Myasthenia Gravis

Description

• A neuromuscular (NM) disease presenting with varying weakness that worsens with exercise and improves with rest
• Three types of myasthenia gravis seen in childhood:
  • Neonatal transient
    • 10–20% of infants born to mothers with autoimmune myasthenia
  • Congenital myasthenia
    • Rare; represents <10% of all childhood myasthenia
    • Weakness usually starts within first 2 years of life.
    • Caused by inherited disorder in NM transmission
    • Classified by mutation site (presynaptic, postsynaptic) or by molecular genetics
  • Juvenile myasthenia
    • Relatively rare: one new diagnosis per million per year
    • Average age of onset 10 to 13 years, with a female predominance of 2:1 or 4:1
    • Autoimmune disorder similar to adult-onset, autoimmune myasthenia gravis; mostly due to production of antibodies against the acetylcholine receptor (AChR)

Epidemiology

• Rare: incidence 4 to 6 per million per year
• Prevalence: 40 to 80 per million
• Children account for 10–15% of cases of myasthenia gravis annually in North America.

Risk Factors

Pathophysiology

• Caused by a disruption in signal transmission from the motor neuron to the muscle. Sensory or cognitive symptoms are absent.
  • The motor nerve terminal lies in close proximity to the end plate, a region of the muscle cell membrane with a high concentration of AChR.
  • Normally, when stimulated, the motor nerve terminal releases acetylcholine that binds receptors, causing muscle contraction. The cleft contains acetylcholinesterase (AChE), an enzyme that breaks down acetylcholine and helps terminate muscle contractions.
• Autoimmune form (juvenile myasthenia or juvenile myasthenia gravis [JMG])
  • Autoantibody blocks AChR activity → increased rate of receptor breakdown → fewer receptors are present → leads to decreased muscle contraction
  • AChR antibody accounts for ~85% of JMG.
  • Thymic pathology is believed to be central to pathogenesis of autoimmune myasthenia; however, thymic pathology (e.g., hyperplasia) is present in <1/3 of children who undergo thymectomy.
  • Of JMG patients without elevated AChR antibody, some are positive for antibodies to muscle-specific kinase (MuSK).
  • A small percentage of autoimmune JMG patients do not have an identified antibody.
• Neonatal (transient) myasthenia: Infants are born with weakness and hypotonia.
  • Due to maternal–fetal transmission of antibodies against AChR
  • Severity of maternal symptoms does NOT predict likelihood that infant will be affected. Occasional arthrogryposis (joint contractures) reflects decreased fetal movement in utero.
  • High levels of maternal antibodies against fetal form of AChR pose an increased risk of disease.
  • Previous pregnancy with affected infant places future child at much higher risk.
  • In rare cases, mother is asymptomatic despite placentally transmitted antibody.
• Congenital myasthenic syndromes: group of genetic disorders of NM junction; classified by site of NM transmission defect and more recently by molecular genetics
  • Includes presynaptic defects, synaptic defect (due to end plate AChE deficiency), postsynaptic defects (primary AChR deficiency, primary AChR kinetic abnormality, or perijunctional skeletal muscle sodium channel mutation)

Commonly Associated Conditions

• In juvenile myasthenia, other autoimmune disorders may occur:
  • Hyperthyroidism in 3–9% of patients
  • Small increase in incidence of type 1 diabetes
• Screening for thymoma at initial diagnosis by chest CT or MRI scan is appropriate:
  • Children appear to have lower incidence of thymic tumor or pathology than adults with autoimmune myasthenia.