Lecture 34 - Other Muscular Dystrophies Flashcards Preview

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Flashcards in Lecture 34 - Other Muscular Dystrophies Deck (36):
1

How are muscular dystophies classified?

1. Age of onset

2. Pattern of weakness
• Muscular dystrophies have typical patterns of muscle involvement (despite same genes in the muscles)
• Thorough physical examination is performed

3. Pattern of inheritance
• e.g. X-linked inheritance immediately narrows it down

4. Involvement of other systems
• e.g. GIT

5. Specific abnormalities on muscle biopsies
• Muscle biopsy not always needed

6. Cause gene (where identified)
• Sometimes gene mutations have more than one clinical phenotype and thus also presentation

2

Why is it important to make a diagnosis?

1. Information about disease
• Life expectancy
• Prognosis

2. Allows monitoring for disease specific complications
• Cardiac
• Respiratory etc.

3. Appropriate treatment
• and to avoid inappropriate treatment

4. Genetic counselling
• Always of benefit
• Assessment of risk in siblings
• Identification of carriers (because carriers can have health problems)

3

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

4

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

5

Describe the process of muscle biopsy, and how this can lead to diagnosis

1. Local anaesthetic

2. Needle extraction of muscle about the size of a die

3. 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

4. Invisible stitches, and goes home the same day

Not a major procedure

6

Describe the use of immunohistochemistry in muscle biopsy

Fluorescent mAbs against specific proteins that might be associated with the disease process:

1. Membrane protein
• Missing in dystrophic muscle
• Present in normal muscle
• Decreased staining in some dystrophies (could be primary or secondary...)

2. 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

7

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)

8

What is 'Anticipation'?

Disease becomes worse in successive generations

9

What are the clinical presentations of myotonic dystrophy?

Three phenotypes:

1. Congenital
• Very severe
• Presentation in first 4 weeks of life

2. 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

10

When does congenital myotonic dystrophy present?

First 4 weeks of life

11

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

12

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)

13

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

14

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

15

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

16

Describe the mechanism of anticipation in DM1

Transmission from which parent shows anticipation?

Anticipation: increase disease severity and decreasing age of onset in successive generations

• DMPK CTP alleles of >35 are unstable
• Repeats can expand in meiosis
• Offspring can inherit repeat sequences that are much longer that the parents'

• Anticipation usually occurs with maternal transmission

17

Describe a case of anticipation

In DM1

Grandmother
• Cataracts

Mother:
• Decreased facial expressions

Son:
• Congenital muscular dystrophy
• Very severe
• Severe cognitive impairment

18

Describe the molecular pathogenesis of DM1

1. RNA transcribed from expanded DMPK gene

2. RNA form hairpin secondary structures

3. Hairpins bind specific proteins and sequester them in the nucleus
• MBNL1: Muscleblind-like 1

4. Loss of function of MBNL1
• Because it has been sequestered

5. Up-regulation of CUGBP1
• Because it is no longer being inhibited by MBNL1

• Disrupted regulation of alternative splicing
• mRNA translation disruption
• Decrease mRNA stability

6. Normally in the embryo:
• Normally increased CUGBP1 and decreased MBNL1
• During development, CUGBP1 levels drop and MBNL1 levels increase
• In DM1, the decreased levels of MBNL1 lead to:

7. Enhanced embryonic isoform expression in adults
• CUGBP1 splices RNA to bring about the expression of different isoforms
• Over-expression of embryonic isoforms leads multiple disease symptoms:

8. Symtoms due to disrupted splicing
• Insulin-receptor like 1 gene → insulin resistance
• Chloride channel → myotonia
• Troponin T in heart → cardiac defects, arrhythmia

19

Which two proteins does the toxic RNA from the BMPK gene bind?

Describe the relationship between these proteins

MBNL1

CUGBP1

Reciprocal inhibition

20

What are the possible therapies for DM1?

RNA-based inhibition of toxic CUG-expanded RNA species

1. Small molecule inhibitors

2. RNA-interference-mediated suppression of mutated DMPK transcripts

3. Antisense oligonucleotides mediated knockout of DMPK

21

List the main features of Limb girdle muscular dystrophies
• Age of onset
• Who is affected
• Clinical presentation
• Pathology
• Differentiation between the various subtypes

• Progressive muscle disorders
• Collection of disorders
• Onset: 10-60 years
• Males and female equally affected

Presentation:
• Muscle weakness and hypertrophy
• First in pelvic girdle
• Then shoulder
• Respiratory and cardiac involvement
• No central nervous system involvement

Pathology:
• Cytoskeletal
• (rather than contractile)

Various subtypes
• Differentiated based on:
- Inheritance
- Pattern of weakness

Inheritance:
LGMD type 2: Autosomal recessive
LGMD type 1: autosomal dominant

22

Which MDs have X-linked inheritance?

