Lecture 33 - Other Muscular Dystrophies Flashcards
Do causative genes for muscular dystrophies have a uniform effect?
No. Have variable effects.
What are the classifications of MDs based on? 1) 2) 3) 4) 5) 6)
1) Age of onset
2) Patterns of inheritance
3) Patterns of weakness
4) Involvement of other systems
5) Patterns of abnormality on muscle biopsies
6) Causative gene (where identified)
Why make a specific diagnosis of a MD? 1) 2) 3) 4)
1) Know course of disease, be able to tell patient prognosis
2) To be able to watch for complications
3) To avoid giving inappropriate treatment
4) To give genetic counselling
Benefits of genetic counselling
1)
2)
3)
1) See recurrence risk in siblings
2) Counsel other family members
3) See when being a carrier is a health risk
What is a MD that is infant-onset?
Congenital muscular dystrophy
What is a MD that is adult-onset?
Limb-girdle muscular dystrophy
Normal response of a baby being picked up by their back
Flexion of back, neck
MD with a focal pattern of weakness
Rigid spine syndrome (significant, early, spinal weakness)
Facial weakness
1)
2)
3)
1) Blank expression
2) Tented upper lip
3) Mouth often open
Other systems that can be affected in MDs 1) 2) 3) 4)
1) Brain
2) Musculoskeletal
3) Ocular
4) Endocrine
Brain involvement in MDs
1)
2)
1) Abnormalities of brain development or maturation
2) Cognitive impairment
Musculoskeletal effects of MDs
1)
2)
3)
1) Muscle weakness
2) Joint contractures (elbow, Achilles tendon, iliotibial band)
3) Spinal rigidity, scoliosis
Eye effects of MDs
1)
2)
1) Structural or retinal abnormalities
2) Cataracts
Mutations in which gene can cause congenital muscular dystrophy?
FKRP gene
Effects of FKRP gene mutation
1)
2)
3)
1) Congenital muscular dystrophy
2) Signature mental retardation
3) Cerebellar cysts
Appearance of congenital muscular dystrophy muscle biopsy
1)
2)
3)
1) Increased central nuclei
2) Increased fat infiltration
3) Increased fibrous tissue
Ways to use a muscle biopsy to diagnose MDs
1)
2)
3) a, b, c, d
1) Histology
2) Electron microscopy
3) Diagnostic screen
a) Immunohistochemistry
b) Western blot
c) Mutation analysis
d) Biochemical analysis
Immunohistochemisty
Staining with fluorescent antibodies
Alpha-dystroglycan immunohistochemical staining in normal muscle
Continuous, homogenous bands surrounding muscle fibres
Alpha-dystroglycan immunohistochemical staining in MD muscle
1)
2)
1) Incomplete or absent staining around muscle fibres
2) As it is attached to other proteins, can cause apparent absence of other proteins in dystroglycan complex too
Myotonic dystrophy mode of inheritance
Autosomal dominant
Prevalence of myotonic dystrophy
1/8000
Which chromosome is myotonic dystrophy inherited on?
Chr19
Myotonic dystrophy effects 1) 2) 3) 4) 5) 6) 7)
1) Multisystem disorder
2) Proximal and distal wasting and weakness
3) Smooth muscle involvement. Constipation, uterine problems
4) Cognitive defects
5) Excessive somnolence
6) Cataracts
7) Endocrine dysfunction (diabetes, infertility)
MD that shows anticipation
Myotonic dystrophy
What is anticipation?
Shows worse phenotype with successive generations
Muscle biopsy of myotonic dystrophy
Very non-specific
How are tests for muscular dystrophies conducted?
