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Medicine - Year 1 > Gait and limp - Genetics > Flashcards

Gait and limp - Genetics Flashcards

1
Q

What are the main clinical features of musclde disorders

A
  • Weakness: proximal, symmetrical, persistent
  • Weakness > wasting
  • Sensation: normal
  • Tendon reflex: normal (or decreased only in areas of prominent weakness)
  • Additional features: myotonia (muscles can’t relax after contracting) , rhabdomyolysis (breakdown of damaged muscle leading to release of muscle cell contents into the blood), cardiomyopathy (any disorder that affects the heart), contractures (a permanent tightening of the muscles, tendons, skin, and nearby tissues that causes the joints to shorten and become very stiff)
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2
Q

Describe the investigations taken for muscle disorders

A
  • Electormyography (EMG)
  • Serum creatine kinase (CK): high
  • Other blood tests (routine biochemistry, enocrine tests etc)
  • Muscle biopsy
  • Antibodies associated with connective tissue disorders (NA, RF, ant-ds DNA, anit-Ro/La, anti Scl-70) and polymyositis (anti Jo-1) and dermatomyositis (anti Mi-2)
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3
Q

Myopathies ca be acquired or inherited. List acquired causes of myopathies

A

Inflammatory myopathies

  • Polymyositis
  • Dermatomyositis
  • Inclusion body myositis

Endocrine and metabolic disorders

  • Thyroid
  • Pituitory
  • Parathyroid
  • Adrenal
  • Hypokalaemia
  • Hypo-hypercalcaemia

Alcohol and other toxins/drugs

Infectious causes e.g., HIV

Paraneoplastic syndrome

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4
Q

Myopathies can be acquired or inherited. List inherited causes of myopathy taht are non dystrophic and also dystrophic

A

Non-dystropic myopathies

  • Congenital
  • Mitochondrial
  • Familial periodic paralysis
  • Metabolid

Muscular dystrophy

  • Becker
  • Duchenne
  • Faciocapulohumeral
  • Myotonic
  • Emery Dreifuss
  • Limb-girdle
  • Oculopharngeal
  • Congenital
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5
Q

Describe the difference between muscular dystrophies and congenital msucular dystrophies

A
  • Muscular dystrophies are associated with progressive muscle injury in patients who have normal muscle funcion at birth
  • Congenital muscular dystrophies, by contrast, are progressive, early-onse diseases. Some arealso associated with malfromations of the CNS
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6
Q

a) What are congenital msucular dytsrophies characterised by?
b) What is the classification based on?

A

a) Progressive degenerative change in muscle fibers, muscle weakness
b) Classification based upon:

  • Clinical distribution of weakness
  • Pattern of inheritance
  • Molecular genetics
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7
Q

List 3 examples of X-linked muscular dystrophies

A
  • Duchenne muscular dystrophie
  • Becker muscular dystrophie
  • Emery-dreifuss syndrome
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8
Q

List 7 examples of autosomal msucular dystrophies

A
  1. Facioscapulohumeral muscular dystrophy (FSHD)
  2. Myotonic muscular dystrophy
  3. Scapulopernoeal dystrophy
  4. Oculopharnygeal
  5. Limb girdle muscular dystrophy (LGMD1)
  6. Limb girdle muscular dystrophy (LGMD2) - autosomal recessive
  7. Scapulohumeral dystrophy - autosomal recessive
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9
Q

Describe the mechanical and functioncal roles of dystrophin

A

Mechanical

  • Stabilization of membrane during contraction and relxation
  • Part of link between intracellular cytoskeleton and extracellular matrix

Functional

  • Enables muscle fibres to differentiate into fast glycolytic type (fast twitch fibres)
  • Organization of post-synaptic membrane and AChRs
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10
Q

a) Describe the genetic features of duchenne muscular dystrophy
b) Describe the epidemilogy

A

a) X-linked, frameshift dystrophin mutations
b) 1 in 3500 malebirths, onset is 3-5 years

