1
MYOPATHIES,
MOTOR NEURON DISEASES
Eva Vlčková, Department of Neurology, University Hospital Brno
MYOPATHIES - DEFINITION
= disorders of skeletal muscles
̶ encompass a wide variety of illnesses that cause weakness, pain, and fatigue
in any combination.
̶ !!! Similar clinical symptoms may result from:
̶ the disorders with primary involvement of the anterior horn cells (e.g.,
amyotrophic lateral sclerosis and the spinal muscular atrophies)
̶ neuromuscular junction disorders (myasthenia gravis, Lambert-Eaton syndrome,
and congenital myasthenia)
̶ and certain polyneuropathies (e.g., chronic inflammatory demyelinating
polyneuropathy)
̶ Consider in differential diagnosis!!!
BASIC TERMS USED
̶ MYOPATHY simply refers to an abnormality of the muscle and has no other connotation.
̶ Muscular dystrophies - inherited (genetic), progressive muscle disorders resulting from
defects in one or more genes needed for normal muscle structure and function (mostly leading
to the disturbance of a structural proteins of the muscle membrane); dystrophic changes (eg,
muscle fiber necrosis and regeneration) are seen on biopsy specimens.
̶ Congenital myopathies are muscle diseases mostly present at birth (congenital), but in some
patients may not be apparent until later in infancy or childhood. They also result from
genetic defects (mostly related to the genes coding contractile proteins or Ca2+ signaling
pathway). The conditions are often stable or slowly progressing.
̶ Metabolic myopathies are inherited myopathies, that refer mainly to abnormalities of muscle
biochemistry that impair the resynthesis of adenosine triphosphate (ATP) (mitochondrial
myopathies) or cause an abnormal storage of material in the cell (m. Pompe, McArdle…).
BASIC TERMS USED II
̶ Myotonias are diseases in which the occurrence of involuntary, persistent muscle activity,
accompanied by abnormal repetitive electrical discharges, distorts the normal contractile process.
This occurs after percussion or voluntary contraction. Mostly inherited (ion channel disorders,
myotonic dystrophies), rarely acquired.
̶ Acquired myopathies are the disorders of skeletal muscles without the genetic background.
̶ Myositis implies an inflammatory disorder and is usually reserved for disorders in which the
muscle histology shows an inflammatory response.
̶ The term endocrine myopathy refers to myopathies associated with disorders of the thyroid and
parathyroid glands and to myopathies associated with increased corticosteroid levels.
̶ Toxic (drug induced) myopathies are acquired muscle diseases caused by a toxic effect of
some external substance including (but not limited to) alcohol or some commonly prescribed
medications (cholesterol lowering medications…). Clinical manifestations of toxic myopathies
range from muscle pain to more serious muscle damage leading to rhabdomyolysis.
MYOPATHIES – TYPICAL FEATURES
̶ The most prominent clinical symptom is the weakness (the loss of strength or power,
manifesting in the inability to generate normal force).
̶ Muscle pain and fatigue may also be present
̶ The decrease of the muscle strength in myopathies is usually proximal and symmetrical.
These often result in particular difficulties arising from chair or squat or holding up one's arm against gravity.
̶ Some of the muscular dystrophies represent an exception – in these conditions, the weakness may affect
mainly certain muscle groups by where in the body symptoms begin and remain most expressed
̶ Deep tendon (muscle stretch) reflexes typically remain normal.
̶ No sensory disturbance (no hypoesthesia, no paresthesias).
MYOPATHIES – TYPICAL FEATURES
̶ The weakness is stable, non fluctuating within the day or during the activity.
̶ NOTE the difference with the neuromuscular junction diseases, which are
characterized by fluctuating strength based on muscle use. For
example, myasthenia gravis results in decreasing power with continuous
contraction. On the other hand, Lambert-Eaton myaesthetic syndrome (LEMS)
results in increased strength with repeated contraction.
