Lecture 34 - Other Muscular Dystrophies Flashcards
How are muscular dystophies classified?
- Age of onset
- Pattern of weakness
• Muscular dystrophies have typical patterns of muscle involvement (despite same genes in the muscles)
• Thorough physical examination is performed - Pattern of inheritance
• e.g. X-linked inheritance immediately narrows it down - Involvement of other systems
• e.g. GIT - Specific abnormalities on muscle biopsies
• Muscle biopsy not always needed - Cause gene (where identified)
• Sometimes gene mutations have more than one clinical phenotype and thus also presentation
Why is it important to make a diagnosis?
- Information about disease
• Life expectancy
• Prognosis - Allows monitoring for disease specific complications
• Cardiac
• Respiratory etc. - Appropriate treatment
• and to avoid inappropriate treatment - Genetic counselling
• Always of benefit
• Assessment of risk in siblings
• Identification of carriers (because carriers can have health problems)
Compare the following in different forms of muscular dystrophy: • Age of onset • Pattern of weakness • Pattern of inheritance • Involvement of other systems • Muscle biopsy
Analysis of all these features differentiate between the various muscular dystrophies
Age of onset:
• Infantile onset: Congenital muscular dystrophy
• Adult onset: Limb-girdle muscular dystrophy
Pattern of weakness:
• Generalised: all over the body including face
• Focal: e.g. Rigid-spine syndrome
Inheritance pattern:
Look for:
• Male to male transmission
• Successive generations affected
Involvement of other systems:
• Brain: structural abnormalities, cognitive abnormalities
• Musculoskeletal: spinal rigidity; scoliosis; joint contractures
• Endocrine systems
• Eye: cataracts; structural abnormalities
Muscle biopsy
• Normal: uniform muscle fibres etc.
• Dystrophic muscle: connective tissue, necrosis, variation in fibres size, fat etc.
• This tells us that it is a muscle dystrophy, but can’t really differentiate between them
What are the features of muscular dystrophy due to FKRP gene mutation?
- Large head
- Early onset joint contractures
- Significant cognitive abnormalities (mental retardation)
- Facial muscle weakness
- CK in the 5000’s: muscular degeneration
- Abnormal myelination (dye-myelination)
- Cerebellar cysts
This is a very characteristic pattern of features that indicate FKRP gene mutation
Describe the process of muscle biopsy, and how this can lead to diagnosis
- Local anaesthetic
- Needle extraction of muscle about the size of a die
- Sent off for:
• Histology
• Electron microscopy
• Specific testing (based on what one thinks is going on)
e.g.
• Western blot
• Mutation analysis
• Immunohistochmistry
Diagnosis:
There is a whole battery of tests that is performed
It is through weighing up of the results of all these different tests that a specific diagnosis can be made.
A single test won’t be definitive
- Invisible stitches, and goes home the same day
Not a major procedure
Describe the use of immunohistochemistry in muscle biopsy
Fluorescent mAbs against specific proteins that might be associated with the disease process:
- Membrane protein
• Missing in dystrophic muscle
• Present in normal muscle
• Decreased staining in some dystrophies (could be primary or secondary…) - α-dystroglycan
(Anchors many proteins in the sarcolemmal membrane)
• Normal staining → normal muscle
• Abnormal staining → doesn’t give a specific diagnosis, just indicates that there is a problem in this protein
• α-dystroglycan is absent both in DMD and Limb girdle muscular dystrophy type IC
Give some features of Myotonic Dystrophy (DM1):
• Mode of inheritance
• Prevalence
• Systems involved
- Most common dystrophy seen in adults
- Chromosome 19
- 1/8000
- Autosomal dominant inheritance
- Variable severity
- Anticipation
- Muscle biopsy not very helpful
A multi-system disorder
• Proximal as well as distal muscle affected
• Smooth muscle affected (GIT and uterine problems)
• Cognitive deficits
• Excessive somnolence
• Personality changes
• Cataracts
• Endocrine dysfunction (diabetes, infertility)
What is ‘Anticipation’?
Disease becomes worse in successive generations
What are the clinical presentations of myotonic dystrophy?
Three phenotypes:
- Congenital
• Very severe
• Presentation in first 4 weeks of life - Classic DM1
• Presents in adolescence of adulthood
• Most common
3. Mild DM1 • Adult onset • Mild phenotype • May only be cataracts and mild myotonia • Can be missed
When does congenital myotonic dystrophy present?
First 4 weeks of life
Give the symptoms of congenital myotonic dystrophy
What is the prognosis for these babies?
- Hypotonia (floppy)
- Facial and proximal muscle weakness
- Delayed motor development
- Feeding difficulties
- Severe intellectual deficits
Prognosis:
Very commonly death within first four weeks due to respiratory failure
Describe the features of classical myotonic dystrophy
- Immobility of facial muscle (no facial expression)
- Frontal balding
- Cataracts
- Wasting of sternocleidomastoid muscle
- Gynecomastia (benign enlargement of breast tissue in males)
What is myotonia?
When is it seen?
“Delayed relaxation of muscles after contraction”
- Uncomfortable, but not extremely debilitating
- Useful for diagnosis
Symptom observed not solely in myotonic dystrophy, but in a number of conditions
• Not seen in babies with DM1
• Present in affected parents
Describe the importance of muscle biopsy in DM1
(Myotonic dystrophy)
Not very helpful because the muscle:
Does not look particular dystrophic
Observations:
• Not very dystrophic, however:
• Many central nuclei
• Ringbinden (aberrant myofibrils wrapping themselves around others)
Often not necessary, because there is a good genetic test for DM1
Describe the genetic basis of myotonic dystrophy (DM1)
Is there a good genetic test?
What is the pattern of inheritance?
DMPK gene
Expanded CTP trinucleotide repeats
Normal: 5-35 Premutation: 35-49 • Slight increase in n° of repeats • Asymptomatic • Increased chance of passing disease on to offspring Full penetrance: >50 repeats • DM1
Genetic test:
• 100% sensitive
Inheritance:
• Autosomal dominant
• Exhibits anticipation