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11
Q

Describe the clinical features of Duchenne musuclar dystrophy

A
  • Progrssive muscle weakness
  • Waddling gait
  • Gower’s sign
  • Muscle pseudohypertrophy - enlarged muscles feel doughy on palpation and are weaker than normal (especially calfs). This is due to muscle replacement with collagen and adipose tiusse
  • Muscoskeletal - scoliosis, contractures
  • Dilated cardiomyopathy
  • Low IQ
  • Premature death - most common between 15-25 due to cardiac and respiratory failure
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12
Q

On the left image is a muscle biopsy of normal dystrophin around rim of muscle fibres. On the right image is Duchenne muscular dystrophy. What is the difference?

A
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13
Q

a) Describe the genetic features of Becker muscle dyrstophy
b) Describe the epidemiology including the onset of disease

A

a) X-linked recessive, in frame dystrophin mutations
b) 1 in 30,000 male births and onset > 7 years (mean age 11 years)

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14
Q

Describe the clinical features of Becker muscle dystrophy

A
  • Slowly progressive
  • Weakness: proximal>distal especially quadriceps, pelvic muscles and arms
  • Toe walking
  • Gower’s sign
  • Calf hypertrophy may be prominent
  • Cardiomyopathy
  • Respiratory msucle involvement
  • Scoliosis
  • Mild learning disability
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15
Q

On the left image is a muscle biopsy of normal dystrophin staining around rim muscle fibers. On the right image is Becker msucle dystrophy. Describe the difference

A
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16
Q

On the far left image is a muscle biopsy of normal dystrophin staining around rim of muscle fibers. On the right are two more images with abnormal dystrophin. Which one is Duchenne and which one is Becker muscle dystrophy? State why you have selected these answers

A

Middle image is Becker muscle dystrophin and far right is Duchenne muscle dytsrophin.

This is because Duchenne has more severe dystrophin levels reduced so the dystrophin muscle fibres are absent, whereas in Becker that is less severe the dystrophin is reduced

17
Q

Which is more severe? Duchenne or Becker muscle dystrophy? Explain why

A

Duchenne

This is because severity is correlated with muscle dystrophin levels and duchenne has less dyrtophin levels, therefore it is more severe

18
Q

a) What are the two types of fascioscapulohumeral dystrophy (FSHD)
b) Describe the genetic features
c) Fasciscapulohuemral is associated with weakness. Where is this weakness found? and what can some of these weaknesses lead to?
d) What are other clinical features?

A

a) FSHD1 and FSHD 2
b) Autosomal dominant - 1/3 de novo mutations

c)

  • Face (upper eyelid droops know as ptosis, can’t whistle)
  • Upper extremity
  • Scapula (winging)
  • Humeral (biceps)
  • Peroneal muscles (foot drop)

d)

  • Cardiac
  • Hearing affected
  • Epilepsy
  • Learning disabilities
19
Q

a) Describe the genetic feaures of myotonic muscular dystrophy (DM)
b) Describe the epidemiology
c) What are the two type?

A

a) Autosomal dominant
b) Commonest form of adult muscular dystrophy, 1/8000
c) DM1 (Steinart’s disease) - several clinical forms

DM2 (Proximal myotonic myopathy PROMM)

20
Q

Describe the clincal features of myotonic muscular dystrophy

A
  • Slowly progressive multi-system disease
  • Frontal blading
  • Cataracts
  • Myopathic facies
  • Muscle wasting/weakness
  • Cardia conduction dfects
  • Cardiomyopathy
  • Sleep apnoea
  • Hypersomnolence (excessive sleepiness)
  • Gynaecomastia (a condition of overdevelopment or enlargememt of the the breasts in men or boys)
  • Diabetes
  • Hypogonadism (diminished functional acitivty of the gonads - the testes or the ovaries - that may result in diminished production of sex hormones)
21
Q

Describe the difference between type 1 and type 2 myotonic dystrophy inclduing the affected gene, area of muscle weakness, anticipation/no anticipation