̶ There is usually minimal atrophy until late in the course (muscle dystrophies again
represent an exception).
̶ Note the difference with motor neuron diseases or sever neuropathies, where
prominent atrophies develop someties even early with the course of the disease
1. Creatine kinase (CK) + myoglobin
levels are often elevated (as well as
ALT/AST, but not GGT levels – note the
difference from hepatopathy –
frequent mistake!)
3. NCS are usually normal (with the
exception of pronaunced atrophies)
Needle EMG may show myopathic
features (see next slides)
+ (4) Muscle MRI becomes a gold
standard– it´s often performed before the
biopsy and genetic testing and may help to
identify target mucles for the biopsy and to select
an appropriate genetic/metabolic test (based on
specific patterns – some muscles are more
severly affected than the others)
+ (5) Metabolic (enzyme activity)
testing (Pompe, McArdle…)
5.
(6.) Performed quite rarely.
3.
In relevant cases perform before the biopsy and genetics.
Pictureadoptedfrom:PaganoniS,AmatoA.Electrodiagnostic
evaluationofmyopathies.PhysMedRehabilClinNAm.
2013;24(1):193-207.doi:10.1016/j.pmr.2012.08.017.
DIAGNOSTIC TESTS
Picture taken from: Paganoni S, Amato A. Electrodiagnostic evaluation of myopathies. Phys Med Rehabil Clin N
Am. 2013;24(1):193-207. doi: 10.1016/j.pmr.2012.08.017.
MUPs are small, short, and
polyphasic and recruit early. In longstanding
disease, a mixed population
of small and long duration MUAPs may
be seen.
In rapidly progressing myopathies (i.e.
mainly in inflammatory myopathies or muscular
dystrophies), there is also the presence of
prominent muscle membrane irritability
(fibrilations, PSWs, and even
myotonic discharges), especially in
proximal muscles – this aktivity is believed to
reflect the ongoing disease activity
In myotonias, myotonic discharges
are frequent.
NOTE that EMG may be normal in
selected myopathies (certain
endocrine, metabolic, congenital, and
mitochondrial myopathies)!
NEEDLE EMG
Picturetakenfrom:PaganoniS,AmatoA.Electrodiagnosticevaluationofmyopathies.
PhysMedRehabilClinNAm.2013;24(1):193-207.doi:10.1016/j.pmr.2012.08.017.
MYOPATHIES -
CLASSIFICATION
1. INHERITED
̶ muscular dystrophies
̶ congenital myopathies
̶ metabolic myopathies
̶ Mitochondrial myopathies
̶ Storage diseases (glycogen, lipid – Pompe, McArdle)
2. ACQUIRED
̶ myositis (inflammatory myopathies, mostly caused by an autoimmune process)
̶ endocrine myopathies
̶ external substance induced myopathy (toxic) (alcoholic, glucocorticoid, statin).
̶ rare others (infectious – infuenza, lyme disease, toxoplasmosis, …)
MUSCULAR
DYSTROPHIES
̶ Muscular dystrophy is a group of diseases that cause
progressive weakness and loss of muscle mass.
̶ Due to gene mutations interfering with the production of
proteins needed to form healthy muscle (mostly
the membrane proteins).
̶ There are many kinds of muscular dystrophy.
̶ In some of them, the symptoms begin in childhood, mostly in
boys (DMD, BMD).
̶ Other types don't surface until adulthood (FSHD, LGMD, MD1,2)
̶ The main sign of muscular dystrophy is progressive
muscle weakness. Specific signs and symptoms begin at
different ages and in different muscle groups, depending on
the type of muscular dystrophy.
̶ The treatment options are limited
̶ Medications and other therapy (physical therapy) can also
help manage symptoms and slow the course of the disease. https://neuromuscular.wustl.edu/musdist/dag2.htm
MEMBRANE-ASSOCIATED
PROTEIN COMPLEXES
DUCHENNE TYPE MUSCULAR
DYSTROPHY (DMD)
̶ Dystrophinopathy (mutations in the dystrophin gene)
̶ the dystrophin protein is absent
̶ Dystrophin is a large protein located on the cytoplasmic face of the
muscle membrane.
