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MBBS - Year 1 > Genetics - Gait and Limp > Flashcards

Genetics - Gait and Limp Flashcards

1
Q

Criteria to be classified as a rare disease

A

Affect <1 in 2,000 people

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2
Q

What is an ataxia

A

Group of disorders that affect co-ordination, balance (gait) and speech

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3
Q

Genetic cause of Duchenne and Becker muscular dystrophy

A

Alteration in DMD genes (frameshift mutation) that can be inherited in an x-linked recessive fashion

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4
Q

What does DMD encode for

A

A muscle protein, dystrophin

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5
Q

What happens in cells lacking dystrophin

A

They are mechanically fragile, and fail after a few years, hence progressive muscle weakness.

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6
Q

Epidemiology of Duchenne muscular dystrophy

A

Most common form of muscular dystrophy in children
The incidence rate of DMD is 10.7 to 27.8 per 100,000 new-born males
Onset 3 to 5 years

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7
Q

Clinical features of DMD usually identified by parents

A

General motor delays
Gait problems, incl persistent toe-walking and flat-footedness
Delay in walking
Learning difficulties (low IQ)

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8
Q

Other clinical features of DMD

A 
Speech problems 
Muscle wasting 
Calf muscle psuedohypertrophy 
Lordosis 
Contractures 
\+ve Gower's sign (not pathognomonic)
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9
Q

Why do we see calf muscle psuedohypertrophy in DMD

A

Due to muscle replacement with collagen and adipose tissue

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10
Q

Complications of DMD

A

Permanent and progressive disability
Decreased mobility
Respiratory or cardiac failure

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11
Q

Prognosis of DMD

A

Most can expect to survive until at least their early 20s, some even longer, and many maintain a good quality of life

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12
Q

What is Friedrichs ataxia

A

Rare, inherited disease that causes progressive damage to the nervous system

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13
Q

What is Friedrichs ataxia caused by

A

Defect in FXN gene
Expansion of GAA trinucleotide repeat in X25 gene, chromosome 9
No anticipation

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14
Q

Frataxin

A

Coded for FXN and X25

Controls important steps in mitochondrial iron metabolism and overall cell iron stability

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15
Q

Epidemiology of Friedrichs ataxia

A

Commonest familial ataxia
Incidence 1/50,000
Carrier Frequency 1/100
Autosomal recessive

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16
Q

Clinical features of Friedrichs ataxia

A

Areflexia in the lower limbs
Pyramidal weakness
Extensor plantar responses
Impaired joint position sense

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17
Q

Systemic features of Friedrichs ataxia

A

Hypertrophic cardiomyopathy (50%)
Scoliosis
Diabetes (10%)

Neurological variants

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18
Q

Prognosis of Friedrich’s ataxia

A

Progression to wheel-chair dependence

Death in mid thirties

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19
Q

ADCAs

A

Autosomal Dominant Cerebellar Ataxias

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20
Q

Causes of ADCA

A

Caused by mutation in DNMT1

Due to CAG repeat expansion and may show anticipation

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21
Q

DNMT1

A

DNA methyltransferase 1 is an enzyme involved in DNA methylation (adding cytosine to nucleotides)

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22
Q

Phenotype of ADCA

A 
Variable:
Cerebellar features*
Spasticity
Ophthalmoplegia
Pigmentary maculopathy (SCA 7)
Tremor (SCA15)
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23
Q

Frameshift mutation

A

Insertion or deletion of bases alters reading frame of gene —> alters codons of nucleotides translated into AA

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24
Q

Anticipation

A

Successive generations are affected more severely by trinucleotide repeat expansions, either the disease presents at an earlier age or the symptoms are worse

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25
Q

Symptoms and signs of muscle disorders

A

Weakness: proximal, symmetrical, persistent
Weakness > wasting
Normal sensation
Tendon reflexes: normal (or decreased only in areas of prominent weakness)

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26
Q

Additional features seen in some myopathies/muscular dystrophies

A

Myotonia
Rhabdomyolysis
Cardiomyopathy
Contractures

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27
Q

Investigations for muscle disorders

A

EMG
Serum CK – high
Other blood tests (routine biochem, endocrine tests etc)
Muscle biopsy

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28
Q

Testing for antibodies when investigating muscle disorders

A

Look for antibodies associated with:
Connective tissue disorders (ANA, RhF, anti-ds DNA, anti Ro/ La, anti Scl-70)
Polymyositis (anti Jo - 1), dermatomyositis (anti Mi-2)

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29
Q

Causes of myopathies

A

Acquired

Inherited

30
Q

Acquired myopathies

A 
Infl myopathies 
Endocrine and metabolic disorders 
Alcohol and other toxins/ drugs 
Infectious causes – viral incl HPV
Paraneoplastic
31
Q

Inflammatory myopathies

A

Polymyositis
Dermatomyositis
Inclusion body myositis

32
Q

Endocrine and metabolic disorders causing myopathies

A 
Thyroid 
Pituitary 
Parathyroid 
Adrenal 
Hypo/hypercalcaemia
33
Q

What can cause inherited muscle disease

A

Mutations in nuclear genes coding for various constituent proteins associated with muscle membrane
Mutations in mitochondrial DNA

34
Q

Types of mutations in nuclear genes

A

X-linked
Autosomal dominant
Autosomal recessive

35
Q

Inherited muscle disease

A

Non-dystrophic myopathies

Muscular dystrophies

36
Q

Non-dystrophic myopathies

A

Congenital (nemaline, mullti-minicore, centronuclear)
Mitochondrial
Familial periodic paralysis
Metabolic

