Muscular dystropies

Duchenne Muscular Dystrophy

• Most common and most severe muscular dystrophy

• Rapidly progressive muscle weakness

Onset

• Early childhood

Main Muscles Affected

• Skeletal muscles

• Cardiac muscle

Key Clinical Features

• Most patient w wheelchair than die in 25-30years of age(respiratory insufficincy,heart failure)

• Delayed sitting, standing(Gower sign), walking

• Progressive muscle weakness(proximal more than distal)

• Calf pseudo atrophy

• Cardiomyopathy

• Learning difficulties may occur

Morphology:

1-Variation in fiber size

2-Increased numbers of internalized nuclei

3- Degeneration, necrosis, and phagocytosis of muscle fibers

4-Regeneration of muscle fibers

5-Proliferation of endomysial connective tissue

Cause (Gene / Protein)

• Mutation in DMD gene

• Deficiency of dystrophin

• Dystrophin stabilizes muscle fibers and aids cell signaling

Inheritance Pattern

• X-linked recessive

• affects males,Female are carrier and they are asymoptomatic but have ⬆creatine kinase and show minimal histologic abnormalities on biopsy

Both of them at risk for dilated cardiomypathy

• Mothers are typically carriers

• Can occur due to new (de novo) mutations

Diagnostic Tests

• ↑ Creatine kinase (CK)

• Genetic testing for DMD mutation

Becker Muscular Dystrophy (BMD)

• Milder form related to Duchenne MD

• Progressive muscle weakness

Onset

• Later childhood or adolescence

Main Muscles Affected

• Legs and pelvis first

• Then shoulders, arms, neck

• Cardiac and respiratory muscles may be involved

Severity

• Less severe than DMD

• Slower progression

Cause

• Mutation in DMD gene (partial dystrophin function preserved)

Inheritance Pattern

• X-linked recessive

Important Note

• Genetic counseling recommended if family history is present

• Myotonic Dystrophy f

• Most common adult-onset muscular dystrophy

• Progressive muscle weakness and wasting

• Presence of myotonia (delayed muscle relaxation/involuntary muscle contraction)

Clincal features:

• Stifness and difficulty in relaxing their grip

• Weakness of footdorsiflexors and intrinsic muscles of hand and wris extonsors

• Atrophy of the facial muscles and ptosis

• Involement of other organ systems(fatal cardiac arrhythmias,cataracts,frontal balding,endocrunopathies,and testicular atorphy)

• Affect proximal musculature of the trunk and limbs

Onset

• Usually 20s–30s

• Can occur at any age

Major Types

🔹 Type 1 (DM1)

• Distal muscles (hands, feet, face)

• More severe

• Shows anticipation

• Most common(95%)

🔹 Type 2 (DM2)

• Proximal muscles (neck, shoulders, hips)

• Milder form

• No clear anticipation

Causes

• DM1: Mutation in DMPK gene

• DM2: Mutation in CNBP gene

Inheritance Pattern

• Autosomal dominant w trinucleotide repeat expansion

• Anticipation occurs only in Type 1

Facioscapulohumeral Muscular Dystrophy (FSHD)

• Slowly progressive muscular dystrophy

• Not usually life-threatening

• Caseud by overexpression of DUX4 target genes

Onset

• Adolescence most common

• Can appear in childhood or adulthood(20 years)

• Majority have normal life

Prevalence

• ~1 in 20,000

• 95% FSHD1, 5% FSHD2

Key Molecular Mechanism

• Hypomethylation of D4Z4 region on chromosome 4

• Leads to abnormal gene activation

Types

🔹 FSHD1

• Autosomal dominant

• D4Z4 contraction (1–10 repeats instead of 11–100)

🔹 FSHD2

• Mutation in SMCHD1 gene (most cases)

• Some cases unknown cause

Inheritance

• Autosomal dominant

• Can be sporadic (de novo mutation)

Congenital Myasthenic Syndrome (CMS)

• Neuromuscular junction disorder

• Muscle weakness worsens with exertion

Onset

• Early childhood

• Can appear later

Main Muscles Affected

• Facial muscles

• Eyelids (ptosis)

• Chewing and swallowing muscles

• Limb muscles

Severe Features

• Breathing difficulties

• Apnea

• Cyanosis (in severe cases)

Major Causative Genes

• CHRNE (most common)

• RAPSN

• CHAT

• COLQ

• DOK7

Pathophysiology

• Defective acetylcholine receptor function

• Impaired neuromuscular transmission

Inheritance Pattern

• Usually autosomal recessive

• Rare autosomal dominant

• Can occur due to new mutations

Walker–Warburg Syndrome

• Rare congenital muscular dystrophy

• Associated with brain and eye abnormalities

Clinical Features

• Severe muscle weakness

• Neurological defects

• Ocular abnormalities

Cause

• Mutations in genes affecting α-dystroglycan glycosylation

• Important genes include:

– POMT1

– POMT2

– CRPPA

– FKTN

– FKRP

– LSRGE1

Pathophysiology

• Defective glycosylation → unstable muscle fibers

Inheritance Pattern

• Autosomal recessive