Muscular Dystrophy Flashcards
Facioscapulohumeral Muscular Dystrophy
Facioscapulohumeral muscular dystrophy (FSHMD) is an autosomal dominant form of muscular dystrophy. As the name suggests it stypically affects the face, scapula and upper arms first. Symptoms typically presents by the age of 20 years.
Facioscapulohumeral dystrophy is usually an autosomal dominant condition and although it affects men and women equally, men may be more symptomatic. Shoulder, upper arm and facial muscles are the most often implicated and lower limb involvement is less common. Winging of the scapulae are one characteristic finding which may necessitate surgical fixation. It is a progressive condition however prognosis is usually good with minor disability and lifespan unaffected.
FSHMD Diagnosis - Example Question
A 19 year old male presents to outpatient clinic with a 3 month history of worsening speech slurring. He finds it extremely embarrassing and is made fun of by his friends in college, who thinks he is turning up to school drunk. He is also finding that he is having difficulty with excessive drooling. Over the past 6 weeks, his has also noted increasing weakness in lifting his right arm. He has no other past medical history, is a non-smoker and drinks alcohol only socially.
On examination, his cranial nerves demonstrate weakness in raising his eyebrows, puffing his cheeks and in pursing his lips. He displays significant scapula winging bilaterally with mild wasting of his right deltoid muscle. Musculature of his left arm is normal. Power of his right shoulder abduction and adduction is 3/5, with 5/5 in all other movements. Reflexes are all present with normal sensory examination.
His blood tests are as follows:
Hb 14.4 g/dl
Platelets 388 * 109/l
WBC 5.8 * 109/l
Na+ 139 mmol/l K+ 4.7 mmol/l Urea 4.6 mmol/l Creatinine 55 µmol/l CRP 2mg/l Creatine kinase 150 IU/l (50-335) TSH 2.3 mu/l Free T4 nmol/l HIV negative
What is the diagnosis?
Myoclonic epilepsy with ragged red fibres (MERRF) Myotonic dystrophy type 1 Polymyositis Limb girdle muscular dystrophy > Facioscapulohumeral dystrophy
This is a difficult question regarding the cause of a myopathy, onset at late adolescence and progresses. Firstly, the normal CK, CRP and lack of systemic features point against a systemic inflammatory condition such as polymyositis. Although also involving proximal muscles and presenting typically without cutaneous manifestations, polymyositis is a multisystem disorder with cardiac, pulmonary features and oesophageal involvement.
Similarly, although myotonic dystrophy type 1 patients also present from age of 20 onwards, it is another multisystem disorder with cardiac structural and conduction abnormalities, respiratory muscle involvement, gastrointestinal symptoms, testicular failure and insulin resistance, amongst a large number of clinical features. Classically, patients with myotonic dystrophy display myotonia, a slowing of relaxation following normal muscular contraction.
An absence of myoclonus makes MERRF less likely. It is a mitochondrial disorder typically presenting with myopathy, peripheral neuropathy and frequently, ataxia, Wolff-Parkinson White syndrome and bilateral deafness. The final assessment of the type of muscular dystrophy relies simply on the muscles involved: in this case, muscles involved are facial and upper limb girdle muscles. Be aware that muscular dystrophies such as facioscapulohumeral dystrophy can initially present asymmetrically before progressing to bilateral involvement.
Myotonic Dystrophy
Myotonic dystrophy (also called dystrophia myotonica) is an inherited myopathy with features developing at around 20-30 years old. It affects skeletal, cardiac and smooth muscle. There are two main types of myotonic dystrophy, DM1 and DM2.
Genetics
autosomal dominant
a trinucleotide repeat disorder
DM1 is caused by a CTG repeat at the end of the DMPK (Dystrophia Myotonica-Protein Kinase) gene on chromosome 19
DM2 is caused by a repeat expansion of the ZNF9 gene on chromosome 3
DM1
- DMPK gene on chromosome 19
- Distal weakness more prominent
DM2
- ZNF9 gene on chromosome 3
- Proximal weakness more prominent
- Severe congenital form not seen
General features myotonic facies (long, 'haggard' appearance) frontal balding bilateral ptosis cataracts dysarthria
Other features myotonia (tonic spasm of muscle) weakness of arms and legs (distal initially) mild mental impairment diabetes mellitus testicular atrophy cardiac involvement: heart block, cardiomyopathy dysphagia
Complications include arrhythmias, cataracts, testicular atrophy and diabetes mellitus.
Myotonic Dystrophy - Example Question
A 40 year-old man presents to the general medical clinic with a one year history of generalised weakness. He mentions his father suffered from the same symptoms, although from a later age.
His past medical history includes type two diabetes mellitus (diet controlled) and eczema.
On examination he has male pattern balding and an expressionless face. You note a diminished left red reflex, with a normal cranial nerve examination. He has symmetrically reduced reflexes throughout, with mild reduced power distally in both upper and lower limbs.
Hb 140 g/l Platelets 200 * 109/l WBC 8 * 109/l CK 70IU/L (reference range 60- 174 IU/L)
What is the most likely diagnosis?