̶ It represents the first step in the connection of actine/myosine
complex to the muscle cell membrane
̶ It´s coded by a gene on the short arm of the X chromosome.
̶ XR – mostly affects boys (although girls can be carriers and mildly
affected)
̶ the incidence in boys of about 200 per million birth (1 out of 5000)
̶ DMD = the most common form of muscular dystrophy
Adoptedfrom:
https://neuromuscular.wustl.edu/musdist/dmd.html
https://en.wikipedia.org/wiki/Becker_muscular_dystrophy
large calf muscles
(pseudohypertrophy)
13
DUCHENNE TYPE MUSCULAR DYSTROPHY (DMD)
̶ Signs/symptoms typically appear in early childhood (mainly 2-5 yrs) and might include:
̶ Frequent falls, muscle pain and stiffness
̶ Difficulty rising from a lying or sitting position
(Gowers sign - standing up with the aid of hands pushing on knees, butt- first)
̶ Trouble running and jumping, wadling gait, loss of ambulation
- usually at the age of 9 - 13 years, later with steroid treatment
̶ Walking on the toes, large calf muscles (pseudohypertrophy)
̶ Dilated cardiomyopathy (especially > 15 years)
̶ Scoliosis
̶ Mental retardation: Mean IQ ~ 88
̶ Progressive generalized weakness in later phases, ventilation support mostly needed
̶ life expectancy is estimated to be around 25-26. The most common direct cause of death in people
with DMD is respiratory failure or dilated cardiomyopathy. With respiratory assistance, the median
survival age can reach up to 40-50.
Definujte zápatí - název prezentace / pracoviště14
DUCHENNE TYPE MUSCULAR DYSTROPHY
̶ The diagnosis based on clinical picture
̶ + very high CK levels!!! (Up to 100x upper limit of normal, decreasing with increasing age
and disability)
̶ + myopathic EMG changes (frequently not necessary, particularly in typical clinical pictures
with very high CK level and/or positive family history).
̶ + genetic examination (type of mutation) + MR + muscle biopsy
̶ Treatment: Prednisone weekly (5-10 mg/kg/week). Treatment effects: walking prolonged by
2 to 5 years, increased strength, improved pulmonary functions.
̶ for particular types of mutations (so called nonsense mutations – about 13 % of DMD
patients) gene therapy is already available (ataluren – translarna) (price about $300.000/yr)
̶ Physical therapy, cardiology follow-up (pacemaker?), respiration assistance
BECKER MUSCULAR DYSTROPHY
̶ Signs and symptoms are similar to those of Duchenne muscular dystrophy
but tend to be milder and progress more slowly.
̶ XR-linked – only boys are affected
̶ The same gene is affected, but the dystrophine is not completely absent
̶ Symptoms generally begin in the teens (above 7 years of age) but might not
occur until the mid-20s or later.
̶ Muscle weakness, mostly proximal, legs and arms, slowly progressive
̶ Failure to walk at the age of 16 - 80 years
̶ The diagnostic and therapeutic options similar to DMD
large calf muscles
(pseudohypertrophy)
+ hyperlordosis
Adoptedfrom:
https://neuromuscular.wustl.edu/musdist/dmd.html
MYOTONIC DYSTROPHY (MD)
̶ the most common muscular dystrophy that begins in adulthood (at least 1 in 8,000 people worldwide)
̶ characterized by progressive muscle wasting and weakness and the inability to relax certain
muscles after use (myotonia, e.g. a person may have difficulty releasing their grip on a doorknob or handle).
̶ Other signs and symptoms of MD include cataracts and cardiac conduction defects.
̶ In affected men, hormonal changes may lead to early balding and infertility.
