Neuromuscular Disease: Muscular Dystrophies and Neuromuscular Junction Disorders

Comprehensive vocabulary flashcards covering the genetics, clinical features, pathophysiology, diagnosis, and management of Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, myasthenia gravis, and Lambert-Eaton myasthenic syndrome.

Neuromuscular Diseases

Disorders that affect both the peripheral nerves controlling muscles and the muscle tissues themselves.

Muscular Dystrophies

A group of more than 30 inherited genetic disorders caused by defects in genes responsible for muscle structure and function, characterized primarily by progressive muscle weakness.

DMD Gene

A massive gene located on the X chromosome spanning $2300\,\text{kb}$ ($1.5\%$ of the chromosome) that codes for dystrophin; its unusually large size confers a high spontaneous mutation rate.

Dystrophin

A crucial structural protein that connects intracellular actin to transmembrane dystroglycan, acting as a shock absorber to stabilize and protect the muscle cell membrane during contraction.

Duchenne Muscular Dystrophy (DMD)

A severe X-linked recessive disorder typically caused by frameshift deletions in the DMD gene, resulting in truncated or completely absent dystrophin, early childhood weakness, loss of ambulation by age $12$, and early mortality.

Becker Muscular Dystrophy (BMD)

A milder X-linked recessive muscular dystrophy caused by non-frameshift mutations in the DMD gene, allowing production of partially functional dystrophin, resulting in later onset, prolonged ambulation, and survival into the $30\text{s}$ or $40\text{s}$.

Frameshift Mutation

An insertion or deletion of nucleotides not divisible by three that alters the DNA reading frame, resulting in truncated or completely absent dystrophin protein in DMD.

Non-Frameshift Mutation

A genetic deletion or insertion that maintains the triplet reading frame of DNA, producing a shortened but partially functional dystrophin protein in BMD.

Myonecrosis

The breakdown and death of muscle tissue resulting from membrane fragility caused by dystrophin deficiency, triggering the release of intracellular muscle enzymes into the bloodstream.

Creatine Kinase (CK)

An intracellular muscle enzyme released into the plasma upon muscle membrane injury; serum levels are markedly elevated in early stages of Duchenne muscular dystrophy.

Gower's Sign

A classic clinical maneuver in which a child uses their hands to push against the floor and thighs to stand up, compensating for severe proximal hip and thigh muscle weakness.

Waddling Gait

An unsteady, duck-like walking pattern caused by weakness of the proximal pelvic girdle and hip muscles, causing the pelvis to drop with each step.

Pseudohypertrophy

False enlargement of muscles (classically the calves) caused by the progressive replacement of degenerated muscle fibers with adipose and fibrous connective tissue rather than real muscle tissue.

Cardiomyopathy (in DMD)

A myocardial complication characterized by myocardial fibrosis, depressed left ventricular ejection fraction (LVEF), and systolic heart failure, serving as a frequent cause of death in DMD.

Glucocorticoids (in DMD)

Standard pharmacological therapy (e.g., prednisone) indicated in newly diagnosed DMD to improve motor function and delay the loss of ambulation.

Myotonic Dystrophy

The most common muscular dystrophy with onset in adulthood, inherited in an autosomal dominant pattern and characterized by progressive muscle wasting, myotonia, and multiorgan dysfunction.

DMPK Gene

A gene located on chromosome $19$ encoding dystrophia myotonica protein kinase that contains an unstable CTG trinucleotide repeat expansion in Type 1 myotonic dystrophy.

CTG Trinucleotide Repeat Expansion

The pathogenic repeat mutation in the DMPK gene that results in abnormal messenger RNA that is transcribed but not translated, accumulating in nuclei and disrupting cellular function.

Myotonia

A cardinal clinical feature consisting of prolonged muscle contraction and delayed muscle relaxation following use, demonstrated by difficulty releasing a handshake or transient locking of the jaw.

Characteristic Facies of Myotonic Dystrophy

A distinct facial appearance characterized by hollowed cheeks and a long, narrow face caused by progressive atrophy of the facial musculature.

Cataracts (in Myotonic Dystrophy)

A common systemic, non-muscle ocular complication characterized by clouding of the lens of the eye.

Myasthenia Gravis (MG)

An autoimmune disorder of the neuromuscular junction caused by autoantibodies directed against postsynaptic nicotinic acetylcholine receptors on skeletal muscle.

Bimodal Age Distribution (in MG)

The epidemiologic pattern of myasthenia gravis presenting with two distinct peak age ranges: females primarily in their $20\text{s}$ to $30\text{s}$, and males predominantly in their $60\text{s}$ to $80\text{s}$.

Muscle Fatigability

The hallmark symptom of myasthenia gravis characterized by muscle weakness that worsens with repetitive activity and improves after rest, driven by reduced acetylcholine availability upon serial stimulation.

Ptosis and Diplopia (in MG)

Drooping of the eyelid and double vision resulting from weakness of extraocular muscles, representing the initial presenting complaints in approximately $50\%$ of MG patients.

Bulbar Symptoms

Neurological deficits affecting muscles innervated by cranial nerves from the lower brainstem, presenting as difficulty chewing, swallowing (dysphagia), and speaking (dysarthria).

Myasthenic Crisis

A life-threatening, acute exacerbation of myasthenia gravis involving severe respiratory muscle weakness or upper airway compromise from bulbar weakness, requiring mechanical ventilatory support.

Plasma Exchange (PLEX)

An emergency therapeutic procedure used in myasthenic crisis that filters the blood to directly remove circulating pathogenic acetylcholine receptor autoantibodies.

Thymus Gland (in MG)

An anterior mediastinal immune organ displaying pathology in most MG patients, including lymphoid follicular hyperplasia in approximately $85\%$ and thymoma in about $15\%$.

Thymectomy

Surgical excision of the thymus indicated in all patients with thymoma and frequently curative or therapeutic in nonthymomatous myasthenia gravis patients under $60$ years of age.

Pyridostigmine

A long-acting acetylcholinesterase inhibitor that acts as first-line chronic therapy for myasthenia gravis by reducing acetylcholine degradation and elevating neurotransmitter concentration at the neuromuscular junction.

Lambert-Eaton Myasthenic Syndrome (LEMS)

A presynaptic disorder of the neuromuscular junction caused by autoantibodies against voltage-gated calcium channels, preventing calcium entry and inhibiting acetylcholine vesicle release.

Paraneoplastic Syndrome (in LEMS)

An indirect effect of malignancy where small cell lung cancer cells express antigens that induce cross-reactive antibodies attacking presynaptic voltage-gated calcium channels.

Compound Motor Action Potential (CMAP) Facilitation

An electrodiagnostic finding in LEMS where repetitive nerve stimulation produces an incremental increase in muscle electrical response due to presynaptic calcium accumulation and subsequent ACh exocytosis.

Deep Tendon Reflexes in LEMS

Tendon jerk responses that are characteristically diminished or absent at baseline due to impaired presynaptic acetylcholine release, contrasting sharply with intact reflexes in myasthenia gravis.

Xerostomia (in LEMS)

Dry mouth resulting from reduced salivary secretion secondary to autonomic nervous system dysfunction, a classic symptom present in LEMS but absent in myasthenia gravis.

Amifampridine (3,4-DAP)

A first-line medication for LEMS that blocks presynaptic potassium efflux channels, delaying repolarization and prolonging nerve action potential depolarization to augment calcium influx and acetylcholine release.