Duchenne Muscular Dystrophy and Genetics
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Questions and Answers

What is the typical consequence of a deletion or frameshift mutation in the dystrophin gene in Duchenne Muscular Dystrophy?

  • A complete absence of muscle weakness
  • An improvement in muscle regeneration
  • A severe, progressive phenotype (correct)
  • A mild, non-progressive phenotype

    • What is the characteristic feature of muscle fibers in muscular dystrophies?

  • Muscle fiber atrophy
  • Muscle fiber inflammation
  • Muscle fiber necrosis and regeneration (correct)
  • Muscle fiber hypertrophy

    • What is the mode of inheritance of Duchenne Muscular Dystrophy?

  • Autosomal recessive
  • Autosomal dominant
  • X-linked (correct)
  • Mitochondrial

    • What is the effect of unfavourable X-chromosome inactivation in female carriers of Duchenne Muscular Dystrophy?

    <p>They are mildly symptomatic</p> Signup and view all the answers

    What is the diagnosis of a patient with muscle weakness, muscle wasting, and an elevated creatine kinase level?

    <p>Duchenne Muscular Dystrophy</p> Signup and view all the answers

    What is the underlying cause of Statin myopathy?

    <p>Toxic effects of statins</p> Signup and view all the answers

    What is the characteristic feature of Myotonic Dystrophy?

    <p>Muscle stiffness and myotonia</p> Signup and view all the answers

    What is the prognosis of Duchenne Muscular Dystrophy?

    <p>Severe, with rapid progression</p> Signup and view all the answers

    What is the rate-limiting step in cholesterol synthesis?

    <p>Conversion of HMG CoA to mevalonate</p> Signup and view all the answers

    What is the effect of high cholesterol levels on the rate-limiting step of cholesterol synthesis?

    <p>Inhibition of HMG-CoA reductase activity</p> Signup and view all the answers

    What is the role of the thymus in the etiology of Myasthenia Gravis?

    <p>It is involved in immune dysregulation and development of autoantibodies</p> Signup and view all the answers

    What is the prevalence of Myasthenia Gravis?

    <p>150-200 per 1 million</p> Signup and view all the answers

    What is the effect of statin drugs on cholesterol synthesis?

    <p>Inhibition of HMG-CoA reductase activity</p> Signup and view all the answers

    What is the product of the reaction catalyzed by HMG-CoA reductase?

    <p>Mevalonate</p> Signup and view all the answers

    What is the association between anti-Ach receptor autoantibodies and thymic abnormalities?

    <p>Strong association</p> Signup and view all the answers

    What is the sex distribution of Myasthenia Gravis in young adults?

    <p>More common in females</p> Signup and view all the answers

    What is the average age of wheelchair dependence in patients with Duchenne Muscular Dystrophy?

    <p>9-10 years</p> Signup and view all the answers

    What is the reason for the decrease in creatine kinase levels in patients with Duchenne Muscular Dystrophy as the disease progresses?

    <p>Due to loss of muscle mass</p> Signup and view all the answers

    What is the mode of inheritance of Becker Muscular Dystrophy?

    <p>X-linked</p> Signup and view all the answers

    What is the pathogenic mechanism of myotonia in Myotonic Dystrophy type I?

    <p>Gain-of-function effect of CGT triplet repeat expansion</p> Signup and view all the answers

    What is the common feature of both Duchenne and Becker Muscular Dystrophy?

    <p>X-linked mutation in dystrophin</p> Signup and view all the answers

    What is the epidemiology of Myotonic Dystrophy?

    <p>1 in 8,000 individuals</p> Signup and view all the answers

    What is the prognosis of patients with Becker Muscular Dystrophy?

    <p>Near-normal life expectancy</p> Signup and view all the answers

    What is the function of the CNBP gene in Myotonic Dystrophy type II?

    <p>Coding for a zinc-finger DNA binding protein</p> Signup and view all the answers

    What is the clinical feature of Myotonic Dystrophy type I that affects involuntary muscles?

    <p>Myotonia of involuntary muscles</p> Signup and view all the answers

    What is the risk of cardiomyopathy in female carriers of Duchenne Muscular Dystrophy?

    <p>Increased risk</p> Signup and view all the answers

    What is the primary characteristic of fibromyalgia?