̶ The features of this disorder often develop during a person's twenties or thirties, although they
can occur at any age. The severity of the condition varies widely among affected people, even
among members of the same family.
̶ There are two major types of myotonic dystrophy with similar signs and symptoms: type 1 and
type 2 (the latter tends to be milder). They are caused by mutations in different genes.
̶ Myotonic dystrophy type 1 is caused by mutations in the DMPK gene (DM1 protein kinase), while type 2
results from mutations in the CNBP gene (CCHC-type zinc finger nucleic acid binding protein, also called ZNF9).: tri/
tetranucleotide repeat expansion.
̶ No specific treatment available, Gene therapy is in the early stages of study in humans
OTHER TYPES OF MUSCULAR DYSTROPHY
̶ Some types of muscular dystrophy are defined by a specific feature or by where in
the body symptoms begin and remain most expressed (before genetic testing, the
classification of muscular dystrophies was based on the distribution of the symptoms):
̶ FACIOSCAPULOHUMERAL (FSHD). Muscle weakness typically begins in the face,
hip and shoulders. The shoulder blades might stick out like wings when arms are
raised. Onset usually occurs in the teenage years but can begin in childhood or as
late as age 50.
̶ LIMB-GIRDLE (LGMD). Hip and shoulder muscles are usually affected first. People
with this type of muscular dystrophy might also have peroneal paresis and so might
trip frequently. Onset usually begins in childhood or the teenage years.
̶ OCULOPHARYNGEAL (OPMD). Dysfagia, tongue weakness, ptosis and external
ophthalmoplegia (often incomplete and asymmetric) are prominent features. Mild
proximal weakness of the lower (70 %) or upper limbs.
FSHD
FSHD
LGMD
FSHD
CONGENITAL MYOPATHIES
̶ Congenital myopathies are rare muscle diseases mostly present at
birth (congenital, but may not be apparent until later in infancy or childhood)
̶ result from genetic defects (mostly related to the genes coding
contractile proteins or Ca2+ signaling pathway).
̶ There are many different types (e.g. central core disease, nemaline
myopathy, centronuclear myopathies) and signs and symptoms and
their severity vary depending on the type.
̶ The conditions are often stable or slowly progressing.
̶ most share common features, including lack of muscle tone and
weakness (including facial weakness and drooping eyelids) + delayed motor skills
̶ Other signs and symptoms of some congenital myopathies include feeding
and breathing difficulties, as well as skeletal conditions, such as curvature of
the spine (scoliosis), weak bones (osteopenia) or hip problems.
̶ The diagnosis is often based on morphological findings on muscle
biopsy (no dystrophic changes, no inflammation). No specific treatment.
Pictures taken from:
https://neuromuscular.wustl.edu/syncm.html
And North KN et al. Approach to the diagnosis of
congenital myopathies. Neuromuscul Disord
2014;24(2):97-116.
POMPE DISEASE, GLYCOGEN
STORAGE DISEASE TYPE II
̶ an inherited AR disorder caused by the accumulation of glycogen in certain organs and tissues
(mainly muscles and liver cells), which impairs their function.
̶ Caused by the mutation of the GAA gene, which encodes an enzyme called acid alphaglucosidase
(also known as acid maltase). This enzyme is active in lysosomes and normaly
breaks down glycogen into glucose, which is impaired in Pompe disease.
̶ Confirmed by enzyme activity examination, followed by genetic testing in relevant cases
̶ Treatment available! – since 2006, enzyme replacement therapy using biologically active
recombinant human alglucosidase alfa (produced in Chinese Hamster Ovary cells) is available
(costs about 300.000 USD per year and must be taken for patients´entire life).
