Genetics - Gait and Limp Flashcards
Criteria to be classified as a rare disease
Affect <1 in 2,000 people
What is an ataxia
Group of disorders that affect co-ordination, balance (gait) and speech
Genetic cause of Duchenne and Becker muscular dystrophy
Alteration in DMD genes (frameshift mutation) that can be inherited in an x-linked recessive fashion
What does DMD encode for
A muscle protein, dystrophin
What happens in cells lacking dystrophin
They are mechanically fragile, and fail after a few years, hence progressive muscle weakness.
Epidemiology of Duchenne muscular dystrophy
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
Clinical features of DMD usually identified by parents
General motor delays
Gait problems, incl persistent toe-walking and flat-footedness
Delay in walking
Learning difficulties (low IQ)
Other clinical features of DMD
Speech problems Muscle wasting Calf muscle psuedohypertrophy Lordosis Contractures \+ve Gower's sign (not pathognomonic)
Why do we see calf muscle psuedohypertrophy in DMD
Due to muscle replacement with collagen and adipose tissue
Complications of DMD
Permanent and progressive disability
Decreased mobility
Respiratory or cardiac failure
Prognosis of DMD
Most can expect to survive until at least their early 20s, some even longer, and many maintain a good quality of life
What is Friedrichs ataxia
Rare, inherited disease that causes progressive damage to the nervous system
What is Friedrichs ataxia caused by
Defect in FXN gene
Expansion of GAA trinucleotide repeat in X25 gene, chromosome 9
No anticipation
Frataxin
Coded for FXN and X25
Controls important steps in mitochondrial iron metabolism and overall cell iron stability
Epidemiology of Friedrichs ataxia
Commonest familial ataxia
Incidence 1/50,000
Carrier Frequency 1/100
Autosomal recessive
Clinical features of Friedrichs ataxia
Areflexia in the lower limbs
Pyramidal weakness
Extensor plantar responses
Impaired joint position sense
Systemic features of Friedrichs ataxia
Hypertrophic cardiomyopathy (50%)
Scoliosis
Diabetes (10%)
Neurological variants
Prognosis of Friedrich’s ataxia
Progression to wheel-chair dependence
Death in mid thirties
ADCAs
Autosomal Dominant Cerebellar Ataxias
Causes of ADCA
Caused by mutation in DNMT1
Due to CAG repeat expansion and may show anticipation
DNMT1
DNA methyltransferase 1 is an enzyme involved in DNA methylation (adding cytosine to nucleotides)
Phenotype of ADCA
Variable: Cerebellar features* Spasticity Ophthalmoplegia Pigmentary maculopathy (SCA 7) Tremor (SCA15)
Frameshift mutation
Insertion or deletion of bases alters reading frame of gene —> alters codons of nucleotides translated into AA
Anticipation
Successive generations are affected more severely by trinucleotide repeat expansions, either the disease presents at an earlier age or the symptoms are worse
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)
Additional features seen in some myopathies/muscular dystrophies
Myotonia
Rhabdomyolysis
Cardiomyopathy
Contractures
Investigations for muscle disorders
EMG
Serum CK – high
Other blood tests (routine biochem, endocrine tests etc)
Muscle biopsy
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)
Causes of myopathies
Acquired
Inherited
Acquired myopathies
Infl myopathies Endocrine and metabolic disorders Alcohol and other toxins/ drugs Infectious causes – viral incl HPV Paraneoplastic
Inflammatory myopathies
Polymyositis
Dermatomyositis
Inclusion body myositis
Endocrine and metabolic disorders causing myopathies
Thyroid Pituitary Parathyroid Adrenal Hypo/hypercalcaemia
What can cause inherited muscle disease
Mutations in nuclear genes coding for various constituent proteins associated with muscle membrane
Mutations in mitochondrial DNA
Types of mutations in nuclear genes
X-linked
Autosomal dominant
Autosomal recessive
Inherited muscle disease
Non-dystrophic myopathies
