Lecture 33 - Other Muscular Dystrophies Flashcards Preview

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1
Q

Do causative genes for muscular dystrophies have a uniform effect?

A

No. Have variable effects.

2
Q
What are the classifications of MDs based on?
1)
2)
3)
4)
5)
6)
A

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
Q
Why make a specific diagnosis of a MD?
1)
2)
3)
4)
A

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
Q

Benefits of genetic counselling
1)
2)
3)

A

1) See recurrence risk in siblings
2) Counsel other family members
3) See when being a carrier is a health risk

5
Q

What is a MD that is infant-onset?

A

Congenital muscular dystrophy

6
Q

What is a MD that is adult-onset?

A

Limb-girdle muscular dystrophy

7
Q

Normal response of a baby being picked up by their back

A

Flexion of back, neck

8
Q

MD with a focal pattern of weakness

A

Rigid spine syndrome (significant, early, spinal weakness)

9
Q

Facial weakness
1)
2)
3)

A

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

10
Q
Other systems that can be affected in MDs
1)
2)
3)
4)
A

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

11
Q

Brain involvement in MDs
1)
2)

A

1) Abnormalities of brain development or maturation

2) Cognitive impairment

12
Q

Musculoskeletal effects of MDs
1)
2)
3)

A

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

13
Q

Eye effects of MDs
1)
2)

A

1) Structural or retinal abnormalities

2) Cataracts

14
Q

Mutations in which gene can cause congenital muscular dystrophy?

A

FKRP gene

15
Q

Effects of FKRP gene mutation
1)
2)
3)

A

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

16
Q

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

A

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

17
Q

Ways to use a muscle biopsy to diagnose MDs
1)
2)
3) a, b, c, d

A

1) Histology
2) Electron microscopy
3) Diagnostic screen
a) Immunohistochemistry
b) Western blot
c) Mutation analysis
d) Biochemical analysis

18
Q

Immunohistochemisty

A

Staining with fluorescent antibodies

19
Q

Alpha-dystroglycan immunohistochemical staining in normal muscle

A

Continuous, homogenous bands surrounding muscle fibres

20
Q

Alpha-dystroglycan immunohistochemical staining in MD muscle
1)
2)

A

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
Q

Myotonic dystrophy mode of inheritance

A

Autosomal dominant

22
Q

Prevalence of myotonic dystrophy

A

1/8000

23
Q

Which chromosome is myotonic dystrophy inherited on?

A

Chr19

24
Q
Myotonic dystrophy effects
1)
2)
3)
4)
5)
6)
7)
A

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
Q

MD that shows anticipation

A

Myotonic dystrophy

26
Q

What is anticipation?

A

Shows worse phenotype with successive generations

27
Q

Muscle biopsy of myotonic dystrophy

A

Very non-specific

28
Q

How are tests for muscular dystrophies conducted?
1)
2)

A

1) Specific, targeted

2) Specific stains (for proteins), histological findings are suggested, based on clinical examination

29
Q

Common muscular feature of myotonic dystrophy

A

Foot drop

30
Q

Most common adult MD

A

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

31
Q

IQ of congenital myotonic dystrophy patients

A

Normally between 50 and 70

32
Q
Muscles commonly affected in myotonic dystrophy
1)
2)
3)
4)
5)
A

1) Arms, forearms
2) Feet, legs
3) Neck
4) Facial muscles
5) Intestinal smooth muscle, heart

33
Q

Three phenotypes of myotonic dystrophy

A

1) Congenital
2) Classical
3) Mild

34
Q
Congenital myotonic dystrophy
1)
2)
3)
4)
A

1) Most severe phenotype
2) Presents in first 4 weeks of life
3) Respiratory failure, feeding problems
4) Early death common

35
Q

Another name for myotonic dystrophy

A

DM1

36
Q

Classic DM1
1)
2)

A

1) Most common form

2) Presents in adulthood or adolescence with muscle weakness

37
Q

Mild DM1
1)
2)

A

1) Cataracts and mild myotonia in adulthood

2) Can be missed

38
Q
Congenital myotonic dystrophy symptoms
1)
2)
3)
4)
5)
6)
7)
A

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
Q
Myotonic dystrophy symptoms in adults
1)
2)
3)
4)
5)
6)
A

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
Q

Woman-specific problem in myotonic dystrophy

A

Wasting of uterine muscles can lead to issues with pregnancy

41
Q

Myotonia

A

Delayed relaxation of muscles after contraction

42
Q

Where does myotonia present?

A

In a number of muscle disorders, EG: myotonic dystrophy

43
Q

Presentation of myotonia in families with myotonic dystrophy

A

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

44
Q

Usefulness of myotonia

A

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

45
Q

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

A

1) Many nuclei in the centre of muscle cells

2) Ringbinden

46
Q

Ringbinden
1)
2)

A

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
Q

Are muscle biopsies often used to diagnose DM1?

A

No.