̶ Clearly prolongs the survival. Early diagnosis and early treatment leads to much better outcomes
21
POMPE DISEASE, GLYCOGEN
STORAGE DISEASE TYPE II
̶ The classic form of infantile-onset Pompe disease begins within a few
months of birth and presents with muscle weakness, hypotonia and
hepatomegaly, and heart defects. Affected infants may also fail to gain
weight and grow at the expected rate and have breathing problems. If
untreated, this form of Pompe disease leads to death from heart failure in the
first year of life.
̶ The late-onset type of Pompe disease may not become apparent until later
in childhood, adolescence, or adulthood. Late-onset Pompe disease is
usually milder than the infantile-onset forms of this disorder and is less likely
to involve the heart. Most individuals with late-onset Pompe
disease experience progressive muscle weakness, especially in the legs
and the trunk, including the muscles that control breathing (with the progress,
it can lead to respiratory failure).
Picture taken from: Van der Beek N et al.
Clinical features and predictors for disease na
tural progression in adults with Pompe diseas
e:a nationwide prospective observational stud
y. Orphanet J Rare Dis. 2012 ;7:88.
SPECIFIC IMMUNE/ INFLAMMATORY MYOPATHIES
̶ Immune myopathies
̶ Polymyositis (mostly antisynthetase antibodies –anti Jo)
̶ Other syndromes (e.g. anti HMGCR – rare immune-mediated myopathy caused by the statins)
̶ Dermatomyositis
̶ Rare others
̶ Infections
̶ Lupus, polymyalgia rheumatica
̶ Celiac disease
̶ Inclusion body myositis – IBM….
Most of the general information applies to the
most frequent ones (dermato-, polymyositis)
(proximal symmetrical progressive
weakness as a dominant feature, pain in
about half of the patients, mostly mild)
INFLAMMATORY MYOPATHIES
̶ Dermatomyositis and polymyositis both have an autoimmune basis, but the basic mechanism
is different. In dermatomyositis, the illness results from humoral attack on the (not only muscle)
capillaries, whereas in polymyositis, the muscle fibers are under attack by cytotoxic T cells.
̶ Typically associated with the presence of autoantibodies (various types in each syndrome)
̶ Both the basic types can be differenciated by:
̶ clinical picture (absence/presence of skin or other systems changes),
̶ autoantibodies present,
̶ CK levels (more elevated in polymyositis since the pathological process is directed against muscle fibers)
̶ muscle biopsy findings.
̶ Treatment: general agreement exists to treat polymyositis and dermatomyositis with
corticosteroids or some other form of immunosuppression (IVIG, azathioprim, methotrexate,
cyclosporine, or even Mycophenolate mofetil), or a combination of these.
POLYMYOSITIS
̶ acute or subacute illness that occurs in adults
̶ more frequent in women than in men, as are other autoimmune diseases
̶ the course commonly relapses and remits, especially when treated with immunosuppression or corticosteroids.
̶ Systemic symptoms are common at onset, such as malaise, fever, and anorexia
̶ Frequent cardiac involvement (myocarditis, pericarditis) – up to 70%
̶ Autoimmune disease, the cause of polymyositis is unknown and may involve viruses (Coxsackie)
and autoimmune factors.
̶ Associated with the presence of autoantibodies of which the Jo-1 antibodies (directed against
histidyl tRNA-synthetase) are the most common.
̶ Serum CK concentration should always be elevated (more than in dermatomyositis or IBM).
̶ Certain risk of cancer (1.4x to 2x increased) (not that high as in dermatomyositis)
DERMATOMYOSITIS
̶ Muscle is not the only tissue involved in
dermatomyositis. Muscle weakness is associated
with:
̶ a characteristic skin rash. It is characteristically
a purplish discoloration of the skin over the
cheeks and eyelids (Heliotrope rash). It often has
a butterfly distribution and blanches on pressure.
The rash may spread widely over the body. The
skin over the elbows, knees, and knuckles is
particularly prone to develop a reddened,
keratotic, indurated appearance (Gottron's sign
and papules). Nailford lesions (petechia and
erythema).