A

Myotonic dystrophy type 1 - DM1

  • Congenital and adultonset forms
  • Muscle weakness - hand, lower leg, neck and face
  • Prominent myotonia (hand, thenar eminence and hypothenar eminence
  • Affected gene is DMK on chromosome19
  • Anticipation (progressively earlier onset and severity of the disease from genertaion to generation)

Myotone dystrophy type 2 - DM2

  • Milder than DM1
  • Muscle weakness - neck flexors, finger flexors, lateral-hip girdle musclles
  • Mutations in gene coding CNBP (cellular nucleic acid binding protein) on chromosome 3
  • Minimal or no anticipation
22
Q

a) What is ataxia and where does it the word ‘ataxia’ come from?
b) What are the two types of ataxic gait ? Describe 2 featurs of each type

A

a) Ataxia = Disturbance of coordination and/or gait and/or speech

Comes from Greek ‘taxis’ meaning ‘order’ (ataxia = lack of order)

b) Cerebellar

  • Wide-based gait
  • Associated intention tremor/limb ataxia

Sensory

  • Unsteady high-stepping gait
  • Worse in dark
23
Q

Cerebellar ataxia can be acquired or inherited. List the causes of acquired ataxia

A
  • Vascular
  • Drugs and toxins
  • Inflammatory (infection and demyelination)
  • Structural causes (tumours)
  • Hypothyroidism
  • Deficiency states (Vitamin E, thiamine)
  • Prion disease (Creutzfeldt-Jakob disease = CJD) - prion is an abnormal infectious protein
  • Paraneoplastic
24
Q

Cerebellar ataxia can be acquired or inherited. List the causes of hereditary ataxia

A
  • Autosomal recessive (Freichreich’s ataxia)
  • Autosomal dominant cerebellar ataxia (ADCA)
  • Autosomal dominant episodic atatxia
  • Mitochondrial disorders
  • Otherss
25
Q

a) Describe the genetic features of Freidrich’s ataxia
b) Describe the epidemiology and onset

A

a)

  • Commonest familial ataxia
  • Autosomal recessive
  • Carrier frequency 1/100
  • Expanions of GAA trinucleotide repeat in X25 gene encoding for frataxin chromosome 9

b)

  • Commonest familial ataxia
  • Incidence 1/50,000
26
Q

Describe the clinical features of Friedreich’s ataxia

A
  • No anticipation
  • Gait and limp ataxia
  • Pes cavus
  • Areflexia in the lower limbs
  • Extensor plantar responses
  • Impaired joint position sense
  • Progression towheel-chair independance
  • Death in mid-thirites
  • Systemic features - hypertophic cardiomyopathy (heart failure and cardiac arrhythmias), scoliosis, diabetes
  • Neurological variants
27
Q

a) When is the usual onset of autosomal dominant cerebellar ataxias (ADCA)
b) How many sub types of ADCA are there? and what are the two subtypes?
c) What is the most known mutation error in ADCA and what does this lead to?

A

a) Adult onset (usually)
b) 27 subtypes identified

  1. Spino-cerbellar ataxias (SCA) - many types
  2. Dentatorubal pallidolysian atrophy (DRPLA)

c) Some of these subtypes are due to CAG repeat expansion in coding region of gene. CAG is coded for glutamine so polyglutamine creates a toxic effect on cell. This may show anticipation

28
Q

Autosomal dominant cerebellar ataxia (ADCA) is a very variable phenotype. It includes ataxia and other features. List 4 clinical features of ADCA

A
  • Cerebellar features
  • Spasticity
  • Ophthalmoplegia (paralysis of the extraocular muscles that control the movemement of the eye)
  • Pigmentary maculopathy (SCA7) [affects mascula (central portion of retina) - a unique type of maculopathy linked to the intersitial cystitis drug, Elmiron tremor (SCA15)]

Medicine - Year 1 (61 decks)

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