    <p>A neurological disorder characterized by abnormalities in pain processing</p> Signup and view all the answers

    In which age group and sex is fibromyalgia most commonly present?

    <p>Young-adult to middle age females</p> Signup and view all the answers

    What is the primary method used to diagnose fibromyalgia?

    <p>Widespread pain index and self-administered patient questionnaire</p> Signup and view all the answers

    What is the purpose of the manual tender-points survey in diagnosing fibromyalgia?

    <p>To identify the presence of tender points in specific body regions</p> Signup and view all the answers

    What is the scoring range for the widespread pain index?

    <p>0-19</p> Signup and view all the answers

    What is the purpose of section 2 of the self-administered patient questionnaire?

    <p>To assess the severity of problems with daytime fatigue, nonrestorative sleep, and cognitive dysfunction</p> Signup and view all the answers

    What is the minimum score required for a diagnosis of fibromyalgia?

    <p>13</p> Signup and view all the answers

    What is the term used to describe fibromyalgia?

    <p>Central sensitivity syndrome</p> Signup and view all the answers

    What is the primary mechanism by which auto-antibodies to acetylcholine receptors lead to muscle weakness in Myasthenia Gravis?

    <p>By decreasing the turnover of acetylcholine receptors, leading to a decrease in their overall number</p> Signup and view all the answers

    What is the most common age of onset for Rhabdomyosarcoma?

    <p>Before age 20</p> Signup and view all the answers

    What is the primary treatment for Myasthenia Gravis?

    <p>Acetylcholinesterase inhibitors</p> Signup and view all the answers

    What is the characteristic feature of Synovial Cell Sarcoma?

    <p>Chromosomal translocation involving the SYT and SSX genes</p> Signup and view all the answers

    What is the primary symptom of Fibromyalgia?

    <p>Persistent widespread pain</p> Signup and view all the answers

    What is the prognosis for Myasthenia Gravis?

    <p>Good, with a significant improvement in symptoms with current therapies</p> Signup and view all the answers

    What is the characteristic location of Synovial Cell Sarcoma?

    <p>Extremities, particularly around the knee</p> Signup and view all the answers

    What is the characteristic feature of Rhabdomyosarcoma cells?

    <p>Presence of myosin and actin filaments</p> Signup and view all the answers

    What is the primary complication of Myasthenia Gravis?

    <p>All of the above</p> Signup and view all the answers

    What is the characteristic feature of the Embryonal type of Rhabdomyosarcoma?

    <p>Tumors occur in the mucosal cavities</p> Signup and view all the answers

    What is the characteristic feature of muscle fibers in a 3-year-old boy with Duchenne Muscular Dystrophy?

    <p>Variable muscle fiber size with clusters of regenerating fibers</p> Signup and view all the answers

    What is the difference between the muscle biopsy of the 3-year-old and 9-year-old brothers with Duchenne Muscular Dystrophy?

    <p>The 3-year-old has slight endomysial fibrosis, while the 9-year-old has extensive fibrosis</p> Signup and view all the answers

    What is the effect of muscle remodeling on the fascicular architecture in Duchenne Muscular Dystrophy?

    <p>It leads to a significant alteration of the fascicular architecture over time</p> Signup and view all the answers

    What is the histological feature that is more prominent in the 9-year-old boy with Duchenne Muscular Dystrophy compared to the 3-year-old boy?

    <p>Variation in muscle fiber size</p> Signup and view all the answers

    What is the change in muscle fiber size that occurs in Duchenne Muscular Dystrophy over time?

    <p>There is a significant variation in muscle fiber size</p> Signup and view all the answers

    What is the effect of Duchenne Muscular Dystrophy on muscle fibers?

    <p>They vary from small atrophic to large hypertrophied fibers</p> Signup and view all the answers

    What is the change in fascicular architecture in Duchenne Muscular Dystrophy?

    <p>It becomes significantly altered over time</p> Signup and view all the answers

    What is the characteristic feature of the muscle biopsy of the 3-year-old boy with Duchenne Muscular Dystrophy?

    <p>Clusters of regenerating muscle fibers with variable muscle fiber size</p> Signup and view all the answers

    What is the primary source of carbon atoms in cholesterol synthesis?

    <p>Acetyl CoA</p> Signup and view all the answers

    Which of the following is NOT a characteristic feature of Myasthenia Gravis?

