Lecture 33 - Other Muscular Dystrophies Flashcards Preview

Molecule to Malady > Lecture 33 - Other Muscular Dystrophies > Flashcards

Flashcards in Lecture 33 - Other Muscular Dystrophies Deck (85):
1

Do causative genes for muscular dystrophies have a uniform effect?

No. Have variable effects.

2

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)

3

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

4

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

5

What is a MD that is infant-onset?

Congenital muscular dystrophy

6

What is a MD that is adult-onset?

Limb-girdle muscular dystrophy

7

Normal response of a baby being picked up by their back

Flexion of back, neck

8

MD with a focal pattern of weakness

Rigid spine syndrome (significant, early, spinal weakness)

9

Facial weakness
1)
2)
3)

1) Blank expression
2) Tented upper lip
3) Mouth often open

10

Other systems that can be affected in MDs
1)
2)
3)
4)

1) Brain
2) Musculoskeletal
3) Ocular
4) Endocrine

11

Brain involvement in MDs
1)
2)

1) Abnormalities of brain development or maturation
2) Cognitive impairment

12

Musculoskeletal effects of MDs
1)
2)
3)

1) Muscle weakness
2) Joint contractures (elbow, Achilles tendon, iliotibial band)
3) Spinal rigidity, scoliosis

13

Eye effects of MDs
1)
2)

1) Structural or retinal abnormalities
2) Cataracts

14

Mutations in which gene can cause congenital muscular dystrophy?

FKRP gene

15

Effects of FKRP gene mutation
1)
2)
3)

1) Congenital muscular dystrophy
2) Signature mental retardation
3) Cerebellar cysts

16

Appearance of congenital muscular dystrophy muscle biopsy
1)
2)
3)

1) Increased central nuclei
2) Increased fat infiltration
3) Increased fibrous tissue

17

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

18

Immunohistochemisty

Staining with fluorescent antibodies

19

Alpha-dystroglycan immunohistochemical staining in normal muscle

Continuous, homogenous bands surrounding muscle fibres

20

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

21

Myotonic dystrophy mode of inheritance

Autosomal dominant

22

Prevalence of myotonic dystrophy

1/8000

23

Which chromosome is myotonic dystrophy inherited on?

Chr19

24

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)

25

MD that shows anticipation

Myotonic dystrophy

26

What is anticipation?

Shows worse phenotype with successive generations

27

Muscle biopsy of myotonic dystrophy

Very non-specific

28

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

29

Common muscular feature of myotonic dystrophy

Foot drop

30

Most common adult MD

Myotonic dystrophy (DMD is more common overall, but DMD patients don't survive to adulthood)

31

IQ of congenital myotonic dystrophy patients

Normally between 50 and 70

32

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

33

Three phenotypes of myotonic dystrophy

1) Congenital
2) Classical
3) Mild

34

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

35

Another name for myotonic dystrophy

DM1

36

Classic DM1
1)
2)

1) Most common form
2) Presents in adulthood or adolescence with muscle weakness

37

Mild DM1
1)
2)

1) Cataracts and mild myotonia in adulthood
2) Can be missed

38

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

39

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

40

Woman-specific problem in myotonic dystrophy

Wasting of uterine muscles can lead to issues with pregnancy

41

Myotonia

Delayed relaxation of muscles after contraction

42

Where does myotonia present?

In a number of muscle disorders, EG: myotonic dystrophy

43

Presentation of myotonia in families with myotonic dystrophy

Myotonia not present in DM1 affected child, but is present in affected parents

44

Usefulness of myotonia

Not normally a threatening condition by itself, but is a useful diagnostic tool

45

Appearance of muscle histology from muscle biopsy of myotonic dystrophy
1)
2)

1) Many nuclei in the centre of muscle cells
2) Ringbinden

46

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

47

Are muscle biopsies often used to diagnose DM1?

No.
A genetic test can be used to diagnose, and is less invasive

48

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

49

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

50

How sensitive is the genetic test for DM1?

100% sensitive

51

How is DM1 inherited?

Autosomal dominant

52

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)

53

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

54

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

55

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)

56

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

57

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

58

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

59

First place of muscle weakness in limb girdle muscular dystrophies

Often the pelvis, as this is weight-bearing

60

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

61

What do most limb girdle muscular dystrophies affect?

Sarcoplasmic membrane

62

Most common type of limb girdle muscular dystrophy

Type 2 (autosomal recessive)

63

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

64

How often is a precise diagnosis made for limb girdle muscular dystrophies?

~75% of the time
~25% of LGMDs can't be categorised

65

The only early-onset limb girdle muscular dystrophy

Emery-Dreifuss muscular dystrophy

66

Universal feature of young boys with Emery-Dreifuss MD

Early contractures

67

Muscle histology in limb girdle muscular dystrophy type 1A
1)
2)

1) Vacuoles in muscle cells
2) Myotilin aggregates in myotilin stain

68

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

69

Fascioscapulohumeral muscular dystrophy inheritance

Dominantly inherited myopathy
Specific gene not known

70

Fascioscapulohumeral MD age of onset

Most patients symptomatic by age 20

71

Fascioscapulohumeral MD prevalence

1/20,000 people affected

72

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)

73

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)

74

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

75

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

76

Where do 90% of fascioscapulohumeral MD inheritance map to?

4q35

77

Number of cases of fascioscapulohumeral MD that are sporadic

10-30%

78

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

79

Repeat sequence associated with fascioscapulohumeral MD

D4Z4 repeat on chromosome 4

80

Normal number of D4Z4 repeats

12-96 copies

81

Fascioscapulohumeral MD number of D4Z4 copies

Under 8

82

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.

83

Genetic test for fascioscapulohumeral MD

Gene probe tests for the number of D4Z4 repeats on chromosome 4

84

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

85

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