Neuromuscular Disorders

Myasthenia Gravis A prototypical autoimmune disorder affecting the neuromuscular junction. Autoantibodies (mainly IgG) target nicotinic ACh receptors on the motor end plate. With fewer functional receptors, each nerve impulse produces a smaller end-plate potential. The characteristic pattern is fatigable weakness — muscle strength decreases with repeated use and recovers with rest. Classic symptoms include ptosis (drooping eyelids, typically asymmetric), diplopia (double vision from extraocular muscle weakness), dysarthria (slurred speech), dysphagia (difficulty swallowing), and proximal limb weakness. Importantly, only voluntary (skeletal) muscle is affected; smooth and cardiac muscle are spared.

Muscular Dystrophy (Duchenne Type) The most common childhood neuromuscular disease. X-linked recessive inheritance (DMD gene on Xp21). Dystrophin protein normally bridges the intracellular actin cytoskeleton to the extracellular matrix. Without it, the sarcolemma is mechanically fragile and tears during contraction. Muscle fibers die and are replaced by fat and fibrous tissue. Clinical hallmarks: onset in early childhood (2-5 years), Gowers' sign (rising from floor by "walking up" the legs), calf pseudohypertrophy $\frac{replacement of muscle by fat}{fibrous tissue}$, progressive proximal muscle weakness, wheelchair-dependent by teenage years.

Bone and Joint Disorders

Osteoporosis The most common metabolic bone disease. Characterized by reduced bone mineral density (BMD) and disrupted microarchitecture, increasing fracture risk. Pathophysiology: estrogen deficiency (post-menopause) removes the inhibitory effect on osteoclasts, causing increased bone resorption that exceeds formation. Fragility fractures (from minimal trauma) of the vertebrae (compression fractures, height loss), hip, and wrist are classic. Diagnosis: DEXA scan (dual-energy X-ray absorptiometry) with T-score ≤ -2.5. Prevention: calcium and vitamin D supplementation, weight-bearing exercise, hormone replacement therapy or bisphosphonates (inhibit osteoclasts).

Gout A crystal arthropathy caused by monosodium urate deposition in joints, periarticular tissues, and kidneys. Hyperuricemia results from overproduction or underexcretion of uric acid (the end product of purine metabolism in humans, unlike other mammals which have uricase). The first metatarsophalangeal joint (big toe) is the classic site (podagra). Attacks are sudden, nocturnal, and exquisitely painful. Triggers include purine-rich meals (organ meats, shellfish), alcohol (especially beer), dehydration, and diuretic use. Chronic gout leads to tophi (urate crystal deposits under skin) and joint destruction.

Rheumatoid Arthritis vs Osteoarthritis These two common arthropathies are frequently confused but have entirely different pathologies. RA is autoimmune — T-cell and B-cell mediated inflammation of the synovial membrane produces cytokines (TNF-α, IL-1, IL-6) and autoantibodies (rheumatoid factor, anti-CCP). The inflamed synovium forms pannus tissue that erodes cartilage and bone. OA is degenerative — mechanical wear-and-tear gradually degrades articular cartilage, exposing underlying bone. RA: young to middle-aged women, symmetric small joints (MCPs, PIPs, wrists), systemic features (fatigue, fever, weight loss), morning stiffness > 1 hour. OA: older adults, asymmetric large weight-bearing joints (knee, hip), no systemic features, pain worse with activity and relieved by rest.