Hyperthyroidism Inclusion body myositis Cushing's disease Becker's muscular dystrophy > Myotonic dystrophy
Myotonic dystrophy is a genetic condition causing by a trinucleotide repeat expansion on chromosome 19. It demonstrates anticipation (earlier onset with successive generations).
Clinical features of the condition include:
Frontotemporal balding Ptosis Distal weakness Depressed tendon reflexes Myotonic (slow relaxation of muscles)
Complications include arrhythmias, cataracts, testicular atrophy and diabetes mellitus.
Cushing’s disease and hyperthyroidism cause a proximal myopathy, and the patient has no symptoms of either.
Becker’s muscular dystrophy causes a proximal myopathy, but the average age of presentation and diagnosis is much younger (average is 11 years old), with several disability at 40.
Inclusion body myositis can cause both a proximal and distal myopathy. This patient’s creatinine kinase is normal, which makes the diagnosis less likely and would not explain the genetic component and facial features.
Facioscapulohumeral Dystrophy - Example Question
A 20-year-old woman presents to a general neurology clinic. Over the last year, she has noted that she is becoming increasingly clumsy with heavy objects. She describes struggling to wash her hair and complete certain house hold chores such as hanging washing up.
Neurological examination findings of the upper limbs have been summarised below. Power has been recorded as per the Medical Research Council (MRC) grading system.
Decreased power 3/5 of shoulder abduction and 4/5 adduction bilaterally
Decreased power 4/5 of elbow flexion in Left Arm
Right Arm supinator reflex - unable to illicit
When examining her cranial nerves it is noted there is drooping of her eyelids and decreased facial expression. Tests for fatigability were unremarkable. There were no other abnormal findings.
What is the most likely diagnosis?
Myasthenia gravis >Facioscapulohumeral dystrophy Multiple sclerosis Miller-Fisher syndrome Becker's muscular dystrophy
The history here is typical of facioscapulohumeral dystrophy, the diagnosis is confirmed by the examination findings which confirm a proximal weakness affecting the limb girdle and subtle signs of weakness in the face.
The absence of fatigability in muscle power excludes myasthenia gravis. The clinical picture is not of Miller-Fisher syndrome which often presents as a triad of ophthalmoplegia, ataxia, and areflexia. Becker’s muscular dystrophy is excluded as it typically affects the limb girdles in males who carry the X-linked gene. The presentation is also atypical of MS.
Dystrophinopathies
Dystrophinopathies
Overview
- X-linked recessive
- due to mutation in the gene encoding dystrophin, dystrophin gene on Xp21
- dystrophin is part of a large membrane associated protein in muscle which connects the muscle membrane to actin, part of the muscle cytoskeleton
- in Duchenne muscular dystrophy there is a frameshift mutation resulting in one or both of the binding sites are lost leading to a severe form
- in Becker muscular dystrophy there is a non-frameshift insertion in the dystrophin gene resulting in both binding sites being preserved leading to a milder form
Duchenne Muscular Dystrophy
Duchenne muscular dystrophy
- progressive proximal muscle weakness from 5 years
- calf pseudohypertrophe
- Gower’s sign: child uses arms to stand up from a squatted position
- 30% of patients have intellectual impairment
Becker Muscular Dystrophy
Becker muscular dystrophy
develops after the age of 10 years
intellectual impairment much less common
Affects the limb girdles in males who carry the X affected gene
BMD is a X-linked disorder of dystrophin, a component of skeletal muscle that reinforces the sarcolemma-glycoprotein complex and prevents degradation. Respiratory, cardiac and bulbar manifestations are common. Diagnosis is made on clinical suspicion, raised CK, EMG suggestive of small polyphasic potentials, a muscle biopsy suggestive of dystrophinopathy and subsequent genetic testing.
Becker’s muscular dystrophy causes a proximal myopathy with an average age of presentation at about 10-11 and several disability by 40.
Example Question
A 14 year old presents to your neurology clinic reporting 9 months of subtle and gradual onset, progressive lower limb weakness. For the past 18 months, he has noticed a difficulty in keeping up with his peers in PE lessons, which he initially put down to ‘not being very sporty’. However, he feels weak whenever he walks and has particular difficulty getting up from a chair.
On examination, you notice significantly hypertrophied calves on inspection. Formal examination of power reveals 4- out of 5 bilaterally in shoulder abduction, adduction and normal 5 out of 5 distally. 4- out of 5 is also noted in hip flexion and extension, 4+ in knee flexion and extension, 5 out of 5 in ankle plantar and dorsiflexion. The weaknesses demonstrated are not fatiguable and are persistent. Reflexes are present in all areas, plantars are downgoing. He has no other past medical history. His family history is unknown as he was adopted. What is the likely diagnosis?
Duchenne muscular dystrophy > Becker muscular dystrophy McArdle syndrome Spinal muscular atrophy Inclusion body myositis
Progressive proximal muscle weakness appears to be the most important symptoms in this teenage patient. The key differentials can be separated by the age of the patient. Duchenne muscular dystrophy (DMD) is a more severe form of Becker muscular dystrophy (BMD) and patients are normally wheelchair bound by early teens. Similarly spinal muscular atrophy produces flaccid paralysis of proximal musculature with absent reflexes, presenting from newborn to under the age of 3.
