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Muscle Disease

Louis J. Ptacek

Departments of Neurology and Human Genetics

Howard Hughes Medical Institute

objectives:

1. To understand basic clinical features of common muscle diseases

2. To appreciate the strong genetic components of muscle disease

3. To appreciate the genetic and clinical features of the common muscle
diseases myotonic dystrophy, duchenne, and FSH

Dystrophinopathies

Duchenne Muscular Dystrophy (DMD) is a relatively common and severe neuromuscular disorder, affecting approximately one in every 3‑4,000 male live births. The hallmark of the disease is the progressive weakness of all muscles; proximal muscles of the limbs are most severely affected. Children usually present with mild delay of the motor milestones such as walking and with tip‑toe and unsteady gait. Difficulties rising from the floor, going upstairs and running are usually evident in the first two to three years of life. Enlarged calves can be seen in most children especially in the early phases of the disease.

A frequently associated feature (30% of cases) is mild learning disability. The presentation with predominantly cognitive problems is not uncommon (speech delay, for example). This is not progressive.

The weakness, however, is progressive and children with DMD will lose ambulation by the age of thirteen years; the mean age being approximately nine years. This is due to a combination of

weakness and contractures affecting the ankles, knees and hips.

Affected children confined to a wheelchair are at high risk of developing spinal curvature; more than 90% will eventually develop a significant scoliosis. Appropriate management (bracing)

reduces the rate and very often spinal surgery is required to stop the progression of the scoliosis.

Respiratory muscles are also affected and this becomes a clinical problem usually in the late teens; respiratory failure causing night time hypoventilation is common at this age and is often followed by death after a few months if not treated (with night time support using facial or nasal mask

ventilation). Cardiac muscle is also affected; however, because of the immobility, patients with

DMD rarely develop signs of cardiac failure.

Diagnosis is performed in centers where there is an expertise to deal with these conditions but

serum creatine kinase (CK) is a very useful initial screening test. If the CK is normal, the diagnosis

of DMD is excluded as affected children invariably have serum levels more than ten times normal.

A muscle biopsy is often take to confirm the diagnosis and a genetic test will also help in establishing the diagnosis and in providing genetic counselling to the family.

DMD is a genetic condition inherited as an X‑linked trait. Often there are no other members of the family affected. This is usually the result of a de‑novo genetic event that has occurred in the

affected child; or the fact that the mother, if she is a carrier of the genetic defect, usually does not

manifest any sign of the disease (because of the X‑linked inheritance). The gene responsible for

DMD is known and mutations can be relatively easily found in approximately two thirds of

affected children.

Clinical

Duchenne muscular dystrophy; Chromosome Xp21; Recessive

Onset 3 to 5 yrs

Weakness

Proximal > Distal; Symmetric; Legs & Arms

Steady decline in strength: After 6 to 11 years

Gowers sign: Standing up with the aid of hands pushing on knees

Failure to walk: 9 ‑ 13 years; Later with steroid treatment

Muscle hypertrophy: Especially calf;

Musculoskeletal

Contractures

Especially ankles; Also hips & knees

Treatment (Ankles)

Non‑surgical: Night splints more effective than passive stretch

Surgical: Contracture release with early ambulation after surgery

Scoliosis after loss of ambulation

Other clinical features

Cardiomyopathy: Dilated; Especially > 15 years

Mental retardation: Mean IQ ~ 88

Progression: Death 15 - 25 years due to respiratory or cardiac failure

Laboratory

Serum CK: Very high

Muscle biopsy

Endomysial fibrosis

Variable fiber size: Small fibers rounded

Hypercontracted (opaque) muscle fbers

Myopathic grouping

Muscle fiber degeneration & regeneration

Muscle fiber internal architecture: Normal or immature

Absent dystrophin staining

Diagnostic testing

Muscle: Staining for dystrophin protein absent

Genetic: Deletion, duplication or small mutation

96% with frameshift mutation

30% with new mutation

10% to 20% of new mutations are gonadal mosaic

Drug treatment:

