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
Clinical presentation of MMD
Myotonia- where muscles are unable to relax after they contract. - Prolonged spasms or stiffening of muscles.
Gait abnormalities - due to weakness of foot dorsiflexors.
Muscle wasting or weakness - weakness of intrinsic muscles of hand, wrist extensors, atrophy of the facial muscles & ptosis.
Cardiomyopathy
Frontal balding
Diabetes
Cataracts
Inheritance & pathophysiology of DM1
Autosomal Dominant
Nucleotide repeat expansion
Mutations in DMPK gene on chromosome 19, that encodes for Dystrophia myotonica protein kinase.
- Normally, gene has 5 to 37 CTG repeats
- In affected individuals, it is 50 to several thousand.
- The longer the repeats, the more severe the disease & earlier the age of onset.
Exhibits anticipation
Congenital & adulthood onset forms
Inheritance & pathophysiology of DM2
Milder than DM 1
Mutations in gene coding for CNBP (cellular nucleic acid binding protein) on chromosome 3.
- Expansion of the CCTG repeat.
- Typically 75 - 11,000 repeats
Shows minimal or no anticipation.
What are ataxias?
a group of disorders that affect co-ordination, balance and speech.
Have difficulties w/:
- Balance and walking
- Speaking
- Swallowing
- Tasks that require a high degree of control, such as writing and eating.
- Vision
What are the two types of ataxias?
- Cerebellar - has a wide-based gait with associated intention tremor.
- Sensory - has an unsteady high-stepping gait that gets worse in the dark.
Inheritance & pathophysiology of Friedrich Ataxia
Autosomal recessive inheritance
Expansion of GAA trinucleotide repeat in FXN gene.
- GAA is normally repeated 5 to 33 times w/in FXN gene.
- In the disease, it is repeated 66 to 1,000 times.
FNX gene codes for the protein frataxin- important in mitochondria.
- Certain nerve & muscle cells cannot function properly w/out frataxin.
No anticipation
Inheritance & pathophysiology of Autosomal Dominant Cerebellar Ataxias (ACDAs)
Autosomal dominant inheritance
Caused by mutation in DNMT1 gene which causes CAG repeat expansion in the coding regions.
gene provide instructions for making enzyme called DNA methyltransferase 1.
- This enzyme is involved in DNA methylation & important for neurone maturation, differentiation & migration.
CAG codes for glutamine - polyglutamine has a toxic effect on cells.
May show anticipation.