McArdle disease is a metabolic disorder affecting proximal muscles caused by myophosphorylase deficiency. Patients frequently report a ‘second wind’ caused by a change to fatty acid metabolism, weakness is hence classically not persistent. Inclusion body myositis classically produces distal to proximal weakness in middle-aged patients. BMD is hence the most appropriate answer.
Muscular Dystrophy - Proximal Distribution - Diagnosis: Example Question
A 35-year old gentleman presents with weakness raising up his arms and some drooping of the eyelids and his shoulder blades are pronounced. He says his symptoms are mild and he probably would not have noticed it except his father had similar symptoms that have steadily got worse. This gentleman has no other past medical history of note and is taking no regular medications. On examination there is mild evidence of scapula winging, proximal weakness of both upper limbs, ptosis and he has difficulty whistling. There is normal power of his lower limbs and reflexes and sensation is intact throughout.
Creatine kinase 220 units/L
A muscle biopsy is sent but is pending, what is the most likely diagnosis?
> Facioscapulohumeral dystrophy Myotonic dystrophy Emery-Dreifuss muscular dystrophy Becker muscular dystrophy Oculopharyngeal muscular dystrophy
Facioscapulohumeral dystrophy is usually an autosomal dominant condition and although it affects men and women equally, men may be more symptomatic. Shoulder, upper arm and facial muscles are the most often implicated and lower limb involvement is less common. Winging of the scapulae are one characteristic finding which may necessitate surgical fixation. It is a progressive condition however prognosis is usually good with minor disability and lifespan unaffected.
Myotonic dystrophy is the most common muscular dystrophy of which symptoms include delayed relaxation of muscles wasting and weakness as well as cardiac conduction deficits, cataracts and characteristic facies. Becker muscular dystrophy usually presents in childhood with predominantly lower limb and girdle weakness. Patients with Emery-Dreifuss muscular dystrophy also usually present in childhood, characteristically with contractures and oculopharyngeal muscular dystrophy presents usually over the age of 40 with eyelid, facial and throat muscle weakness initially followed by pelvic and shoulder weakness.
Myotonic Dystrophy - Diagnosis: Example Question
A 23-year-old male presents with a 5-day history of increasing shortness of breath, exertional dyspnoea and bilateral ankle swelling. He has no previous past medical history and was previous a keen sportsman. On examination, his heart sounds I + II are present with a pansystolic murmur and a displaced apex. Auscultation of his chest demonstrates bibasal crackles. His ECG demonstrates a PR interval of 190 ms but sinus rhythm. Further neurological examination demonstrates bilateral partial ptosis noted associated with bilateral foot drop. You also note slow release of finger flexion. What is the underlying diagnosis?
> Myotonic dystrophy Myasthenia gravis Inflammatory myositis Facioscapulohumeral dystrophy (FSD) Guillain Barre syndrome
The patient has presented with clinical heart failure on a background of systemic disease, involving structural heart disease, conductive heart block, bilateral ptosis bilateral foot drop and slow finger flexion release suggestive of myotonia. It would not be possible to distinguish at this stage between DM1 or DM2 myotonic dystrophy, the latter being less severe than DM1. The diagnosis would be clinched with genetic testing for an expanded CTG repeat in the DMPK gene: normally, 5-34 CTG repeats are found. Greater than 50 alleles is strongly diagnostic of disease manifestations.
Dystrophia Myotonica DM1
The Ds Distal weakness initially Autosomal Dominant Diabetes Dysarthria
Differentials of Proximal Myopathy
Differentials of proximal myopathy:
- Becker’s muscular dystrophy
- Duchennes muscular dystrophy
- Fascioscapulohumeral muscular dystrophy
- Myotonic dystrophy (DM2 affects proximal muscles more than distal)
- Polymyositis -involves proximal muscles and presenting typically without cutaneous manifestations, polymyositis is a multisystem disorder with cardiac, pulmonary features and oesophageal involvement. Raised CK SEEN
- Inclusion body myositis can cause both a proximal and distal myopathy, raised CK, CRP
- McArdle disease is a metabolic disorder affecting proximal muscles caused by myophosphorylase deficiency. Patients frequently report a ‘second wind’ caused by a change to fatty acid metabolism, weakness is hence classically not persistent.
- Spinal muscular atrophy produces flaccid paralysis of proximal musculature with absent reflexes, presenting from newborn to under the age of 3.
Myotonic Dystrophy - Presentation
Myotonia = Clinical heart failure on a background of systemic disease, involving structural heart disease, conductive heart block, bilateral ptosis, bilateral foot drop and slow finger flexion release
DM2 myotonic dystrophy is less severe than DM1.
The diagnosis for DM1 would be clinched with genetic testing for an expanded CTG repeat in the DMPK gene: normally, 5-34 CTG repeats are found. Greater than 50 alleles is strongly diagnostic of disease manifestations.