Prolongs ability to walk by 2 to 3 years

Prednisone

Doses

Daily: 0.75 mg/kg/day starting dose

Weekly: 5 mg/week starting dose

2.5 mg on Friday & Saturday

Fewer side effects than daily dose

Effects: Prolongs walking by 2 to 3 years; é Strength

Deflazacort: 0.9 to 1.2 mg/kg/day starting dose

Oxandrolone 0.1 mg/kg/day

Becker dystrophy:

Onset > 7 yrs

Muscle

Weakness

Proximal > Distal; Symmetric; Legs & Arms

May be especially prominent in quadriceps or hamstrings

Slowly progressive

Severity and age of onset correlate with dystrophin levels in muscle

Calf pain on exercise

Muscle hypertrophy: Especially calves

Failure to walk 16 ‑ 80 years

Systemic

Cardiomyopathy: May occur before severe weakness

Mental retardation: Associated with deletion of Dp140 transcription unit

Laboratory

Serum CK: Very high

Muscle biopsy

Myopathic: Varied muscle fiber size; increased endomysial connective tissue

< 12 years of age: Myopathic grouping, Degeneration & Regeneration

Reduced dystrophin staining: Rule out 2° change due to Sarcoglycanopathy

Genotype: Dystrophin mutations

Deletion - 70% of patients: Usually In‑frame; 16% with frameshift mutation

New mutations rare

Point mutations

> 70 identified

Mutations in CpG: All C to T; None G to A

? Related to direct or inverted gene repeats

Dystrophin gene

79 exons are only 0.6% of gene due to large introns

14kb dystrophin mRNA: Encodes 3685 amino acid 427kDa protein

Dystrophin protein

Sequence: Homologies to spectrins & "‑actinins

Localization: Subsarcolemmal region in skeletal and cardiac muscle

Organized periodically in costameres

Enriched at myotendinous and neuromuscular junctions

Cardiac muscle: Associated with T‑tubules also

Smooth muscle

Discontinuous along membranes

Alternates with vinculin

Dystrophin functions

Mechanical

? Stabilization of membrane during contraction & relaxation

Part of link between intracellular cytoskeleton & extracellular matrix

(See Figure)

Functional

Plays role in ability of muscle fibers to differentiate into fast glycolytic type

May play a role in organization of postsynaptic membrane & AChRs

Domains

NH2‑terminus

1st 240 amino acids

"‑actinin homology

F‑actin binding

3 distinct regions

Links dystrophin to F‑actin subsarcolemmal cytoskeleton

Rod: Coiled‑coiled

2400 amino acids

3 helix segments: 109 amino acids

Contain 2 proline‑rich turns

Repeated 24 times

Helix segments disrupted by non‑helical regions

4 Proline‑rich regions: ? Act as hinges

WWP domain: ? Involved in cell signalling

Spectrin homology

Function: Confers flexibility & elasticity to dystrophin

Deletion of rod region (Exons 17 to 48): Human disease & Mouse knockouts

Normal localization of dystrophin‑associated proteins to membrane

Mild or no myopathy

Cysteine‑rich

Amino acids 3080 to 3360

Some homology to "‑actinin carboxy‑terminus

Contains 2 incomplete EF‑hand calcium binding motifs

Functions: Required for membrane attachment to cytoskeleton via binding to $‑Dystroglycan & indirectly to Dystrophin‑associated glycoproteins

Carboxy‑terminal domain

Last 420 amino acids

Homology to utrophin & dystrobrevin

Contains many potential phosphorylation sites

Binds to Syntrophins (Exon 74) ± DAGs

Myotonic dystrophy (DM) is a multisystem disorder that affects skeletal muscle and smooth muscle, as well as the eye, heart, endocrine system, and central nervous system. The clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classical, and congenital. Mild DM is characterized by cataract and mild myotonia (difficulty relaxing the muscles after contraction); life span is normal. Classical DM is characterized by muscle weakness and wasting, myotonia, cataract, and often by cardiac conduction abnormalities; adults may become physically disabled and may have a shortened life span. Congenital DM is characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; mental retardation is common.

