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Survey of Human Genetic Disorders Second Half > Neuromuscular > Flashcards

Neuromuscular Flashcards

1
Q

What is the most common genetic change in Charcot Marie Tooth syndrome?

A

17p duplication

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2
Q

What is another common genetic change in Charcot Marie Tooth syndrome?

A

PMP22

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3
Q

What is the phenotype of Charcot Marie Tooth syndrome?

A

Atrophy of muscles in legs, feet, and hands
High arched feet
Hammer toes

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4
Q

What percentage of SMN1 are deletions?

A

95%

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5
Q

What percentage of SMN1 mutations are de novo?

A

2%

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6
Q

What percentage of SMA cases is one parent a silent carrier?

A

4%

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7
Q

What is the problem with using copy number analysis of SMN1 for SMA?

A

Silent carriers are not detected
Also misses people with point mutations

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8
Q

What percentage of SMN1 are point mutations?

A

5%

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9
Q

In what NM disorder is onset <5 years, wheelchair <13 years, and lifespan 20-30 years?

A

DMD

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10
Q

What are features of DMD

A

Gower sign
Pseudohypertrophy of calf
Elevated CPK
Muscle weakness starts in proximal legs/pelvis
Awkward gait
Possible motor or developmental delay
Eventual respiratory issues

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11
Q

What is the Gower sign?

A

The child assumes the hands-and-knees position and then climbs to a stand by “walking” his hands progressively up his shins, knees, and thighs

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12
Q

What percentage of DMD is due to deletions?

A

80%

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13
Q

What is the testing strategy with DMD?

A

Start with del/dup analysis followed by sequencing

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14
Q

What cardiac finding occurs in DMD carriers and what percentage are affected?

A

DCM 8%

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15
Q

What is the age of onset of BMD?

A

5-60 years

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16
Q

What differentiates the muscular presentation in BMD versus DMD?

A

Preservation of neck flexor muscle strength in BMD

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17
Q

What genes are affected in Facioscapulohumeral Muscular Dystrophy?

A

DUX4 (AD)
SMCHD1 (<5%)

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18
Q

What muscles are affected in Facioscapulohumeral Muscular Dystrophy?

A

Face, shoulder blades, upper arms, abs, lower legs

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19
Q

What is the onset of Facioscapulohumeral Muscular Dystrophy and how long do patients live?

A

Onset <20 years
Normal life span

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20
Q

What is the mode of inheritance of Limb Girdle Muscular Dystrophy Type I and II?

A

Type I: AD
Type II: AR

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21
Q

What is the phenotype of Limb Girdle Muscular Dystrophy?

A

Affects proximal muscles around hips and shoulders
Waddling gait, trouble standing and with stairs, raising arms, may eventually need mobility assistance
Cardiomyopathy associated with some types
Elevated CK

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22
Q

What gene causes Oculopharyngeal Muscular Dystrophy?

A

PABPN1 (AD)

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23
Q

What are the features of Oculopharyngeal Muscular Dystrophy?

A

Affects eyelids, throat, facial, and limbs
Difficulty swallowing and keeping eyes open, some mobility issues
Onset 4-5 decade

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24
Q

What are the features of Emery Dreifuss Muscular Dystrophy?

A

Early contractures in elbows, neck and heels are common
Wasting of shoulders, upper arms, and calves
Cardiac conduction issues may show as fainting

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25
Q

When does Emery Dreifuss Muscular Dystrophy occur?

A

Onset by 10 years

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26
Q

What are the features of Charcot Marie Tooth caused by PMP22 mutations?

A

Progressive distal neuropathy of the arms and legs
Weakness in feet or hands
High arched feet
Can have sensorineural hearing loss

27
Q

What percentage of individuals with CMT have duplications in PMP22?

A

50%

28
Q

What is caused by deletions in PMP22?

A

Hereditary neuropathy with liability to pressure palsies

29
Q

What gene is associated with Ataxia Telangiectasia?

A

ATM (AR)

30
Q

What are the features of Ataxia Telangiectasia?

A

Gait and truncal ataxia, head tilting, slurred speech
Oculomotor apraxia-inability to follow an object across a visual field
Telangiectasias in eye
Immunodeficiency
Hypersensitivity to ionizing radiation
Carriers have increased risk of breast CA

31
Q

What genes are associated with Walker Warburg syndrome?

A

POMT1/2 (AR)

32
Q

What are the features of Walker Warburg syndrome?

A

Muscular dystrophy
Brain and eye anomalies
–Lissencephaly, encephalocele
Hypotonia
DD, ID
Seizures

33
Q

What is the onset of Walker Warburg syndrome?

A

Present at birth

34
Q

What is the onset of Ataxia Telangiectasia?

A

1-4 years

35
Q

What are some prenatal findings in neuromuscular disorders?

A

polyhydramnios (caused by decreased fetal swallowing)
fetal akinesia (paucity of movement)
malpresentation (often in the breech position)

36
Q

How do you distinguish between upper and lower motor neuron disorders by checking reflexes?