    <p>Increased creatine kinase levels</p> Signup and view all the answers

    What is the effect of statin drugs on cholesterol synthesis?

    <p>Decrease the rate of cholesterol synthesis</p> Signup and view all the answers

    What is the product of the reaction catalyzed by HMG-CoA reductase?

    <p>Mevalonate</p> Signup and view all the answers

    What is the prevalence of Myasthenia Gravis per 1 million people?

    <p>150-200</p> Signup and view all the answers

    What is the rate-limiting step of cholesterol synthesis?

    <p>Formation of mevalonate</p> Signup and view all the answers

    What is the association between anti-Ach receptor autoantibodies and thymic abnormalities in Myasthenia Gravis?

    <p>Strong association</p> Signup and view all the answers

    What is the sex distribution of Myasthenia Gravis in young adults?

    <p>More common in females</p> Signup and view all the answers

    What is the primary mechanism by which dystrophin deficiency leads to muscle weakness in Duchenne Muscular Dystrophy?

    <p>Disruption of the sarcolemma, leading to muscle fiber necrosis</p> Signup and view all the answers

    Which of the following is a characteristic feature of Becker Muscular Dystrophy?

    <p>Truncated dystrophin protein with partial function</p> Signup and view all the answers

    What is the pathogenic mechanism underlying myotonia in Myotonic Dystrophy type I?

    <p>Abnormal splicing of mRNA transcripts of the DMPK gene</p> Signup and view all the answers

    What is the average age of death in patients with Duchenne Muscular Dystrophy?

    <p>25-30 years</p> Signup and view all the answers

    Which of the following is a common feature of both Duchenne and Becker Muscular Dystrophy?

    <p>Progressive muscle weakness</p> Signup and view all the answers

    What is the primary clinical feature of Myotonic Dystrophy type I that affects involuntary muscles?

    <p>Gastrointestinal dysmotility</p> Signup and view all the answers

    What is the epidemiology of Myotonic Dystrophy?

    <p>Affects 1 in 8,000 individuals</p> Signup and view all the answers

    What is the function of the CNBP gene in Myotonic Dystrophy type II?

    <p>Codes for a zinc-finger DNA binding protein</p> Signup and view all the answers

    What is the risk of cardiomyopathy in female carriers of Duchenne Muscular Dystrophy?

    <p>Increased risk</p> Signup and view all the answers

    What is the prognosis of patients with Becker Muscular Dystrophy?

    <p>Near-normal life expectancy</p> Signup and view all the answers

    What is the primary mechanism by which auto-antibodies to acetylcholine receptors lead to muscle weakness in Myasthenia Gravis?

    <p>Blocking the activation of acetylcholine receptors</p> Signup and view all the answers

    What is the primary characteristic of fibromyalgia?

    <p>A neurosensory disorder characterized by abnormalities in pain processing</p> Signup and view all the answers

    Which of the following is a characteristic feature of Rhabdomyosarcoma cells?

    <p>Rich in myosin and actin filaments</p> Signup and view all the answers

    What is the primary complication of Myasthenia Gravis?

    <p>All of the above</p> Signup and view all the answers

    What is the purpose of the self-administered patient questionnaire in diagnosing fibromyalgia?

    <p>To assess the severity of problems with daytime fatigue, nonrestorative sleep, and cognitive dysfunction</p> Signup and view all the answers

    Which of the following is a characteristic feature of Synovial Cell Sarcoma?

    <p>All of the above</p> Signup and view all the answers

    What is the scoring range for the widespread pain index (WPI)?

    <p>0-19</p> Signup and view all the answers

    What is the term used to describe fibromyalgia?

    <p>A central sensitivity syndrome</p> Signup and view all the answers

    What is the primary treatment for Myasthenia Gravis?

    <p>Acetylcholinesterase inhibitors</p> Signup and view all the answers

    What is the characteristic feature of the Embryonal type of Rhabdomyosarcoma?

    <p>Tumors in mucosal cavities</p> Signup and view all the answers

    What is the epidemiology of fibromyalgia?

    <p>It can occur in patients of either sex or any age, but most commonly presents in young-adult to middle-aged females</p> Signup and view all the answers

    What is the prognosis for Myasthenia Gravis?

