GENETIC DISEASES OF THE MUSCLES DR. MARWA.pdf

GENETIC DISEASES OF THE MUSCLES BY/ DR. MARWA KAMEL LECTURER OF MEDICAL BIOCHEMISTRY &MOLECULAR BIOLOGY  Lecture’s Objectives ⦿ Describe disorders due to genetic mutations of proteins involved in muscle contraction. ⦿ Recognize disorders due to inherited mutations in genes coding for enzyme...

GENETIC DISEASES OF THE MUSCLES BY/ DR. MARWA KAMEL LECTURER OF MEDICAL BIOCHEMISTRY &MOLECULAR BIOLOGY  Lecture’s Objectives ⦿ Describe disorders due to genetic mutations of proteins involved in muscle contraction. ⦿ Recognize disorders due to inherited mutations in genes coding for enzymes involved in metabolic pathways.  1. Duchenne Muscular Dystrophy (DMD) Due to Mutation in the gene coding for dystrophin- glycoprotein complex Cause: deficiency of dystrophin, resulting in progressive loss of muscle fibers  Dystrophin anchors (bridges) the actin cytoskeleton to the extracellular matrix at the interior face of the plasma membrane.  Such link is important for assembly of the synaptic junction. 1. Duchenne Muscular Dystrophy (cont.)  1. Duchenne Muscular Dystrophy (cont.) X linked recessive disease; males affected Serious form of muscular dystrophy; usually fatal by the age of 30 Typical feature: The child uses his hands to climb up (Gower’s sign) ,while getting up from the floor. Wheelchair by age 12, Fatal by age 30 Progressive muscle weakness, that becomes apparent by age 4 and Cardiomegaly Enlargement occurs due to gradual degeneration & necrosis of muscle fibers that are replaced by more fibrous & fatty tissue. Gowers sign 1. Duchenne Muscular Dystrophy (cont.)  2. Inherited Cardiomyopathies  Definition:  It is a heterogenous group of disease of myocardium, associated with mechanical and/or electrical dysfunction, which is usually exhibits inappropriate ventricular hypertrophy or dilation.  They are due to variety of etiologies that frequently are genetic.  Characterized by myocyte damage.  Multiple etiologies with similar resultant pathophysiology.  In 20-50 % of cases, the disease is recognized as familial.  mutations in several cardiac structural or metabolic genes have been identified.  2. Inherited Cardiomyopathies  Disorders of cardiac energy metabolism occur due to: 1. Mutations in genes of enzymes involved in fatty acid oxidation or oxidative phosphorylation.  N.B. fatty acid oxidation is an important energy source for cardiac muscle. 2. Mutations in genes encoding proteins involved in or affecting myocardial contraction. (myosin, tropomysin, troponins,…etc).  Some cardiomyopathies are monogenic disorders  Some show genetic heterogeneity (e.g., distinct genes that cause the same disease).  Some show allelic variation (distinct mutations in the same gene).  3. Muscle Disorders due to Metabolic Defects  Some of Glycogen Storage Disease affect muscles. What are glycogen storage diseases (GSD)?  They are metabolic defects concerned with the glycogen synthesis and degradation. These disorders are due to defects in the enzymes and characterized by deposition of normal or abnormal type of glycogen in one or more tissues.  The muscle forms (type II, V and VII) have mild symptoms appearing during strenuous exercises owing the inability to provide energy for muscle contraction (MS. GLYCOGEN).  Type II (GSD-II), Pompe’s disease.  Type V, McArdle disease.  Type VII, Tarui’s disease.  3. Muscle Disorders due to Metabolic Defects (cont.) 1. Type II (GSD-II), Pompe’s disease: (lysosomal Storage Disease)  Cause:  The deficiency of the lysosomal enzyme alpha-1,4-glucosidase leads to the accumulation of glycogen in many tissues.  Clinical feature: In the infantile form, accumulation of glycogen in cardiac muscle leads to cardiac failure. Accumulation may also occur in the liver, which results in hepatomegaly and elevation of hepatic enzymes. Glycogen accumulation in muscle and peripheral nerves causes hypotonia and weakness.  3. Muscle Disorders due to Metabolic Defects (cont.) 2. Type V GSD, McArdle's disease Cause: Myophosphorylase deficiency. Affected tissue: Skeletal Muscle. Clinical features:  hypotonia, reduced reflexes, severe muscle cramps and fatigue in the first few minutes of activity.  Some adults develop a progressive proximal motor weakness.  About one half of all patients will have experienced myoglobinuria (dark urine) following intense exercise, with muscle cramps after exercise, Increased plasma creatine kinase activity at rest, failure of ischemic exercise to increase serum lactate concentrations while producing an exaggerated increase in ammonia, myoglobinuria.  3. Muscle Disorders due to Metabolic Defects (cont.)  Tarui ’s disease Type VII, (Phosphofructokinase deficiency)  Cause: Phosphofructokinase (PFK) deficiency. This disease is one of the metabolic muscle disorders that interferes with the processing of food for energy production.  Affected tissue: Muscle.  Clinical features:  Exercise intolerance, muscle cramping, exertional myopathy, compensated haemolysis and myoglobinuria and hyperbilirubinemia.  Note : Symptoms can be similar to McArdle's Glycogen Storage Disease but more severe.  Patients have abnormal glycogen in muscle.  Glycogen Storage Diseases  Definition: a group of genetic diseases characterized by accumulation of normal or abnormal glycogen due to deficiency of one of the enzymes of glycogen metabolism  rare (overall incidence of ~1:25,000 births).  A particular enzyme defect in a single tissue, such as the liver, or the defect may be more generalized, affecting liver, muscle, kidney, intestine, and myocardium.  The severity of the glycogen storage diseases (GSDs) ranges from fatal in infancy to mild disorders that are not life-threatening.  Deficiency of Enzymes of either glycogen synthesis or glycogen break down.  Deposition of normal or Abnormal Glycogen in tissues & Disorders of Glycogen metabolism. Glycogen Storage Diseases  Glycogen storage diseases (cont.)  Types: 1. Hepatic (I, III, IV ,VI and VIII) 2. Myopathic (type II, V and VII) General features: ❑ Hypoglycemia, hepatomegaly (due to accumulation of glycogen in liver). ❑ lactic acidosis, Muscle weakness, cramps, pain , easy fatigue in myopathic forms. ❑ Hepatic fibrosis, poor exercise tolerance.