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Block 4 Week 1 Meg > TBL: Muscular Dystrophies > Flashcards

TBL: Muscular Dystrophies Flashcards

1
Q

Group of inherited, progressive muscle diseases in which

there is necrosis of muscle tissue

A

muscular dystrophies

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2
Q

Muscular dystrophies are caused by distinct (blank) in genes affecting proteins found in the cell membrane (sarcolemma), muscle nuclei, ECM, muscle enzymes and contractile proteins.

A

mutations

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3
Q

A mutation in dystrophin can lead to one of these two disorders

A

Duchenne’s muscular dystrophy

Becker’s muscular dystrophy

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4
Q

A mutation in laminin-2 can lead to this disorder

A

MDC1A

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5
Q

Ancillary tests for muscular dystrophy

A

Creatine kinase levels

MRI

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6
Q

X-linked recessive diseases related to dystrophin

A

dystroglycanopathies

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7
Q

The major dystroglycanopathies

A

DMD

BMD

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8
Q

The most common form of muscular dystrophy with an incidence of ~1/3,500 live male births. The mutation rate is about 1/3 of the incidence of the disease in males, or about 1/10,000

A

DMD

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9
Q

Incidence rate of DMD

A

1/3500

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10
Q

Incidence of BMD

A

1/18,000 to 1/31,000 male births

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11
Q 
X-linked dilated cardiomyopathy
Isolated quadriceps myopathy
Muscle cramps with myoglobinuria
Asymptomatic elevation of muscle enzymes
Manifesting DMD and BMD carrier females
A

Other dystroglycanopathies that occur at lower incidence

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12
Q

a structural protein which provides integrity to the sarcolemma

A

Dystrophin

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13
Q

The dystrophin gene is on the (blank) chromosome and is a huge gene. What are some kinds of mutations that can cause dystroglycanopathies?

A

X-chromosome; 66% deletions, 5-10% point mutations, 5% duplications

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14
Q

Incidence of DMD vs prevalence

A

1/3500 is the incidence

1/18,000 is the prevalence

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15
Q

What fraction of DMD occurs as a result of spontaneous mutations?

A

1/3

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16
Q

How do most male children present at birth? When do they begin to have a wide-base, waddling gait and increasing leg weakness and falls?

A

appear normal at birth; these symptoms begin around age 2-6

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17
Q

What is the clinical sign that is characteristic of DMD?

A

Gower sign

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18
Q

Is weakness worse proximally or distally? In the lower limbs or upper limbs?

A

worse proximally; worse in lower limbs

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19
Q

By what age do children have difficulty climbing stairs?

By what age are they confined to a wheelchair?

A

8; 12

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20
Q

Development of kyphoscoliosis and joint contractures

The biceps brachii, triceps and quadriceps reflexes diminish and are absent in 50% of children by 10 years of age

Respiratory function gradually declines and leads to death in most patients in their early twenties

Cardiac dysrhythmias and congestive heart failure can occur late in the disease

Central nervous system involvement is involved in DMD.

A

DMD clinical features

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21
Q

What is markedly elevated in DMD (50-100X normal) at birth and peaks around 3 y/o

A

serum creatine kinase

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22
Q

These two liver enzymes are usually elevated in DMD

A

ALT

AST

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23
Q

What can an MRI reveal in DMD patients?

A

fat and connective tissue replacement in muscle

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24
Q

What can histology reveal in DMD patients?

A

reduced or absent dystrophin

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25
Q

What can muscle biopsies reveal in DMD patients?

A

scattered necrotic and regenerating myofibers, variability in myofiber size, increased CT, and small rounded regenerating myofibers

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26
Q

Histology of dystrophic tissue will show what three features?

A

increased connective tissue
central nuclei (instead of peripheral)
presence of regenerating and degenerating fibers

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27
Q

T/F: When comparing DMD and BMD, it is important to quantify the amount of protein in specific tissue and the size of protein.

A

True

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28
Q

Two ways to analyze protein expression in DMD patients

A

immunohistochemistry

Western blot

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29
Q

What is the ultimate diagnostic tool for muscular dystrophy?

A

gene sequencing

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30
Q

Milder form of dystroglycanopathy and can be distinguished from DMD clinically by the slower rate of progression and presence of dystrophin

A

Becker muscular dystrophy

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31
Q

Incidence of BMD?

A

5/100,000

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32
Q

Clinical features that help with diagnosis of BMD

A

family history compatible with X-linked recessive inheritance
ambulation past 15 years of age
Limb Girdle pattern of muscle weakness
Calf hypertrophy

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33
Q

T/F: In BDM, there are cardiac abnormalities similar to DMD, and a reduced life expectancy.

A

Truth be told!

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34
Q 
What is observed for the following in BMD:
Serum CK
EMG
MRI
Histopathology
A

serum CK elevated
EMG abnormal
MRI can show fatty tissue replacement in affected muscles
Histopath similar to DMD, but less severe

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35
Q

Immunostaining reveals the presence of dystrophin with (blank) reactive antibodies but not (blank) reactive antibodies (truncated dystrophin protein) in most BMD cases

A

N-terminal; C-terminal

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36
Q

Immunoblot reveals (blank) quantity and (blank) size of dystrophin protein.