    <p>Good prognosis with current therapies</p> Signup and view all the answers

    What is the minimum score required for a diagnosis of fibromyalgia?

    <p>13 or greater</p> Signup and view all the answers

    What is the characteristic location of Synovial Cell Sarcoma?

    <p>Any part of the appendicular skeleton</p> Signup and view all the answers

    What is the purpose of the manual tender-points survey in diagnosing fibromyalgia?

    <p>It is used during physical exam to assess tenderness, but is not required for diagnosis</p> Signup and view all the answers

    What is the primary symptom of Fibromyalgia?

    <p>Persistent widespread pain</p> Signup and view all the answers

    What is the primary method used to diagnose fibromyalgia?

    <p>Widespread pain index (WPI) and self-administered patient questionnaire</p> Signup and view all the answers

    Which of the following is a characteristic feature of Rhabdomyosarcoma?

    <p>Malignant mesenchymal tumor with skeletal muscle differentiation</p> Signup and view all the answers

    Study Notes

    Skeletal Muscle Pathology

    Muscular Dystrophies

    • Muscular dystrophies are a group of inherited muscle disorders leading to progressive weakness and muscle wasting.
    • Characterized by muscle fiber necrosis and regeneration.
    • Three types: Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Myotonic Dystrophy.

    Duchenne Muscular Dystrophy

    • Etiology: X-linked, loss-of-function mutation of a structural protein called dystrophin.
    • Epidemiology: 1 in 5,000 male births.
    • Clinical Features:
      • Normal at birth, but early motor milestones are met, and walking is often delayed.
      • Clumsiness and inability to keep up with peers are the first indications of muscle weakness.
      • Weakness begins in pelvic girdle muscles and extends to shoulder girdle.
      • (+) Gower's sign: patients often have to push off the thighs to stand from sitting.
      • Pseudohypertrophy of lower leg.
      • Cognitive impairment and learning disability are common.
    • Prognosis:
      • Eventual progression to wheelchair dependence (average age ~9.5 years).
      • Patients develop joint contractures, scoliosis, worsening respiratory reserve, and sleep hypoventilation.
      • Development of cardiomyopathies and arrhythmias can occur in older patients.
      • Mean age of death: 25-30 years of age (commonly from respiratory insufficiency, pulmonary infection, or heart failure).

    Becker Muscular Dystrophy

    • Etiology: X-linked mutation in dystrophin.
    • Epidemiology: 1 in 30,000 male births.
    • Clinical Features:
      • Onset later in childhood, adolescence, or adulthood.
      • Generally similar to Duchenne Muscular Dystrophy but less severe and with slower progression.
      • Patients are still at risk of developing dilated cardiomyopathy, but this is very rare.
    • Prognosis: Near-normal life expectancy.

    Myotonic Dystrophy

    • Etiology: Autosomal dominant disorder caused by expansion of triplet repeats.
    • Epidemiology: Affects 1 in 8,000 individuals.
    • Pathogenesis: Not well understood, but may result from a "toxic" gain-of-function effect by the CGT triplet repeat expansion.
    • Clinical Features:
      • Onset begins in adolescence or young adulthood.
      • Type I: Myotonia, weakness, and wasting of peripheral muscles and facial muscles.
      • Can also include: cardiomyopathy, intellectual disability, cataracts, and endocrine disorders.

    Statin Myopathy

    • Etiology: Caused by the cholesterol-lowering "statin" drugs.
    • Pathogenesis: Blocking the rate-limiting step of cholesterol synthesis.

    Myasthenia Gravis

    • Etiology: Autoimmune condition associated with autoantibodies directed against acetylcholine receptors.
    • Epidemiology: Prevalence of 150-200 per 1 million.
    • Pathogenesis: Ab-Ach receptor complexes lead to a variety of problems, ultimately limiting the ability of the myofiber to respond to Ach at the neuromuscular junction.
    • Clinical Features:
      • Fluctuating proximal muscle weakness.
      • Ptosis and diplopia are common initial findings.
      • Proximal muscle involvement, including diaphragm, neck, and facial muscles.
      • Weakness is usually worse with activity/exercise and improves with rest.
    • Diagnosis & Treatment:
      • Diagnosis based on clinical history, physical exam findings, (+) antibody screen, and electrophysiologic studies.
      • Prognosis has improved significantly with current therapies.
      • Complications can include pneumonia, falls, and myasthenic crisis.