37
Q

Types of muscular dystrophies

A 
Becker*
Duchenne *
Facioscapulohumeral
Myotonic 
Emery Dreifuss 
Limb-girdle 
Oculopharyngeal
Congenital
38
Q

What are muscular dystrophies

A

Genetically determined diseases characterised by:
Progressive degenerative change in muscle fibres
Muscle weakness

39
Q

What is classification of muscular dystrophies based upon

A

Clinical distribution of weakness
Pattern of inheritance
Molecular genetics

40
Q

X linked muscular dystrophies

A

Duchenne and Becker dystrophies

Emery-Dreifuss syndrome

41
Q

Autosomal dominant muscular dystrophies

A 
Facioscapulohumeral muscular dystrophy (FSHD)*
Myotonic muscular dystrophy*
Scapuloperoneal dystrophy
Oculopharyngeal
Limb girdle muscular dystrophy (LGMD1)
Distal
42
Q

Autosomal recessive muscular dystrophies

A

Limb girdle muscular dystrophy (LGMD2)
Scapulohumeral dystrophy
Distal

43
Q

Mechanical functions of dystrophin

A

Stabilization of membrane during contraction & relaxation

Part of the link between intracellular cytoskeleton and extracellular matrix

44
Q

Functional aspects of dystrophin

A

Enables the muscle fibres to differentiate into fast glycolytic type (fast twitch fibres)
Organisation of postsynaptic membrane and Ach receptors

45
Q

Clinical features of Becker muscular dystrophy

A

Slowly progressive
Weakness in proximal muscles
Toe walking
Gower’s sign

46
Q

Weakness in Becker muscular dystrophy

A

Proximal >distal
Especially quadriceps and pelvic muscles
Arms

47
Q

Systemic features of Becker muscular dystrophy

A

Cardiomyopathy
Respiratory muscle involvement
Scoliosis
Mild LD

48
Q

What is the severity of Becker muscular dystrophy correlated with

A

Muscle dystrophin levels (milder than Duchenne)

49
Q

Types of FSHD

A

Changes to 4q:
FSHD1
FSHD2

50
Q

Weakness in FSHD

A 
Face (ptosis, can’t whistle)
Upper extremity
Scapular (winging) 
Humeral (biceps)
Peroneal muscles (foot drop
51
Q

Other features of FSHD

A

Cardiac
Hearing
Epilepsy
LD

52
Q

Epidemiology of myotonic muscular dystrophy

A

Commonest form of adult muscular dystrophy
1 in 8,000
Autosomal dominant

53
Q

Myotonic muscular dystrophy as a multi-system disease

A 
Muscular wasting
Myotonia (inability of muscle to relax after contraction)
Cataracts
Cardiac abnormalities
Endocrine changes
54
Q

Types of myotonic muscular dystrophy

A

DM1 (Steinert’s disease) – several clinical forms

DM2 (proximal myotonic myopathy PROMM)

55
Q

Clinical features of myotonic dystrophy

A 
Frontal balding
Cataracts
Myopathic facies
Muscle wasting/weakness
Myotonia
Cardiac conduction defects
Cardiomyopathy
Sleep apnea
Hypersomnolence
Gynaecomastia
Diabetes
Hypogonadism
56
Q

DM1

A 
Congenital and adult onset forms
Muscle weakness (hand, lower leg, neck and face)
Prominent myotonia (hand, thenar eminence, tongue)
57
Q

Genetic causes of DM1

A

Affected gene is DMPK on chromosome 19
CTG expansion within the gene
Anticipation

58
Q

CTG expansions within DMPK

A

5-37 repeats normal
38-49 repeats pre-mutation (unstable)
>50 repeats symptomatic (unstable)
Longer repeats more severe disease and earlier age of onset

59
Q

DM2 - PROMM

A

Milder than DM1

Affects mainly neck flexors, finger flexors, later hip-girdle muscles

60
Q

Genetic causes of DM2

A

Mutations in gene coding for CNBP on chromosome 3
Expansion of the CCTG repeat in intron 1
Typically 75 – 11,000 repeats
Minimal or no anticipation

61
Q

CNBP

A

Cellular nucleic acid binding protein

62
Q

Types of ataxic gait

A

Cerebellar

Sensory

63
Q

Sensory ataxic gait

A

Unsteady high-stepping gait

Worse in dark

64
Q

Cerebellar ataxic gait

A

Wide based gait

Associated intention tremor/ limb ataxia

65
Q

Acquired causes of cerebellar ataxia

A 
Vascular
Drugs and toxins
Inflammatory (infections and demyelination)
Structural causes (tumours)
Hypothyroidism
Deficiency states (vitamin E, thiamine)
Prion diseases (CJD)
Paraneoplastic
66
Q

Hereditary causes of cerebellar ataxia

A

Autosomal recessive (Friedreich’s ataxia)
ADCA
Autosomal dominant episodic ataxia
Mitochondrial disorders

67
Q

DMD vs BMD

A

Symptoms of BMD are usually milder and more varied.

Muscle weakness becomes apparent later in childhood or in adolescence and worsens at a much slower rate.

68
Q

What proportion of DMD cases are caused by de novo mutations

69
Q

Rhabdomyolysis

A

Results from the death of muscle fibers and release of their contents into the bloodstream —> renal failure

70
Q

Areflexia

A

Muscles (reflexes) do not react to stimuli

71
Q

Myotonia

A

Delayed relaxation (prolonged contraction) of muscles

MBBS - Year 1 (93 decks)

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