A

Abnormally brisk reflexes with clonus suggest involvement of the
upper tract.

Absent reflexes are consistent with a neuropathic lesion or severe
myopathy.

37
Q

Tongue fasciculations are typically associated with what NM disorder?

A

SMA

(can also be seen in glycogen storage diseases, hypoxic-ischemicinjury, and infantile neuronal degeneration)

38
Q

Is cerebral palsy associated with increased or decreased tone?

A

Increased

39
Q

What disorders result from disruption of components of the muscle extracellular matrix and its interaction with the sarcolemmal membrane?

A

Congenital muscular
dystrophies

40
Q

What disorders are caused by abnormalities of the contractile matrix, or structures supporting efficient excitation-contraction coupling, including the T tubules, sarcoplasmic reticulum, and other supporting structures?

A

Congenital myopathies

41
Q

What are the most common congenital muscular dystrophies?

A

Collagen VI–related and merosin-deficient congenital muscular dystrophies are the most common

42
Q

What is the most common congenital muscular dystrophy in Japan?

A

Fukuyama muscular dystrophy predominates because of a common founder mutation in the FKTN gene

43
Q

What is the most common genetic cause of central core myopathy?

A

RYR1-related central core myopathies

44
Q

Which genes account for 16% of genetically confirmed congenital myopathies?

A

SELENON
ACTA1

45
Q

What level of CK should prompt testing for a dystrophic disorder?

A

CK elevations of 5 times or more

46
Q

What is the most common form of congenital muscular dystrophy?

A

LAMA2-related (merosin-deficient) muscular dystrophy

1/3 of cases

47
Q

What two disorders account for 25% of congenital muscular dystrophy each?

A

Collagen VI–related congenital muscular dystrophy

α-dystroglycan–related congenital muscular dystrophy

48
Q

What are the features of Collagen VI–related congenital muscular dystrophy?

A

Progressive muscle weakness
Distal joint hyperlaxity
Proximal joint contractures.

Other features:
Normal to mildly elevated CK
Soft skin on palms and soles
Bulbous calcaneus
Keloid scars and hyperkeratosis pilaris (dry rough patches of skin with bumps)

49
Q

What are types of Collagen VI–related muscular dystrophies?

A

Ullrich congenital muscular dystrophy
Bethlem myopathy

50
Q

What are the most common dominant mutation in patients with collagen VI–related muscular dystrophies?

A
  1. Missense mutations resulting in substitution of the conserved glycine residue in the triple helical domain or
  2. Splicing mutations involving exon skipping in the triple helical domain
51
Q

What are the most common recessive mutation in patients with collagen VI–related muscular dystrophies?

A

Null alleles (nonsense, frameshift, and large deletions) do not allow incorporation of abnormal chains

52
Q

How do LAMA2-related CMD cases present?

A

Prominent hypotonia and weakness in infancy
Congenital contractures are common findings in hands and feet

53
Q

What is the mode of inheritance for LAMA2-related congenital dystrophy and what are the typical type of mutations?

A

Nonsense mutations resulting in complete loss of transcript (anywhere throughout gene)

54
Q

What is the clinical presentation of individuals with mutations in LMNA?

A

skeletal myopathies
Emery-Dreifuss muscular dystrophy phenotype most typical

55
Q

What are some of the differences between congenital myopathies versus CMD?

A

Weakness is congenital myopathies is less progressive
CK is usually normal
No CNS involvement

56
Q

What is seen on a muscle biopsy in congenital myopathies?

A

Nemaline rods, cores, and central nuclei

57
Q

Nemaline myopathies are most often caused by mutations in which genes?

A

NEB (50% of cases)
ACTA1 (20% of cases)

Can have a very severe neonatal course that is typically not progressive.

58
Q

What are the most common types of mutations in NEB?

A

Splicing (34%)
Shift in reading frame (32%)
Premature termination (23%)

Missense rarely pathogenic

59
Q

Are RYR1-related congenital myopathies AD or AR?

A

Both

60
Q

What is the phenotype of RYR1-mediated AD myopathies?

A

Spectrum of severity but usually relatively mild
Low tone and weakness in dominant cases.

Weakness can be exacerbated by physical activity, and facial and
extraocular weakness is less common than in nemaline myopathies

61
Q

What is the phenotype of RYR1-mediated AR myopathies?

A

More severe than AD
symptoms can mirror those of severe nemaline myopathies
*including severe weakness from the newborn period
*fetal akinesia
*congenital arthrogryposis
*respiratory failure

62
Q

What is the phenotype of SELENON-related myopathy?

A

Independent ambulation despite motor delays

Early respiratory compromise is severe and out of proportion to the muscle weakness and precedes loss of ambulation.

63
Q

Which types of muscular dystrophy have early respiratory compromise and may require noninvasive ventilation while asleep, even while still ambulatory?

A

Collagen VI–related muscular dystrophy
SELENON-related muscular dystrophy

Survey of Human Genetic Disorders Second Half (10 decks)

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