    Skeletal Muscle Tumours

    • Rhabdomyosarcoma:
      • Malignant mesenchymal tumour with skeletal muscle differentiation.
      • 4 subtypes: Alveolar, Embryonal, Pleomorphic, Spindle cell/sclerosis.
      • Epidemiology: Alveolar and embryonal rhabdomyosarcoma are the most common soft tissue sarcoma of childhood.
      • Etiology: Chromosomal translocations commonly found, typically involving transcription factor involved in skeletal muscle differentiation.
    • Synovial Cell Sarcoma:
      • Most common soft tissue tumour in adolescents and young adults.
      • Epidemiology: 5-10% of all soft tissue sarcomas.
      • Etiology: Chromosomal translocation has been found in >90% of cases.

    Fibromyalgia

    • Epidemiology: Can occur in patients of either sex or any age, but most commonly presents in young-adult to middle-aged females.
    • Etiology & Pathogenesis: Not known, but considered a neurosensory disorder characterized by abnormalities in pain processing by the CNS.
    • Diagnostic Criteria:
      • Widespread pain index (WPI) and self-administered patient questionnaire.
      • Diagnosis is based on WPI and a score of 13 or greater on the polysymptomatic distress scale.

    Chronic Fatigue Syndrome

    • Epidemiology: Not specified.
    • Etiology & Pathogenesis: Not specified.
    • Clinical Features: Not specified.
    • Diagnostic Criteria: Not specified.

    Duchenne Muscular Dystrophy

    • Pathology:
      • Muscle biopsy shows variable muscle fiber size, clusters of regenerating muscle fibers, and slight endomysial fibrosis
      • Muscle fascicular architecture is initially preserved but becomes abnormal over time with muscle remodeling
    • Clinical Features:
      • Normal at birth, but early motor milestones are met, and walking is often delayed
      • Clumsiness and inability to keep up with peers are first indications of muscle weakness
      • Weakness begins in pelvic girdle muscles and extends to shoulder girdle
      • (+) Gower's sign: patient often has to push off the thighs to stand from sitting
      • Pseudohypertrophy of lower leg
      • Cognitive impairment and learning disability are common
    • Prognosis:
      • Eventual progression to wheelchair dependence at an average age of 9.5 years
      • Development of joint contractures, scoliosis, worsening respiratory reserve, and sleep hypoventilation
      • Development of cardiomyopathies and arrhythmias can occur in older patients due to the impact of dystrophin on cardiac muscle
      • Mean age of death is 25-30 years old, commonly due to respiratory insufficiency, pulmonary infection, or heart failure

    Becker Muscular Dystrophy

    • Etiology:
      • X-linked mutation in dystrophin, resulting in a truncated dystrophin protein that retains partial function
      • Milder phenotype than Duchenne muscular dystrophy with a later age of onset
    • Epidemiology:
      • Less common than Duchenne muscular dystrophy, with an incidence of 1 in 30,000 live male births
    • Clinical Features:
      • Onset later in childhood, adolescence, or adulthood
      • Generally similar to Duchenne muscular dystrophy but with a slower progression
      • Patients are still at risk of developing dilated cardiomyopathy, but this is rare compared to Duchenne muscular dystrophy
    • Prognosis:
      • Near-normal life expectancy

    Myotonic Dystrophy

    • Etiology:
      • Autosomal dominant disorder caused by expansion of triplet repeats
      • Type 1: expansion of CGT trinucleotide repeat within the myotonic dystrophy protein kinase (DMPK) gene
      • Type 2: CCTG repeat expansion within the gene nucleic acid-binding protein (CNBP) gene
    • Epidemiology:
      • Affects 1 in 8,000 individuals
    • Pathogenesis:
      • Not well understood, but type 1 may result in a "toxic" gain-of-function effect by the CGT triplet repeat expansion, disrupting splicing of mRNA transcripts of other proteins, including the transcript of a chloride channel (CLC1)
      • Lack of CLC1 may explain myotonia
    • Clinical Features:
      • Onset begins in adolescence or young adulthood
      • Type 1:
        • Myotonia, weakness, and wasting of peripheral muscles and facial muscles
        • Can also include cardiomyopathy, intellectual disability, cataracts, and endocrine disorders
      • Type 2:
        • CNBP gene codes for a zinc-finger DNA-binding protein