1)
2)
1) Specific, targeted
2) Specific stains (for proteins), histological findings are suggested, based on clinical examination
Common muscular feature of myotonic dystrophy
Foot drop
Most common adult MD
Myotonic dystrophy (DMD is more common overall, but DMD patients don’t survive to adulthood)
IQ of congenital myotonic dystrophy patients
Normally between 50 and 70
Muscles commonly affected in myotonic dystrophy 1) 2) 3) 4) 5)
1) Arms, forearms
2) Feet, legs
3) Neck
4) Facial muscles
5) Intestinal smooth muscle, heart
Three phenotypes of myotonic dystrophy
1) Congenital
2) Classical
3) Mild
Congenital myotonic dystrophy 1) 2) 3) 4)
1) Most severe phenotype
2) Presents in first 4 weeks of life
3) Respiratory failure, feeding problems
4) Early death common
Another name for myotonic dystrophy
DM1
Classic DM1
1)
2)
1) Most common form
2) Presents in adulthood or adolescence with muscle weakness
Mild DM1
1)
2)
1) Cataracts and mild myotonia in adulthood
2) Can be missed
Congenital myotonic dystrophy symptoms 1) 2) 3) 4) 5) 6) 7)
1) Presents at birth or in neonatal period
2) Hypotonia (‘floppy’ baby)
3) Facial and proximal muscle weakness
4) Delayed motor development
5) Often die of respiratory insufficiency
6) Feeding difficulties
7) Severe intellectual impairment
Myotonic dystrophy symptoms in adults 1) 2) 3) 4) 5) 6)
1) Frontal balding
2) ‘Hatchet face’ from atrophy of temporalis muscle
3) Ptosis of eye, drooping of mouth from facial muscle weakness
4) Cataracts
5) Wasting of sternocleidomastoid muscle
6) Gynecomastia
Woman-specific problem in myotonic dystrophy
Wasting of uterine muscles can lead to issues with pregnancy
Myotonia
Delayed relaxation of muscles after contraction
Where does myotonia present?
In a number of muscle disorders, EG: myotonic dystrophy
Presentation of myotonia in families with myotonic dystrophy
Myotonia not present in DM1 affected child, but is present in affected parents
Usefulness of myotonia
Not normally a threatening condition by itself, but is a useful diagnostic tool
Appearance of muscle histology from muscle biopsy of myotonic dystrophy
1)
2)
1) Many nuclei in the centre of muscle cells
2) Ringbinden
Ringbinden
1)
2)
1) Aberrant myofibrils that wrap themselves around an existing muscle fibre in a tight spiral
2) Often present in muscles affected by neurogenic atrophy
Are muscle biopsies often used to diagnose DM1?
No.
A genetic test can be used to diagnose, and is less invasive
Gene resulting in DM1
1)
2)
1) Extended CTG trinucleotide repeat in the gene DMPK
2) Fully-penetrant mutants have over 50 CTG repeats in DMPK
Stages of DMPK trinucleotide repeat
1)
2)
3)
1) Normal - 5-35 CTG repeats
2) Pre-mutation - 35-49 CTG repeats
3) DM1 - Over 50 CTG repeats
How sensitive is the genetic test for DM1?
100% sensitive
How is DM1 inherited?
Autosomal dominant
DM1 anticipation
1)
2)
1) DMPK CTG repeats of over 35 are unstable, and can extend during meiosis
2) Offspring can have repeat lengths much longer than their parent (often mother)
How do extended CTG repeats in DMPK lead to myotonic dystrophy?
1)
2)
3)
1) Encode RNA with a gain of function
2) RNA forms a hairpin structure
3) CUG repeats sequester specific proteins
Function gained by DMPK RNA in myotonic dystrophy 1) 2) 3) 4)
1) Hairpin with CUG repeats binds muscleblind-like-1 and CUG-binding protein 1
2) Muscleblind-like 1 is sequestered on RNA, leading to loss of function
3) Muscleblind-like 1 has an inhibitory effect on CUG-binding protein 1. When muscleblind-like 1 is inhibited, CUG-binding protein is upregulated
4) Upregulation of CUG-binding protein 1 leads to downstream effects
Downstream effects of upregulated CUG-binding protein 1 1) 2) 3) 4)
1) Disrupted mRNA regulation of alternate splicing
2) Disrupted regulation of mRNA stability
3) Disrupted regulation of mRNA translation
4) Misregulation of mRNA splicing leads to organ-specific effects of DM1 (EG: insulin insensitivity)
Effect of muscleblind-like 1 and CUG-binding protein 1 ratios in development
1)
2)
3)
1) Muscleblind-like 1 levels increase in adulthood
2) CUG-binding protein 1 levels decrease in adulthood
3) This leads to a change from foetal to adult RNA splicing
Possible therapeutic strategies for DM1
1)
2)
3)
1) Small-molecule inhibitors of CUG-expanded RNA species (EG: pentamidine-like compounds)
2) RNAi-mediated interference of mutant DMPK transcripts
3) Antisense oligonucleotide knockdown of DMPK
Limb girdle muscular dystrophies general features 1) 2) 3) 4) 5) 6)
1) Generally progressive muscle disorders
2) Onset in second to sixth decade of life
3) Muscle weakness, hypertrophy
4) Respiratory and cardiac involvement common
5) CNS is often spared
6) Pathology is generally cytoskeletal rather than contractile
First place of muscle weakness in limb girdle muscular dystrophies
Often the pelvis, as this is weight-bearing
Limb girdle muscular dystrophy classifications
1)
2)
3)
1) LGMD type 1 - Autosomal dominant
2) LGMD type 2 - Autosomal recessive
3) DMD, BMD - X-linked
What do most limb girdle muscular dystrophies affect?