DMD
BMD

23

How is LGMD diagnosed?

Only get a specific diagnosis in about 75% of cases

1. Clinical presentation
• Pattern of weakness
• Pattern of inheritance
• Family history

2. Creatine kinase levels

3. Muscle histology
• Immunohistochemistry

4. Genetic testing

24

Describe an example of how pattern of weakness can guide diagnosis?

Early onset contractures
→ Emery-Dreifuss Muscular Dystrophy
(an X-linked LGMD)

25

Describe the muscle pathology in LGMD

Features observed:
• Vaculoes

• Myotilin accumulation in LGMD type 1 (observed with myotilin stain)

These features are highly suggestive of LGMD and, more specifically, LGMD type 1

This would prompt specific genetic testing

26

What is the typical pattern of weakness in LGMDs?
What is the underlying cause of this?

Prominent contractures:
• Achilles tendons
• Elbows
• Spine

Humeroperoneal muscle weakness

Underlying cause:
• Lamin A/C mutations

27

Compare mode of inheritance in:
• LGMD type 1
• LGMD type 2

Which is more common?

LGMD type 1: autosomal dominant

LGMD type 2: autosomal recessive
• more common

28

What other problems are often seen in LGMD type 2?

Cardiomyopathy
Respiratory involvement

29

Describe the features of Facioscapulohumeral muscular dystrophy (FSHD)
• Mode of inheritance
• Prevalence
• Age of onset
• Symptoms

• Dominantly inherited
• 1/20 000
• Age of onset: 20

Symptoms:
• Very characteristic pattern of muscle weakness
• Facial weakness
• Scapula winging
• Proximal arm weakness
• Leg weakness (less prominent)
• Proneal weakness → foot drop
• Sleep with eyes open
• Can't whistle
• Poorly developed pectoral muscles
• Chest deformities: pigeon chest (prominent chest wall)

30

Describe the selective muscle involvement in FSHD

• Patchy and asymmetric
• Weakness mostly on dominant side
• Beevor sign:
- belly button goes up when head raised from a supine position

Not understood why it is so patchy

31

Describe the genetic basis for FSHD

• Gene still unidentified
• Dominantly inherited

• 90% cases map to Chromosome 4q
• 10% cases sporadic

Incomplete penetrance:
• 30% of people affected have no symptoms throughout life
• Symptoms more common in males than females

• Germline mosaicism occasionally seen

D4Z4 repeat sequence:
• On chromosome 4
• Affected in most cases FSHD, but we don't know how this brings about the disorder

32

Compare number of D4Z4 repeats in normal cases, and in people with FSHD

Finish the sentence:
The fewer n° of repeats, ...

Normal: 12-96 copies
FSHD: <8 copies

The fewer n° of repeats:
• The more severe the FSHD
• The earlier the onset

33

Why is genetic diagnosis of FSHD from the D4Z4 repeat sequence problematic?

How has this been overcome?

-- Problem --
There is a very similar sequence on chromosome 10
(Homologous)

Difficult to differentiate between the two

5% of people with FSHD have a negative gene test

There can also be translocation of the repeats to chromosome 10 which are not picked up on the test

-- New approach --

More complex gene probes
Able to distinguish between changes on 4q and 10q

These new probes also pick up translocations to chromosome 10

34

When can mutation occur, bringing about FSHD?

Why is this sometimes tricky?

1. Somatic mutations
• Mutation in the mothers somatic cells (but she's not affected)

-- New mutations --
2. Germline mosaicism
• Mutation during development (of the mother)
• Some of mothers cells affected: the gametes
• Somatic cells do not have the mutation

3. De novo
• e.g. mutation in a single sperm

Makes it hard for genetic counselling, as it is unclear whether the mother has zero chance of having another child with FSHD

35

Which other muscular dystrophies were talked about in this lecture?

DM1: Myotonic dystrophy

LGMD: Limb girdle muscular dystrophies

FSHD: Facioscapulihumoral dystrophy

36

Compare inheritance of the following muscular dystrophies:
• DMD
• FSHD
• LGMD type 1
• BMD
• LGMD type 2
• EDMD
• DM1

DMD: X-linked

FSHD: autosomal dominant

LGMD type 1: autosomal dominant

BMD: X-linked

LGMD type 2: autosomal recessive

Emery Dreifuss MD: X-linked

DM1: autosomal dominant