Duchenne and Becker Muscular Dystrophy

Incidence of Duchenne

1 in 3,500

Genetic testing for DMD & BMD

1. Deletions/duplications: 60-70% of mutations in the genes; reading frame rule: Phenotype dependent upon disruption of reading frame which is true for ~90% of cases 2. Point mutations or small insertion/deletion mutations: 30-40% Start with del/dup testing since it is more common.

Biochemical features of DMD & BMD

1. Elevated creatine kinase (CK) levels is a sign of muscle damage. 2. Elevated transaminase levels.

Elevated creatine kinase (CK) levels

1. Enzyme in muscle cells that catalyzes production of ATP for energy, released during muscle breakdown/damage. 2. Typical range in healthy person is up to 200 U/L -varies: DMD is 10 time normal & BMD is 5 times the normal level.

Initial symptoms of DMD & BMD

1. Gowers' sign: proximal muscle weakness. 2. Motor delays/clumsiness. 3. Muscle, specifically the calf, pseudohypertrophy, Muscle tissue replaced by fat

Muscle biopsy can be helpful because...

1. It can quantify dystrophin expression. 2. usually not needed because genetic testing is typically definitive. consider performing when genetic testing negative or 3. can predict disease severity when genetic testing is uninformative, i.e. disease phenotype does not match test genotype.

Musculoskeletal management

1. Physical therapy/stretching: maintain joint range, prevent contractures. 2. Motor function tests to assess disease progression. 3. Most boys with DMD lose ambulation ~12 yrs. 4. BMD: lose ambulation later or not at all.

Symptoms of DMD & BMD that develop over time

1. Progressive muscle weakness. 2. Dilated cardiomyopathy, present in all boys with DMD and can proceed to heart failure. 3. Respiratory insufficiency, hard to breath properly with muscle weakness.

Glucocorticoid corticosteroids

1. Slows muscle decline and prolongs ambulation. 2. Reduction in scoliosis risk, delay of respiratory and cardiac function decline. 3. Side effects: weight gain, growth delays, behavioral changes, glucose intolerance, osteoporosis.

Elevated transaminase levels

1. Transaminase primarily found in liver, but also in muscle cells. 2. "elevated liver enzymes" in DMD usually secondary to muscle breakdown, not liver disease.

Reading Frame Rule

3 bases make up a codon, each codon codes for an amino acid. Deletion that is a multiple of 3 is an in-frame mutation. If not a multiple of 3 it is out-of-frame mutation.

Incidence of Becker

3 in 100,000

Exons of DMD gene and how they fit together

79 exons of gene, arrows show how exons fit together across the whole reading frame. between exon 47 & 48 there is a completion of a full codon at the end of 47 and a new codon at exon 48. Between 50 & 51, the first base of a codon is at 50 and the beginning of exon 51 contains the 2nd and 3rd bases of the codon.

Cardiac management

Almost all boys with DMD will develop Cardiomyopathy /DCM progressing to heart failure. Arrhythmia is also a risk. DCM also a risk for female carriers

Gene of interest

DMD 'dystrophin', expressed in cardiac, smooth, skeletal muscle, and the brain

Dystrophin function

Disruption of the complex due to DMD mutation, this causes instability of the whole complex causing subsequent muscle cell breakdown, fibrosis, and fatty replacement

Diagnosis of DMD & BMD

Genetic testing is preferred & muscle biopsy

DMD / BMD management

Glucocorticoid corticosteroids, Musculoskeletal, pulmonary, nutrition, cardiac

Reading Frame Rule Example 2

If there was a deletion of GAUC were deleted, then the reading frame would be shifted and incorrect amino acids would be assembled producing a non-functional protein.

Reading Frame Rule Example 1

If we had deletion of GAU, then the Asp amino acid would not be encoded for but the rest of the amino acids would be, so most of protein is produced and therefore almost functional. This individual probably has BMD.

Physical features of DMD & BMD

Initial symptoms & symptoms that develop over time.

Pathology

Loss of function of dystrophin protein 'caused by mutations' leads to contraction-induced muscle cell damage leading to progressive proximal-to-distal muscle weakness.

Pulmonary management

Progressive respiratory muscle weakness leads to respiratory failure. Boys will eventually use respiratory ventilation BiPAP

Inheritance pattern for Becker and Duchenne dystrophies

X-linked recessive

Are other proteins in this complex are associated with other muscular dystrophies?

Yes

2 conditions caused by same disease is called

allelic conditions

Dystrophin-glycoprotein complex

connects the extracellular matrix to the cytoskeleton

Reading Frame Rule: Duchenne-Out-of-frame mutations

disrupts mRNA translational reading frame producing a truncated nonfunctional protein

Reading Frame Rule: Becker- In-frame mutations

maintains translational reading frame and reult in semifunctional protein

Duchenne

most patients diagnosed by 4-5 yrs, with life expectancy into late 20s/early 30s

Becker

most patients diagnosed in childhood or as teens, variable, ~normal life span unless disease is more progressive

Nutrition management

prone to weight gain from steroids. Monitoring nutrient intake and weight

Exon skipping therapies

synthesize an oligonucleotide to block translation of an exon and restore a reading frame. E.g. block exon 51 of person who has a deletion of exon 50 because exons 49 & 52 will be back in frame with one another.

If we had a deletion of exon 50...

that would be an out-of-frame mutation because we would be shifting the reading frame starting with exon 51.

Mutations in DMD cause dirusption of the dystrophin protein as well as...

the complex as a whole, other proteins found in the complex, dystroglycans and sarcoglycans, can have reduced expression too.

If we had a deletion at exons 47 & 48...

then that would be an in-frame mutation, the edges of the remaining exons fit together.