A 10-year-old boy is brought to the physician because of recurring episodes of achy muscle pain in his legs. He has a history of poor school performance despite tutoring and has been held back two grades. He is at the 40th percentile for height and 30th percentile for weight. Examination shows ptosis, a high-arched palate, and muscle weakness in the face and hands; muscle strength of the quadriceps and hamstrings is normal. Sensation is intact. Percussion of the thenar eminence causes the thumb to abduct and then relax slowly. Which of the following is the most likely underlying cause?

CTG trinucleotide expansion in the DMPK gene

Defect of voltage-gated sodium channels of the sarcolemmal membrane

Complete impairment of the dystrophin protein

Apoptosis of lower motor neurons

Humoral immune attack against the endomysial blood vessels

A 62-year-old woman is referred to a tertiary care hospital with a history of diplopia and fatigue for the past 3 months. She has also noticed difficulty in climbing the stairs and combing her hair. She confirms a history of 2.3 kg (5.0 lb) weight loss in the past 6 weeks and constipation. Past medical history is significant for type 2 diabetes mellitus. She has a 50-pack-year cigarette smoking history. Physical examination reveals a blood pressure of 135/78 mm Hg supine and 112/65 while standing, a heart rate of 82/min supine and 81/min while standing, and a temperature of 37.0°C (98.6°F). She is oriented to time and space. Her right upper eyelid is slightly drooped. She has difficulty in abducting the right eye. Pupils are bilaterally equal and reactive to light with accommodation. The corneal reflex is intact. Muscle strength is reduced in the proximal muscles of all 4 limbs, and the lower limbs are affected more when compared to the upper limbs. Deep tendon reflexes are bilaterally absent. After 10 minutes of cycling, the reflexes become positive. Sensory examination is normal. Diffuse wheezes are heard on chest auscultation. Which of the following findings is expected?

Incremental pattern on repetitive nerve conduction studies

Thymoma on CT scan of the chest

Periventricular plaques on MRI of the brain

Antibodies against muscle-specific kinase

A 13-year-old girl is brought to the physician by her mother because of a 1-month history of abnormal movements of her muscles that she cannot control. She has a younger brother with cognitive disabilities and epilepsy. Examination shows frequent, brief, involuntary contractions of the muscle groups of the upper arms, legs, and face that can be triggered by touch. An EEG shows generalized epileptiform activity. A trichrome stain of a skeletal muscle biopsy specimen shows muscle fibers with peripheral red inclusions that disrupt the normal fiber contour. Which of the following is the most likely underlying mechanism of the patient's symptoms?

Defective oxidative phosphorylation

CTG trinucleotide repeat expansion

Mutation of the methyl-CpG binding protein 2 gene

Autoimmune endomysial destruction

A 32-year-old woman presents with diplopia. She says that she has been experiencing drooping of her eyelids and severe muscle weakness. She reports that her symptoms are worse at the end of the day. Which of the following additional findings would most likely be seen in this patient?

Increased acetylcholine receptor antibody

Albuminocytological dissociation in the cerebrospinal fluid

Increased calcium channel receptor antibodies

Increased serum creatine kinase levels

Increased antinuclear antibodies

You are conducting a lab experiment on skeletal muscle tissue to examine force in different settings. The skeletal muscle tissue is hanging down from a hook. The experiment has 3 different phases. In the first phase, you compress the muscle tissue upwards, making it shorter. In the second phase, you attach a weight of 2.3 kg (5 lb) to its lower vertical end. In the third phase, you do not manipulate the muscle length at all. At the end of the study, you see that the tension is higher in the second phase than in the first one. What is the mechanism underlying this result?

Lengthening of the muscle in phase 2 increases passive tension.

The tension in phase 1 is only active, while in phase 2 it is both active and passive.

Shortening the muscle in phase 1 pulls the actin and myosin filaments apart.

There are more actin-myosin cross-bridges attached in phase 2 than in phase 1.

Shortening of the muscle in phase 1 uses up ATP stores.