A genetic test can be used to diagnose, and is less invasive

48
Q

Gene resulting in DM1
1)
2)

A

1) Extended CTG trinucleotide repeat in the gene DMPK

2) Fully-penetrant mutants have over 50 CTG repeats in DMPK

49
Q

Stages of DMPK trinucleotide repeat
1)
2)
3)

A

1) Normal - 5-35 CTG repeats
2) Pre-mutation - 35-49 CTG repeats
3) DM1 - Over 50 CTG repeats

50
Q

How sensitive is the genetic test for DM1?

A

100% sensitive

51
Q

How is DM1 inherited?

A

Autosomal dominant

52
Q

DM1 anticipation
1)
2)

A

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
Q

How do extended CTG repeats in DMPK lead to myotonic dystrophy?
1)
2)
3)

A

1) Encode RNA with a gain of function
2) RNA forms a hairpin structure
3) CUG repeats sequester specific proteins

54
Q
Function gained by DMPK RNA in myotonic dystrophy
1)
2)
3)
4)
A

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
Q
Downstream effects of upregulated CUG-binding protein 1
1)
2)
3)
4)
A

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
Q

Effect of muscleblind-like 1 and CUG-binding protein 1 ratios in development
1)
2)
3)

A

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
Q

Possible therapeutic strategies for DM1
1)
2)
3)

A

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
Q
Limb girdle muscular dystrophies general features 
1)
2)
3)
4)
5)
6)
A

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
Q

First place of muscle weakness in limb girdle muscular dystrophies

A

Often the pelvis, as this is weight-bearing

60
Q

Limb girdle muscular dystrophy classifications
1)
2)
3)

A

1) LGMD type 1 - Autosomal dominant
2) LGMD type 2 - Autosomal recessive
3) DMD, BMD - X-linked

61
Q

What do most limb girdle muscular dystrophies affect?

A

Sarcoplasmic membrane

62
Q

Most common type of limb girdle muscular dystrophy

A

Type 2 (autosomal recessive)

63
Q
Clinical clues looked for when diagnosing limb girdle muscular dystrophies 
1)
2)
3)
4)
5)
A

1) Pattern of weakness
2) Family history
3) Creatine kinase levels
4) Muscle histology
5) Muscle immunoanalysis

64
Q

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

A

~75% of the time

~25% of LGMDs can’t be categorised

65
Q

The only early-onset limb girdle muscular dystrophy

A

Emery-Dreifuss muscular dystrophy

66
Q

Universal feature of young boys with Emery-Dreifuss MD

A

Early contractures

67
Q

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

A

1) Vacuoles in muscle cells

2) Myotilin aggregates in myotilin stain

68
Q
Contracture and weaknes patterns in limb girdle muscular dystrophies 
1)
2)
3)
4)
5)
A

1) Contractures of Achilles tendon
2) Contractures of elbows
3) Contractures of spine
4) Contractures of knees
5) Humeroperoneal weakness

69
Q

Fascioscapulohumeral muscular dystrophy inheritance

A

Dominantly inherited myopathy

Specific gene not known

70
Q

Fascioscapulohumeral MD age of onset

A

Most patients symptomatic by age 20

71
Q

Fascioscapulohumeral MD prevalence

A

1/20,000 people affected

72
Q
General features of fascioscapulohumeral MD
1)
2)
3)
4)
A

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
Q
Signs on examination of fascioscapulohumeral MD
1) 
2) 
3) 
4)
5)
A

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
Q
Pattern of muscle involvement in fascioscapulohumeral MD
1)
2)
3)
4)
A

1) Asymmetrical
2) Scapular, pectoral muscles affected early
3) Lower 1/3 of abdomen affected (Beevor’s sign)
4) Heart, respiratory muscles unaffected

75
Q

Beevor’s sign
1)
2)

A

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
Q

Where do 90% of fascioscapulohumeral MD inheritance map to?

A

4q35

77
Q

Number of cases of fascioscapulohumeral MD that are sporadic

A

10-30%

78
Q
Penetrance of fascioscapulohumeral MD
1) 
2) 
3) 
4)
A

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
Q

Repeat sequence associated with fascioscapulohumeral MD

A

D4Z4 repeat on chromosome 4

80
Q

Normal number of D4Z4 repeats

A

12-96 copies

81
Q

Fascioscapulohumeral MD number of D4Z4 copies

A

Under 8

82
Q

Is there a correlation between the number of D4Z4 repeats and fascioscapulohumeral MD severity?

A

Yes. Fewer repeats results in more severe phenotype, earlier age of onset.

83
Q

Genetic test for fascioscapulohumeral MD

A

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

84
Q

Problems with genetic test for fascioscapulohumeral MD
1)
2)
3)

A

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
Q

Can fascioscapulohumeral MD be casued by de novo mutations?

A

Yes

Germline mosaicism, from post-zygotic mutation in one allele of a pair of genes in a cell