? Related to loss of serotonin (5‑HT) neurons in dorsal raphe & superior central nucleus of brainstem

Diagnosis in symptomatic patient: Confirm typical, or uncertain atypical, syndrome

Increased initial CTG repeat size 6 increase progression of size heterogeneity over time

(CTG)5 allele probably arose from mutation of (CTG)9‑17 allele on Alu+ chromosome

Facioscapulohumeral muscular dystrophy (Landouzy‑Déjérine disease) is an inherited muscle disease, commonly called FSH or FSHD. Progressive weakening and loss of skeletal muscle are its major effects. It has significant medical and health impacts on individuals, families and society. Details about the nature of the disease and some basic knowledge of inheritance of genetic diseases are important to better understand FSHD.

FSHD is a common form of muscular dystrophy, defined by a specific set of symptoms that collectively characterize the disease. Its major symptom is the progressive weakening and loss of skeletal muscles. The usual location of these weakness at onset is the origin of the name: face (facio), shoulder girdle (scapulo) and upper arms (humeral). Early weakness of the muscles of the eye (open and close) and mouth (smile, pucker, whistle) are distinctive for FSHD. These symptoms, in combination with weakness in the muscles that stabilize the scapulae (shoulder blades), are often the basis of the physician’s diagnosis of FSHD. Other skeletal muscles invariably weaken. Involvement of muscles of the foot, hip girdle, and abdomen is common. Although the progression of FSHD is quite variable, it is usually slow. With FSHD, most affected people develop asymmetric weakness. The reason for this asymmetry is unknown.

In more than half of FSHD cases, there are other symptoms like high‑frequency hearing loss and/or abnormalities of blood vessels in the back of the eye. The vascular abnormalities in the back of the eye lead to visual problems in only about 1% of cases. Since such abnormalities are common in the general population, one must be cautious of the fact that their presence alone, in an FSHD at‑risk individual, is insufficient for a diagnosis of FSHD.

It is difficult to calculate the exact incidence of FSHD. It may be under reported, but an accepted estimate of its occurrence in the general population is one in 20,000. FSHD occurs in all racial groups. It occurs with equal frequency in both sexes.

Although the FSHD gene is present at birth, weakness are generally noticeable during the second decade. A physician can usually recognize and diagnose FSHD beyond the age of 20. However, it is important to realize that the onset of FSHD is variable. Sometimes, muscle weakness are slight throughout adulthood. In perhaps 5% of cases of FSHD, a young child or an infant develops symptoms. In infantile FSHD (IFSHD) there is early facial weakness during the first two years of life, typical muscle weakness of FSHD, and in some of these children, early hearing loss and retinal abnormalities.

FSH is caused by reduction in size of a DNA fragment at telomere of chromosome 4q (4q35)

Pathogenic feature: Number of KpnI DNA repeats is reduced to less than 9 but more than 0

Extra 4q35 repeats on chromosome 10qter produce increased homology between chromosomes 10 & 4

Severe disease: More commonly 2° to new mutations, or mutations transmitted through maternal lines

Muscle to biopsy (Rarely necessary): Biceps or Suprascapular; Deltoid often spared

Ptá…ek LJ, Johnson KJ, Griggs RC. Mechanisms of Disease: Genetics and Physiology of the Myotonic Muscle Disorders; N Eng J Med 1993; 328:482-489.

Mendell J, Griggs RC, Ptá…ek LJ. Diseases of Muscle. In: Harrison's Textbook of Internal Medicine, ed 14. New York, McGraw-Hill, 1998 pp. 2473-2483.