosis
Treatment
There is no curative treatment, but management focuses on symptom control and complication monitoring.
Prognosis
KSS is a progressive disorder, and prognosis depends on the severity and extent of organ involvement. Cardiac complications, particularly heart block, are a significant cause of morbidity and mortality and require careful monitoring. Some individuals can live into adulthood with appropriate management, although life expectancy is often reduced.
Myoadenylate Deaminase Deficiency (MADD)
Introduction
Myoadenylate deaminase deficiency (AMP deaminase deficiency) is a metabolic myopathy affecting skeletal muscle energy metabolism. It results from a deficiency of the enzyme myoadenylate deaminase, which plays a key role in the purine nucleotide cycle and is important for ATP regeneration during exercise. The condition can be inherited (primary) or acquired (secondary).
Epidemiology
Primary MADD is relatively common, with a prevalence estimated between 1% and 2% in the general population, although many individuals are asymptomatic. It is inherited in an autosomal recessive pattern and is most frequently caused by mutations in the AMPD1 gene.
Pathophysiology
Myoadenylate deaminase is essential for converting AMP to IMP and ammonia during muscle contraction. In deficiency states, the inability to process AMP properly leads to impaired ATP regeneration, particularly during periods of high energy demand like exercise. This results in muscle fatigue and exercise intolerance. Accumulation of AMP can also cause secondary metabolic disturbances.
Pathology
Muscle biopsy in affected individuals is often normal or may show subtle abnormalities. Histochemical staining for myoadenylate deaminase activity can confirm enzyme deficiency. There is typically no evidence of inflammation or necrosis.
Clinical Manifestations
Symptoms of myoadenylate deaminase deficiency typically begin in adolescence or adulthood and may include exercise-induced muscle pain, fatigue, cramps, and weakness. Some individuals experience myoglobinuria after intense physical activity. Others may remain asymptomatic and are diagnosed incidentally through muscle biopsy or genetic testing.
Diagnosis
Treatment
Prognosis
The prognosis is generally excellent. Many individuals with MADD are asymptomatic or have only mild symptoms. With lifestyle modification, most patients can lead normal lives without significant limitations.
Myopathy Due to Other Metabolic Pathway Disorder
Phosphoglycerate Kinase Deficiency (PGK Deficiency)
Introduction
Phosphoglycerate kinase (PGK) deficiency is a rare X-linked metabolic disorder that affects glycolysis, the process by which cells generate energy from glucose. The condition is caused by mutations in the PGK1 gene, which encodes the enzyme phosphoglycerate kinase 1. This enzyme is essential for ATP production during glycolysis and is expressed in most tissues, especially red blood cells and muscle.
Epidemiology
PGK deficiency is rare, with only a few hundred cases reported globally. Due to its X-linked inheritance, it primarily affects males, although carrier females may sometimes show mild symptoms.
Pathophysiology
PGK1 catalyzes the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate with the generation of ATP. Deficiency in this enzyme impairs glycolysis, especially under anaerobic conditions, leading to reduced energy production. This primarily affects tissues with high energy demands, such as red blood cells, skeletal muscle, and the brain.
Pathology
Muscle biopsy typically does not reveal specific findings, although some patients may show mild myopathic changes. Hemolysis in red blood cells can result in elevated bilirubin or other markers of hemolysis. The enzyme assay in red blood cells or fibroblasts confirms reduced PGK activity.
Clinical Manifestations
Phosphoglycerate kinase (PGK) deficiency presents various symptoms that can vary between individuals. Common features include hemolytic anemia, which may be chronic or triggered by stress or infection, and muscle-related symptoms such as exercise intolerance, cramps, and rhabdomyolysis. Some patients also exhibit neurological symptoms like developmental delay or seizures, and hyperuricemia may occur due to excess purine breakdown. The combination and severity of symptoms depend on the specific gene mutation and the level of remaining enzyme activity.
Diagnosis
Treatment
Prognosis
Prognosis varies depending on the phenotype. Some patients may have only mild anemia and live relatively normal lives, while others with severe myopathy or neurological involvement may have significant disability.
