Mutations associated with muscular dystrophies & ataxias Flashcards
List the patterns of inheritance
Autosomal dominant inheritance
autosomal recessive inheritance
x-linked dominant inheritance
x-linked recessive inheritance
y- linked inheritance
mitochondrial inheritance
NOTE: week 1 LO
Give examples of mutation mechanisms
- Frameshift mutation:
- insertion or deletion of a number of bases- alters the reading of the frae
- I.e. alters the codons that are translated into amino acid
- affects every codon downstream to the insertion or deletion - Trinucleotide repeat expansion.
- Mutation occurs in genes with repeats of 3 bases (trinucleotides).
- Mutation causes an increase in number of repeats
- a threshold number fo extra repeats need to occur before we can see the disease
- Associated w/ ‘anticipation’- successive generations are affected more severely due to mutation increasing in size
- E.g. Huntingdon’s, Fragile x-syndrome & autosomal dominant cerebellar ataxias
NOTE: view diagram on notes!
What is Muscular Dystrophy?
A group of diseases that cause progressive weakness & loss of muscle mass.
Patients have normal muscle function at birth
Mutations in genes interfere w/ production of proteins to form healthy muscle
Examples of diseases that cause Muscular Dystrophy.
Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
Facioscapulohumeral dystrophy
Myotonic Muscular Dystrophy
Epidemiology of Duchenne Muscular Dystrophy (DMD)
Onset= 3-5 yr
Most common form of muscular dystrophy
In UK, 100 boys are born w/ DMD each year
Rare
Inheritance & Pathophysiology of DMD
X-linked recessive inheritance
Frameshift mutation in DMD gene caused by deletion.
Gene codes for Dystrophin- protein that connects muscle membrane (sarcolemma) to actin & myosin filaments
Function of Dystrophin:
- Stabilises the membrane during contraction & relaxation
- Links the intracellular cytoskeleton w/ the extracellular matrix
- Allows muscle fibres to differentiate into fast twitch
- Organises the postsynaptic membrane & acetylcholine receptors
In DMD, mutated DMD gene faults to produce functional Dystrophin
-Muscle cells that lack dystrophin are mechanically fragile & fail after a few years = progressive muscle weakness.
- Muscles are vulnerable to tears during contraction- leads to Ca 2+ influx = disrupts intracellular signalling
Clinical features of DMD
Delay in walking & falls
Muscle weakness- usually proximal muscles affected (if distal are affected, its more likely to be neuropathy).
- Symmetrical& persistent.
Muscle wasting- calf muscle atrophy.
- Weakness is more common than wasting. (Lots of wasting suggests neuropathy).
Muscle psuedohypertrophy - where the muscle looks like it is enlarging.
- caused by muscle being replaced by collagen & scar tissue
- Early finding.
Scoliosis
Contractures - tightening of the muscles.
Gait problems - including persistent toe-walking & flat-footedness
- Can lead to waddling gait.
Dilated cardiomyopathy- where the ventricle stretches and thins so it can’t pump blood as effectively.
Respiratory muscles - become impaired later on in the disease.
Positive Gower’s sign- patient that has to use their hands & arms to “walk” up their own body to stand due to a lack of hip and thigh muscle strength.
NOTE: view images in notes
Investigations for DMD
Serum creatine kinase (CK) - usually elevated 10 - 20 times.
Electromyography- a measure of muscle response or electrical activity in response to a nerve’s stimulation of a muscle
DNA test to look for mutations in Dystrophin gene
Muscle biopsy
- absent dystrophin around muscle fibres
NOTE: view image on notes
Antibody testing:
- Connective tissue disorders - ANA, anti-ds DNA, anti-Ro, anti-La, anti Scl-70 & RF.
- Polymyositis - anti-Jo-1
- Dermatomyositis - anti-Mi-2
Prognosis of DMD
- Most can expect to survive until at least their early 20.
- Premature death common btw 15 - 25 due to respiratory or cardiac failure.
Epidemiology of Becker Muscular Dystrophy (BMD)
Very rare
Onset > 7 years (mean age is 11) = slower onset.
Slowly progressively - slower than Duchenne.
Inheritance and pathophysiology of BMD?
X-linked recessive inheritance.
In frame DMD gene mutation.
Dystrophin is partially functional = protects the muscles from degenerating as badly or as quickly as in Duchenne.
Clinical features of BMD?
Has the same clinical features as DMD but w/ a later onset & slower progression of the disease.
Patients can be in their teens or early 20s before diagnosis.
Muscle Biopsy shows reduced dystrophin staining UNLIKE DMD (absent)
Inheritance and pathophysiology of Facioscapulohumeral dystrophy
Autosomal dominant inheritance
Genetic changes involve the long arm (q) of chromosome 4
Disease caused when a region of chromosome, D4Z4, doesn’t have enough methyl groups added (hypomethylated)
- This stops the DUX4 gene being silenced.
Unknown what DUX4 does to cause muscle damage
Clinical presentation of Facioscapulohumeral dystrophy
Muscle weakness:
- Face = ptosis (droopy eye lids) & can’t whistle.
- Upper extremities
- Scapular = winging
- Humeral = biceps weakness
- Peroneal muscles = foot drop
Other features:
- Cardiac
- Hearing
- Epilepsy
Epidemiology of Myotonic Muscular Dystrophy (MMD)
Rare
Commonest form of adult muscular dystrophy
2 types:
- DM1- Steinert’s disease
- DM 2- Proximal myotonic myopathy