A

abnormal; reduced

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37
Q

What happens to women who are carriers of the DMD or BMD gene?

A

Women who are carriers are normally non-symptomatic, but a few develop muscle weakness- explained by the Lyon hypothesis: skewed X-inactivation of the normal X-chromosome and dystrophin gene

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38
Q

T/F: Females with translocations at the chromosomal Xp21 site or Turners may develop dystroglycanopathies

A

True

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39
Q

T/F: Manifesting carriers typically develop a mild limb-girdle phenotype similar to BMD. Laboratory and histologic features of manifesting carriers are similar to DMD and BMD.

A

That’s true..

40
Q

What can be used to treat dystrophinopathies?

A

corticosteroids!

41
Q

This has been shown to increase muscle strength and function since as early as 10 days and sustained for up to 3 years. Slows the rate of deterioration in children with DMD

A

Prednisone

42
Q

What’s this: weight gain, excessive hair growth, irritability, stunted growth and hyperactivity, increased chance of infection, glucose intolerance, cataract formation, oestoporosis, osteonecrosis, problems with cardiac function

A

side effects of high doses of corticosteroid treatment

43
Q

This is critical for DMD and BMD patients because of the contractures that develop early in the disease

A

physical therapy

44
Q

This is a common complication of DMD resulting in pain, aesthetic damage and sometimes ventilator (respiratory) compromise.

A

scoliosis

45
Q

This is considered with patients exceeding 35° scoliosis and in significant discomfort often improves life quality but does not improve respiratory function.

A

spinal fusion

46
Q

Genes encoding dystrophin, glycerol kinase (GKD) and Adrenal hypoplasia congenita (DAX1) can occur together as contiguous genes on Chr Xp21. Gene order is Xpter-DAX1-GKD-DMD-centromere. Why is this important?

A

Depending on the extent of the mutation patients may exhibit combined diseases e.g. children with DMD and GKD exhibit in addition to severe muscle weakness, severe pyschomoter delay, episodic nausea, vomiting and stupor associated with GKD deficiency

47
Q

● Most common form is mutations in Emerin, a nuclear scaffolding protein localized to the inner nuclear membrane, involved in the attachment of heterochromatin

● X-linked recessive

● Wasting and weakness in upper arms, shoulders and legs

● Cardiac complications are frequent and include ventricular myocardial disease and conduction block leading to sudden death.

● Female carriers may develop cardiac dysfunction at older age that can lead to sudden death. There carriers should get regular ECG’s

● CK is elevated. Emerin is found in many tissues therefore skin biopsy can be used in diagnosis and confirmed by DNA testing

A

Emery-Driefuss muscular dystrophy

48
Q

Emery-Driefuss muscular dystrophy caused by a mutation in (blank).

A

Emerin

49
Q

Emerin is found in many tissues therefore what procedure can be used in diagnosis and confirmed by DNA testing?

A

skin biopsy

50
Q

Autosomal dominant forms of Limb-girdle muscular dystrophy have what number in their name? Autosomal recessive forms of Limb-girdle muscular dystrophy have what number in their name?

A

1; 2

51
Q

Which two forms of Limb-girdle muscular dystrophy are X-linked?

A

Dystrophin (DMD/BMD)

Emerin (EDMD)

52
Q

Heterogeneous group of disorders that clinically resemble dystroglycanopathies except genes are autosomal

A

limb-girdle muscular dystrophies

53
Q

Autosomal dominant LGMDs are classified as type (blank), while autosomal recessive are type (blank).

A

1; 2

54
Q

What is the prevalence of LGMDs?

A

rare! 8 per million

55
Q

caused by mutations in the myotilin gene

A

LGMD 1A

56
Q

What does myotilin do?

A

it’s a sarcomeric protein that colocalizes with alpha actinin at the Z-disk

57
Q

caused by mutations in lamin

A

LGMD 1B

58
Q

What does lamin do?

A

it is required for nuclear cytoskeleton organization

59
Q

caused by mutations in caveolin-3

A

LGMD 1C

60
Q

Where is caveolin-3 located? What is it involved in?

A

located on the sarcolemma; involved in cell signaling and regulation of sodium channels

61
Q

Histopathology of this disease reveals decreased caveoli.

A

LGMD 1C

62
Q

caused by mutations in the calpain-3 gene

A

LGMD 2A

63
Q

This LGMD has a normal life expectancy

A

LGMD 2A

64
Q

What can be used to test for calpainopathies?

A

Western Blot

65
Q

What is a classic clinical feature of LGMD 2A, or calpainopathy?

A

winged scapula

66
Q

Caused by mutations in the dysferlin gene

A

LGMD 2B

Miyoshi Myopathy

67
Q

Both LGMD2B and Miyoshi Myopathy are caused by mutations in dysferlin. They are both autosomal recessive. Adult-onset, slowly progressive. So what distinguished them from one another?

A

LGMD2B presents as muscle weakness in proximal lower girdle muscles
Miyoshi Myopathy presents as muscle weakness in calf muscles

68
Q

How can you remember that Miyoshi Myopathy is just in the calf muscles?