    Myasthenia Gravis

    • Etiology:
      • Autoimmune condition associated with autoantibodies directed against acetylcholine receptors
      • Strong association between anti-Ach receptor autoantibodies and thymic abnormalities (thymoma or thymic hyperplasia)
    • Epidemiology:
      • Prevalence of 150-200 per 1 million
      • In young adults, more commonly found in females, and in older adults, more commonly found in males
    • Pathogenesis and Pathophysiology:
      • Autoantibodies against the post-synaptic acetylcholine receptors (nicotinic receptors)
      • Ab-Ach receptor complexes lead to a variety of problems, ultimately limiting the ability of the myofiber to respond to Ach at the neuromuscular junction
    • Clinical Features:
      • Fluctuating proximal muscle weakness
      • Ptosis and diplopia are common initial findings
      • Proximal muscle involvement, including diaphragm, neck, and facial muscles
      • Weakness is usually worse with activity/exercise and improves with rest
    • Diagnosis and Treatment:
      • Based on clinical history, physical exam findings, (+) antibody screen, and electrophysiologic studies
      • Prognosis has improved significantly with current therapies
      • Complications can include pneumonia, falls, and myasthenic crisis
      • Treatment includes acetylcholinesterase inhibitors, plasmapheresis, and immunosuppressive drugs, and thymectomy for patients with a thymoma

    Skeletal Muscle Tumors

    • Nearly all skeletal muscle tumors are malignant
      • Occur in younger patients, usually with an onset before age 20
    • Rhabdomyosarcoma:
      • Malignant mesenchymal tumor with skeletal muscle differentiation
      • 4 subtypes: Alveolar, Embryonal, Pleomorphic, and Spindle cell/sclerosis
      • Epidemiology:
        • Alveolar and embryonal rhabdomyosarcoma are the most common soft tissue sarcoma of childhood
        • Incidence of 6/1,000,000/year in children under 15 years
      • Etiology:
        • Chromosomal translocations commonly found, typically involving transcription factor (PAX) involved in skeletal muscle differentiation
      • Clinical Features:
        • Tumor is detected as a mass, sometimes painful, and metastases tend to cause respiratory difficulties, bone pain, and bone marrow failure
        • Tumors can occur anywhere in the body, including head and neck, extremities, and genitourinary tract
      • Treatment and Prognosis:
        • Tumors are aggressive, with a poor survival rate in older children/adults and those with metastatic disease
        • Younger children with localized disease have a survival rate of about 80% 5 years after diagnosis
    • Synovial Cell Sarcoma:
      • Epidemiology:
        • Most common soft tissue tumor in adolescents and young adults
        • Represents 5-10% of all soft tissue sarcomas
        • Incidence: 2.75 per 100,000
      • Etiology:
        • Chromosomal translocation has been found in >90% of cases (fusion of SYT and SSX genes)
        • Origin and pathophysiology are unclear
      • Clinical Features:
        • Usually, a history of a long-standing nodule
        • Present for years, then increases rapidly in size over a few months
        • Tumor spreads along fascial planes, much more widespread than apparent on initial evaluation
        • Mass is often painless and deep
        • Usually situated around the knee, hands, and feet

    Fibromyalgia

    • Syndrome of persistent widespread pain, stiffness, fatigue, disrupted sleep, and cognitive difficulties
      • Often accompanied by anxiety/depression and impairment of activities of daily living
    • Epidemiology:
      • Can occur in patients of either sex or any age, but most commonly presents in young-adult to middle-aged females
    • Etiology and Pathogenesis:
      • Unknown
      • Now considered a neurosensory disorder characterized by abnormalities in pain processing by the CNS
      • Considered a central sensitivity syndrome
    • Diagnostic Criteria:
      • Diagnosis is based on widespread pain index (WPI) and self-administered patient questionnaire
      • Widespread pain index – score of 0-19
      • Self-administered patient questionnaire – score of 0-12
      • WPI/Section 1 is combined with total points for sections 2 & 3 to yield a score out of 0-31 (Polysymptomatic distress scale)
      • A score of 13 or greater, with symptoms being present at a similar level or severity for at least 3 months, and not explained by another disorder, is diagnostic of fibromyalgia

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