Sarcoplasmic membrane
Most common type of limb girdle muscular dystrophy
Type 2 (autosomal recessive)
Clinical clues looked for when diagnosing limb girdle muscular dystrophies 1) 2) 3) 4) 5)
1) Pattern of weakness
2) Family history
3) Creatine kinase levels
4) Muscle histology
5) Muscle immunoanalysis
How often is a precise diagnosis made for limb girdle muscular dystrophies?
~75% of the time
~25% of LGMDs can’t be categorised
The only early-onset limb girdle muscular dystrophy
Emery-Dreifuss muscular dystrophy
Universal feature of young boys with Emery-Dreifuss MD
Early contractures
Muscle histology in limb girdle muscular dystrophy type 1A
1)
2)
1) Vacuoles in muscle cells
2) Myotilin aggregates in myotilin stain
Contracture and weaknes patterns in limb girdle muscular dystrophies 1) 2) 3) 4) 5)
1) Contractures of Achilles tendon
2) Contractures of elbows
3) Contractures of spine
4) Contractures of knees
5) Humeroperoneal weakness
Fascioscapulohumeral muscular dystrophy inheritance
Dominantly inherited myopathy
Specific gene not known
Fascioscapulohumeral MD age of onset
Most patients symptomatic by age 20
Fascioscapulohumeral MD prevalence
1/20,000 people affected
General features of fascioscapulohumeral MD 1) 2) 3) 4)
1) Scapular winging
2) Facial weakness
3) Proximal arm weakness
4) Less-prominent leg weakness (affects peroneal rather than proximal muscles, leads to foot drop)
Signs on examination of fascioscapulohumeral MD 1) 2) 3) 4) 5)
1) Weakness of eye closure (don’t close eyes when asleep)
2) Often not able to whistle
3) Poorly-developed pectoral and scapular muscles
4) Pectus carinatum (pigeon chest)
5) Foot drop (peroneal muscle weakness)
Pattern of muscle involvement in fascioscapulohumeral MD 1) 2) 3) 4)
1) Asymmetrical
2) Scapular, pectoral muscles affected early
3) Lower 1/3 of abdomen affected (Beevor’s sign)
4) Heart, respiratory muscles unaffected
Beevor’s sign
1)
2)
1) Sign of fascioscapulohumeral MD
2) Patient lie on back, asked to raise head. Normally, lower 1/3 of abdominal muscles lower into abdomen. With FSHD, they raise
Where do 90% of fascioscapulohumeral MD inheritance map to?
4q35
Number of cases of fascioscapulohumeral MD that are sporadic
10-30%
Penetrance of fascioscapulohumeral MD 1) 2) 3) 4)
1) Incomplete
2) 30% of inherited cases are asymptomatic
3) Males more likely to be symptomatic than females
4) Germline mosaicism is sometimes seen
Repeat sequence associated with fascioscapulohumeral MD
D4Z4 repeat on chromosome 4
Normal number of D4Z4 repeats
12-96 copies
Fascioscapulohumeral MD number of D4Z4 copies
Under 8
Is there a correlation between the number of D4Z4 repeats and fascioscapulohumeral MD severity?
Yes. Fewer repeats results in more severe phenotype, earlier age of onset.
Genetic test for fascioscapulohumeral MD
Gene probe tests for the number of D4Z4 repeats on chromosome 4
Problems with genetic test for fascioscapulohumeral MD
1)
2)
3)
1) Gene probe tests for D4Z4 repeats on chr4. Very similar repeats exist on chr10
2) Chr4 repeat arrays can translocate to chr10, leading to a negative gene test result, even though someone has FSHD
3) A new test allows identification of changes on chr4 and chr10
Can fascioscapulohumeral MD be casued by de novo mutations?
Yes
Germline mosaicism, from post-zygotic mutation in one allele of a pair of genes in a cell