A

Think of a weenie little Asian boy with no calves

69
Q

● Onset 1st-3rd decade
● Loss of ambulation 2nd-4th decade
● CK markedly 
● Cardiac involvement

A

sarcoglycanopathies

70
Q

Mutations in any of the four sarcoglycan genes can cause LGMD2C, LGMD2D, LGMD2E and LGMD2F. All are autosomal recessive

A

sarcoglycanopathies

71
Q

T/F: The sarcoglycans are a tightly associated protein complex and loss of one member of the complex often results in loss or reduced levels of the others making exact diagnosis tricky

A

True

72
Q

Account for >10% of patients with a limb-girdle pattern and positive dystrophin

A

sarcoglycanopathies

73
Q

T/F: In sarcoglycanopathies, disease severity is dependent on which protein is absent.

A

True

74
Q

In this disease, the onset is variable. Wide range of phenotypes. Commonest form in UK/Germany. Calf/leg/tongue hypertrophy. Increased CK, risk of cardiomyopathy and respiratory failure.

A

LGMD 2I - FKRP

75
Q

Calf hypertrophy is present in all forms of LGMD except which?

A

2B (dysferlin)

76
Q

Which two LGMDs have cardiac involvement? In which is it rare?

A

sarcoglycan and FKRP

rare in calpain and dysferlin deficiency

77
Q

Which LGMDs have DMD-like phenotype?

A

sarcoglycan, FKRP, and calpain

78
Q

Which LGMD has a range of phenotypes?

A

FKRP

79
Q

Clinical presentation of congenital muscular dystrophies? Pathology

A

hypotonia, weakness, onset at birth to 6 months, increased CK
pathology: dystrophic biopsy

80
Q

What is a congenital muscular dystrophy which is merosin deficient and causes no or minor brain abnormalities?

A

MDC1A

81
Q

Caused by mutations in the LAMA2 gene

A

MDC1A

82
Q

What protein is completely or partially absent in MDC1A?

A

laminin 211 and 221 (merosin)

83
Q

Severe weakness of the trunk and limbs and hypotonia at birth
Prominent contractures of the feet and hips are present
Although intelligence is normal, the incidence of epilepsy is 12% to 20%
Brain MRI can reveal increased signal in the white matter on T2-weighted images. Computed tomography (CT) of the head reveals lucencies of the white matter.

A

MDC1A

84
Q

Selenoprotein N disorders are associated with two autosomal recessive conditions

A

multi-mini core disease

rigid spine syndrome

85
Q

Two Collagen VI muscular dystrophies. Which is mild, which is severe?

A

Bethlem myopathy is mild, Ullrich Congenital MD is severe

86
Q

Which collagen VI muscular dystrophy is associated with contractures and distal laxity?

A

Ullrich

87
Q

Dystroglycanopathies are associated with major brain abnormalities. List three of em.

A

Fukuyama
Muscle Eye Brain Disease
Walker Warburg syndrome

88
Q

This is a severe dystroglycanopathy, detected on early antenatal ultrasound, encephalocoeles frequent, type II lissencephaly

A

Walker Warburg Syndrome

89
Q

Problem gene POMT1 which codes for O-mannosyltransferase and the glycosylation of alpha-dystroglycan

A

Walker Warburg Syndrome

90
Q

Problem gene POMGnT1, seen in all populations, secondary merosin and alpha DG deficiency

A

Muscle eye brain disease

91
Q

Severe phenotype clinically and histopathologically
generalised leg hypertrophy, macroglossia
Increased CK, (N) brain, (N) intellect, (N) NCS

LGMD2I - allelic variant - most common
LGMD in UK (>20%)
dilated cardiomyopathy very common

A

MDC1C - FKRP

92
Q

Mutations in the Fukutin gene. Autosomal recessive.

A

Fukuyama congenital muscular dys

93
Q

What is Fukutin involved in?

A

Fukutin is a glycosyl transferase and is involved in the glycosylation of alpha-dystroglycan

94
Q

Patients are typically of Japanese origin
It is a homozygous founder mutation
Pts die by avg age 16
Heterozygous for a point mutation

A

Fukuyama CMD

95
Q

Characterized by progressive muscle wasting and weakness and myotonia. Caused by mutations in myotonic dystrophy protein kinase gene. CTG repeats expand into the hundreds or thousands, and the mutation shows anticipation. Typical presentation is early teenage onset, weakness in hands and distal muscles and footdrop. Long face with mournful expression

A

myotonic dystrophy type 1

96
Q

Characterized by progressive muscle wasting and weakness and myotonia. Allelic disorder. Caused by CCTG expansion. Most people manifest disease between 20-60 y/o. Starts with pain and stiffness in thigh muscles. Anticipation is milder.

A

myotonic dystrophy type 2 or PROMM

97
Q

Autosomal dominant MD caused by a deletion in a repeating sequence D4Z4. When this region is hypomethylated it causes a myopathy. Expression of DUX4 gene is responsible. Severity of disease depends on size of deletion.

A

Facioscapulohumeral dystrophy

Block 4 Week 1 Meg (13 decks)

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