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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
Symptoms and signs of muscle disorders
Weakness: proximal, symmetrical, persistent Weakness > wasting Normal sensation Tendon reflexes: normal (or decreased only in areas of prominent weakness)
26
Additional features seen in some myopathies/muscular dystrophies
Myotonia Rhabdomyolysis Cardiomyopathy Contractures
27
Investigations for muscle disorders
EMG Serum CK – high Other blood tests (routine biochem, endocrine tests etc) Muscle biopsy
28
Testing for antibodies when investigating muscle disorders
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)
29
Causes of myopathies
Acquired | Inherited
30
Acquired myopathies
``` Infl myopathies Endocrine and metabolic disorders Alcohol and other toxins/ drugs Infectious causes – viral incl HPV Paraneoplastic ```
31
Inflammatory myopathies
Polymyositis Dermatomyositis Inclusion body myositis
32
Endocrine and metabolic disorders causing myopathies
``` Thyroid Pituitary Parathyroid Adrenal Hypo/hypercalcaemia ```
33
What can cause inherited muscle disease
Mutations in nuclear genes coding for various constituent proteins associated with muscle membrane Mutations in mitochondrial DNA
34
Types of mutations in nuclear genes
X-linked Autosomal dominant Autosomal recessive
35
Inherited muscle disease
Non-dystrophic myopathies | Muscular dystrophies
36
Non-dystrophic myopathies
Congenital (nemaline, mullti-minicore, centronuclear) Mitochondrial Familial periodic paralysis Metabolic
37
Types of muscular dystrophies
``` Becker* Duchenne * Facioscapulohumeral Myotonic Emery Dreifuss Limb-girdle Oculopharyngeal Congenital ```
38
What are muscular dystrophies
Genetically determined diseases characterised by: Progressive degenerative change in muscle fibres Muscle weakness
39
What is classification of muscular dystrophies based upon
Clinical distribution of weakness Pattern of inheritance Molecular genetics
40
X linked muscular dystrophies
Duchenne and Becker dystrophies | Emery-Dreifuss syndrome
41
Autosomal dominant muscular dystrophies
``` Facioscapulohumeral muscular dystrophy (FSHD)* Myotonic muscular dystrophy* Scapuloperoneal dystrophy Oculopharyngeal Limb girdle muscular dystrophy (LGMD1) Distal ```
42
Autosomal recessive muscular dystrophies
Limb girdle muscular dystrophy (LGMD2) Scapulohumeral dystrophy Distal
43
Mechanical functions of dystrophin
Stabilization of membrane during contraction & relaxation | Part of the link between intracellular cytoskeleton and extracellular matrix
44
Functional aspects of dystrophin
Enables the muscle fibres to differentiate into fast glycolytic type (fast twitch fibres) Organisation of postsynaptic membrane and Ach receptors
45
Clinical features of Becker muscular dystrophy
Slowly progressive Weakness in proximal muscles Toe walking Gower’s sign
46
Weakness in Becker muscular dystrophy
Proximal >distal Especially quadriceps and pelvic muscles Arms
47
Systemic features of Becker muscular dystrophy
Cardiomyopathy Respiratory muscle involvement Scoliosis Mild LD
48
What is the severity of Becker muscular dystrophy correlated with
Muscle dystrophin levels (milder than Duchenne)
49
Types of FSHD
Changes to 4q: FSHD1 FSHD2
50
Weakness in FSHD
``` Face (ptosis, can’t whistle) Upper extremity Scapular (winging) Humeral (biceps) Peroneal muscles (foot drop ```
51
Other features of FSHD
Cardiac Hearing Epilepsy LD
52
Epidemiology of myotonic muscular dystrophy
Commonest form of adult muscular dystrophy 1 in 8,000 Autosomal dominant
53
Myotonic muscular dystrophy as a multi-system disease
``` Muscular wasting Myotonia (inability of muscle to relax after contraction) Cataracts Cardiac abnormalities Endocrine changes ```
54
Types of myotonic muscular dystrophy
DM1 (Steinert’s disease) – several clinical forms | DM2 (proximal myotonic myopathy PROMM)
55
Clinical features of myotonic dystrophy
``` Frontal balding Cataracts Myopathic facies Muscle wasting/weakness Myotonia Cardiac conduction defects Cardiomyopathy Sleep apnea Hypersomnolence Gynaecomastia Diabetes Hypogonadism ```
56
DM1
``` Congenital and adult onset forms Muscle weakness (hand, lower leg, neck and face) Prominent myotonia (hand, thenar eminence, tongue) ```
57
Genetic causes of DM1
Affected gene is DMPK on chromosome 19 CTG expansion within the gene Anticipation
58
CTG expansions within DMPK
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
DM2 - PROMM
Milder than DM1 | Affects mainly neck flexors, finger flexors, later hip-girdle muscles
60
Genetic causes of DM2
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
CNBP
Cellular nucleic acid binding protein
62
Types of ataxic gait
Cerebellar | Sensory
63
Sensory ataxic gait
Unsteady high-stepping gait | Worse in dark
64
Cerebellar ataxic gait
Wide based gait | Associated intention tremor/ limb ataxia
65
Acquired causes of cerebellar ataxia
``` Vascular Drugs and toxins Inflammatory (infections and demyelination) Structural causes (tumours) Hypothyroidism Deficiency states (vitamin E, thiamine) Prion diseases (CJD) Paraneoplastic ```
66
Hereditary causes of cerebellar ataxia
Autosomal recessive (Friedreich’s ataxia) ADCA Autosomal dominant episodic ataxia Mitochondrial disorders
67
DMD vs BMD
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
What proportion of DMD cases are caused by de novo mutations
1/3
69
Rhabdomyolysis
Results from the death of muscle fibers and release of their contents into the bloodstream ---> renal failure
70
Areflexia
Muscles (reflexes) do not react to stimuli
71
Myotonia
Delayed relaxation (prolonged contraction) of muscles

MBBS - Year 1 (93 decks)

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