Myotonic syndromes

Myotonic syndromes are a heterogenous group of inherited disorders with similar pathological mechanisms. Myotonic dystrophies, the most prevalent myotonic syndromes, are one of the most common forms of adult-onset muscular dystrophy. Both types, myotonic dystrophy type I (Curschmann-Steinert disease) and myotonic dystrophy type II (proximal myotonic myopathy), are autosomal dominant conditions with CTG trinucleotide repeat and CCTG tetranucleotide repeat expansions respectively. Type I is a severe (often life-threatening) form of disease, while type II is usually mild. Both present with skeletal muscle weakness and myotonia, muscle pain, heart conduction defects, cataracts, testicular atrophy, and frontal balding. Electromyography may confirm myotonia that is not identified during clinical examination; however, genetic tests usually confirm the diagnosis. As no curative therapy exists, treatment is symptomatic. Except for DM1, patients with myotonic syndromes have a normal lifespan.

• Myotonic dystrophies
  • One of the most common forms of adult-onset muscular dystrophy
  • Myotonic dystrophy type I: congenital, juvenile, or adult onset
  • Myotonic dystrophy type II: usually adult onset

References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• Myotonic dystrophies
  • Autosomal dominant conditions
  • Type 1: CTG trinucleotide repeat expansion in the DMPK gene → changes in myotonin protein kinase expression
  • Type 2: CCTG tetranucleotide repeat expansion of the ZNF9 gene (CNBP gene)

Myotonic dystrophy type I (DM1, Curschmann-Steinert disease)	Myotonic dystrophy type II (DM2, proximal myotonic myopathy)
Skeletal muscle weakness (due to muscle atrophy) Myotonia: delayed muscle relaxation following normal muscle contraction Myalgia Arrhythmia Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Frontal balding Hypogammaglobulinemia Features of insulin resistance Cognitive impairment
Most common in the distal sections of extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the hand. Myopathic facies Long, narrow face Hollowed cheeks, and high arched palate Ptosis Sternocleidomastoid muscle atrophy Clinical myotonia: Classically manifests as difficulty releasing a handshake. Respiratory involvement, dysphagia, dysarthria, irritable bowel-like symptoms (e.g., abdominal pain, bloating), impaired sleep, daytime somnolence are common	Most common in the proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors Mild clinical myotonia Uncommon symptoms: respiratory muscle involvement, dysphagia, dysarthria, irritable bowel-like symptoms (e.g., abdominal pain, bloating), impaired sleep, daytime somnolence are uncommon

Myotonic dystrophy type I is caused by a CTG nucleotide repeat expansion and results in Cataracts, Toupee (premature hair loss in men), and Gonadal atrophy.

References:^[1]

• Electromyography: (EMG): identifies myotonia
• Genetic diagnostics (confirmatory test): detection of trinucleotide repeat expansion mutation in leukocytes
• Biopsy: to distinguish between an inflammatory and a metabolic cause of the myopathy
• Other supportive tests
  • ↑ CK, IgG and IgM hypogammaglobulinemia, ↑ FSH and ↓/↔︎ testosterone
  • ECG: to exclude cardiac arrhythmias and other abnormalities
  • MRI: signs of global atrophy

References:^[3][1]

	Myotonic dystrophies		Duchenne muscular dystrophy	Becker muscular dystrophy	Non-dystrophic myotonic syndromes
	Type 1 (DM1; Curschmann-Steinert disease)	Type 2 (DM2; Proximal Myotonic Myopathy, PROMM)			Myotonia congenita Thomsen (Thomsen's disease)	Myotonia congenita Becker (Becker's disease)	Paramyotonia congenita Eulenburg (Eulenburg's disease)
Onset	Congenital, juvenile, or adult-onset	Adulthood	2–5 years of age	Usually > 15 years of age	From childhood	5–35 years	From infancy
Genetics	Autosomal dominant CTG trinucleotide repeat in the region of the DMPK gene (a gene that encodes dystrophia myotonica protein kinase)	Autosomal dominant Expanded CCTG tetranucleotide repeat expansion on the ZNF9 gene (CNBP gene)	X-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome (Xp21) → frameshift mutation	X-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome (Xp21) → in-frame mutation	Autosomal dominant	Autosomal recessive	Autosomal dominant
Defect	Myotonin-protein kinase in skeletal and heart muscle, gonads, and the brain		Complete impairment (DMD) of the dystrophin protein	Partial impairment (DMD) of the dystrophin protein	Chloride channel	Chloride channel	Sodium channel
Clinical features	Myalgia Arrhythmias Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Frontal balding		Paresis and atrophy starting in the proximal lower limbs, later spreading to the upper body and distal areas Weak reflexes Bilateral Trendelenburg's sign Gower maneuver Calf pseudohypertrophy	Symptoms identical to those of Duchenne muscular dystrophy, but less severe Slower progression Heart involvement is more common compared to DMD.	No atrophy, but hypertrophy Initial difficulties in muscle relaxation Primarily affected muscles: legs, eyes, tongue, jaw	No atrophy, but hypertrophy Initial difficulties in muscle relaxation Primarily affected muscles: legs, eyes, tongue, jaw Possibly upper extremities affected	Muscle weakness in the cold
	Severe disease Skeletal muscle weakness and myotonia is more common in the distal muscles of the extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the hand Myopathic facies	Mild disease Skeletal muscle weakness and myotonia is more common in proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors

References:^[4][1]

The differential diagnoses listed here are not exhaustive.