Muscular dystrophies
Non-dystrophic myopathies
Congenital (nemaline, mullti-minicore, centronuclear)
Mitochondrial
Familial periodic paralysis
Metabolic
Types of muscular dystrophies
Becker* Duchenne * Facioscapulohumeral Myotonic Emery Dreifuss Limb-girdle Oculopharyngeal Congenital
What are muscular dystrophies
Genetically determined diseases characterised by:
Progressive degenerative change in muscle fibres
Muscle weakness
What is classification of muscular dystrophies based upon
Clinical distribution of weakness
Pattern of inheritance
Molecular genetics
X linked muscular dystrophies
Duchenne and Becker dystrophies
Emery-Dreifuss syndrome
Autosomal dominant muscular dystrophies
Facioscapulohumeral muscular dystrophy (FSHD)* Myotonic muscular dystrophy* Scapuloperoneal dystrophy Oculopharyngeal Limb girdle muscular dystrophy (LGMD1) Distal
Autosomal recessive muscular dystrophies
Limb girdle muscular dystrophy (LGMD2)
Scapulohumeral dystrophy
Distal
Mechanical functions of dystrophin
Stabilization of membrane during contraction & relaxation
Part of the link between intracellular cytoskeleton and extracellular matrix
Functional aspects of dystrophin
Enables the muscle fibres to differentiate into fast glycolytic type (fast twitch fibres)
Organisation of postsynaptic membrane and Ach receptors
Clinical features of Becker muscular dystrophy
Slowly progressive
Weakness in proximal muscles
Toe walking
Gower’s sign
Weakness in Becker muscular dystrophy
Proximal >distal
Especially quadriceps and pelvic muscles
Arms
Systemic features of Becker muscular dystrophy
Cardiomyopathy
Respiratory muscle involvement
Scoliosis
Mild LD
What is the severity of Becker muscular dystrophy correlated with
Muscle dystrophin levels (milder than Duchenne)
Types of FSHD
Changes to 4q:
FSHD1
FSHD2
Weakness in FSHD
Face (ptosis, can’t whistle) Upper extremity Scapular (winging) Humeral (biceps) Peroneal muscles (foot drop
Other features of FSHD
Cardiac
Hearing
Epilepsy
LD
Epidemiology of myotonic muscular dystrophy
Commonest form of adult muscular dystrophy
1 in 8,000
Autosomal dominant
Myotonic muscular dystrophy as a multi-system disease
Muscular wasting Myotonia (inability of muscle to relax after contraction) Cataracts Cardiac abnormalities Endocrine changes
Types of myotonic muscular dystrophy
DM1 (Steinert’s disease) – several clinical forms
DM2 (proximal myotonic myopathy PROMM)
Clinical features of myotonic dystrophy
Frontal balding Cataracts Myopathic facies Muscle wasting/weakness Myotonia Cardiac conduction defects Cardiomyopathy Sleep apnea Hypersomnolence Gynaecomastia Diabetes Hypogonadism
DM1
Congenital and adult onset forms Muscle weakness (hand, lower leg, neck and face) Prominent myotonia (hand, thenar eminence, tongue)
Genetic causes of DM1
Affected gene is DMPK on chromosome 19
CTG expansion within the gene
Anticipation
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
DM2 - PROMM
Milder than DM1
Affects mainly neck flexors, finger flexors, later hip-girdle muscles
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
CNBP
Cellular nucleic acid binding protein
Types of ataxic gait
Cerebellar
Sensory
Sensory ataxic gait
Unsteady high-stepping gait
Worse in dark
Cerebellar ataxic gait
Wide based gait
Associated intention tremor/ limb ataxia
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
Hereditary causes of cerebellar ataxia
Autosomal recessive (Friedreich’s ataxia)
ADCA
Autosomal dominant episodic ataxia
Mitochondrial disorders
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.
What proportion of DMD cases are caused by de novo mutations
1/3
Rhabdomyolysis
Results from the death of muscle fibers and release of their contents into the bloodstream —> renal failure
Areflexia
Muscles (reflexes) do not react to stimuli
Myotonia
Delayed relaxation (prolonged contraction) of muscles