Skeletal muscle diseases for USMLE Step 1: High-Yield Pathology Lessons

Muscle Histology & Injury - The Basic Blueprint

Basic Units:
- Type 1 Fibers: Slow-twitch, red, high myoglobin/mitochondria (oxidative).
- Type 2 Fibers: Fast-twitch, white, low myoglobin/mitochondria (glycolytic).
Organization:
- Fibers are arranged in a checkerboard pattern.
- Motor Unit: A single motor neuron and all the muscle fibers it innervates.
Injury & Repair:
- Segmental Necrosis: Damage to a portion of a myofiber.
- Regeneration: Satellite cells are the muscle stem cells.

⭐ Fiber type grouping (loss of checkerboard pattern) is the histologic hallmark of chronic denervation and reinnervation.

Muscular Dystrophies - Genetic Muscle Wasting

Inherited, progressive disorders causing muscle fiber degeneration and weakness.
Duchenne Muscular Dystrophy (DMD):
- X-linked recessive frameshift mutation in the dystrophin (DMD) gene → absent dystrophin.
- Onset before age 5. Progressive proximal weakness.
- Features: Gowers sign, calf pseudohypertrophy (fibrofatty replacement), waddling gait, markedly ↑ CK.
- Death from cardiomyopathy or respiratory failure.
Becker Muscular Dystrophy (BMD):
- Milder X-linked recessive non-frameshift DMD mutation → altered/reduced dystrophin.
- Later onset and slower progression.
Myotonic Dystrophy:
- Autosomal dominant, CTG trinucleotide repeat expansion (DMPK gene).
- Myotonia (sustained contraction), cataracts, frontal balding, gonadal atrophy.

⭐ Gowers Sign: Classic in DMD; patients use their hands to climb up their own body from a seated position due to profound hip and thigh muscle weakness.

Gowers sign in Duchenne muscular dystrophy

Inflammatory Myopathies - Autoimmune Muscle Attack

Autoimmune-mediated muscle injury presenting with symmetric proximal muscle weakness, elevated Creatine Kinase (CK), and specific autoantibodies.

Dermatomyositis (DM)
- Perimysial inflammation (CD4+ T cells), perifascicular atrophy.
- Skin findings: Heliotrope rash (eyelids), Gottron's papules (knuckles), Shawl sign.
- Antibodies: Anti-Mi-2, Anti-Jo-1.
Polymyositis (PM)
- Endomysial inflammation with CD8+ T cells directly invading muscle fibers.
- Spares the skin.
Inclusion Body Myositis (IBM)
- Asymmetric weakness, often affecting distal muscles (finger/wrist flexors).
- Biopsy: "Rimmed" vacuoles, protein aggregates (TDP-43).
- Most common inflammatory myopathy in patients > 50 years old.

⭐ Dermatomyositis in adults is strongly associated with an underlying malignancy (e.g., ovarian, lung, gastric adenocarcinoma).

Gottron papules on hand in dermatomyositis

NMJ & Toxic Myopathies - Signal Failure Syndromes

Myasthenia Gravis (MG): Autoantibodies to postsynaptic ACh receptors. Weakness worsens with repetition. Ptosis, diplopia. Thymoma/thymic hyperplasia common.
Lambert-Eaton (LEMS): Autoantibodies to presynaptic Ca²⁺ channels → ↓ ACh release. Weakness improves with repetition. Strong paraneoplastic link.
Botulism: Toxin cleaves SNARE proteins, blocking presynaptic ACh release. Causes descending flaccid paralysis.
Toxic Myopathies: Direct muscle damage. Common culprits: statins, corticosteroids, alcohol.

Neuromuscular Junction Pathology: MG, LEMS, Botulism

⭐ In Lambert-Eaton syndrome, repetitive nerve stimulation leads to increased muscle response, a key diagnostic finding differentiating it from Myasthenia Gravis.

High‑Yield Points - ⚡ Biggest Takeaways

Duchenne muscular dystrophy: X-linked recessive frameshift mutation in the dystrophin gene; presents with Gowers sign.

Myotonic dystrophy: Autosomal dominant CTG repeat expansion; features myotonia, cataracts, and arrhythmias.

Myasthenia gravis: Postsynaptic ACh receptor autoantibodies; weakness worsens with muscle use.

Lambert-Eaton syndrome: Presynaptic Ca²⁺ channel autoantibodies; weakness improves with muscle use; associated with small cell lung cancer.

Dermatomyositis: Perimysial inflammation with Gottron papules and heliotrope rash; increased risk of malignancy.

Polymyositis: Endomysial inflammation of CD8+ T cells without skin involvement.

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