Gottron's sign and papules
DERMATOMYOSITIS
̶ Vascular abnormalities, such as Raynaud's phenomenon.
̶ Cardiac involvement ranges from conduction defects to congestive cardiac failure secondary to cardiomyopathy.
̶ Interstitial pneumonitis and fibrosis may cause a nonproductive cough and respiratory distress.
̶ Delayed gastric and esophageal emptying occurs in the illness, indicating an abnormality in
the smooth muscle of the upper gastrointestinal tract.
̶ The illness often follows a relapsing-remitting course, although occasionally the illness is clearly
monophasic even to the point of recovering spontaneously without treatment.
̶ Juvenile or adult form. The latter is associated with an increased risk for cancer (3x to 6x
increased). Up to 32 % of adults will develop a cancer, mostly within 2 to 3 years of presentation of the myositis.
̶ The serum CK concentrations are usually elevated but can be normal earlier in the course or in
patients with a very indolent course.
OTHER ACQUIRED MYOPATHIES
̶ Endocrine myopathies - associated with disorders of the thyroid and parathyroid
glands and to myopathies associated with increased corticosteroid levels.
̶ External substance induced myopathy (alcoholic, glucocorticoid, statin).
̶ Rare others (infectious – infuenza, lyme disease, toxoplasmosis, …)
̶ Mostly quite typical clinical pattern (proximal weakness + myalgia)
̶ CK and myoglobine usually only mildly elevated
̶ Minimal or even no EMG changes
̶ Treatment: no specific, treat the causing disease (if possible) (infectious or
endocrine diseases, cessation of toxic substances)
28
MOTOR NEURON DISEASES
̶ term refers to the broader family of disorders that may affect the upper and/or
lower motor neuron system as well as nonmotor systems
̶ Some of the units affect only the function or upper or lower motor neuron, while
others typically combine the impairment of both types of motor neurons.
̶ The most important diagnostic units in this group are the following:
̶ Amyotrophic lateral sclerosis (motor neuron disease) (ALS) and it´s variants
̶ Spinal muscular atrophy (SMA)
̶ Spinobulbar muscular atrophy (SBMA, Kennedy's Disease)
̶ Mostly inherited or degenerative conditions, rarely affected by infection (acute
poliomyelitis) or other causes
29
MOTOR NEURONS
̶ The upper motor neuron (UMN) is a motor
neuron, the cell body of which lies within the
motor cortex of the brain, and the axon of
which forms the corticobulbar and
corticospinal tracts.
̶ Lower motor neurons (LMNs) lye in the
brainstem motor nuclei and the anterior
horns of the spinal cord and directly
innervate skeletal muscles.
̶ The UMNs are rostral to the LMNs and
exert direct or indirect supranuclear control
over the LMNs
30
SIGNS AND SYMPTOMS OF UPPER MOTOR
NEURON INVOLVEMENT
̶ Weakness (decreased muscle strength – mostly mild) + the loss of dexterity
̶ Increased muscle tone (spasticity)
̶ Increased deep tendon reflexes (hyperreflexia) (even in atrophic limb = probable UMN sign)
̶ Decrease of exteroceptive reflexes + the presence of pathological reflexes (Babinsky….)
̶ Pseudobulbar palsy (or spastic bulbar palsy) develops when there is disease
involvement of the corticobulbar tracts that exert supranuclear control over those motor
nuclei that control speech, mastication, and deglutition.
̶ The prefix “pseudo-” is used to distinguish this condition from “true” bulbar palsy that results
from pure LMN involvement in brainstem motor nuclei.
̶ Clinically, articulation, mastication, and deglutition are impaired, and combined with
spontaneous or unmotivated crying and laughter (This is also termed emotional lability,
hyperemotionality, labile affect, or emotional incontinence)
̶ often very stressfull for the the patient.
31
SIGNS AND SYMPTOMS OF LOWER
MOTOR NEURON INVOLVEMENT
̶ Loss of muscle strength (moderate to severe weakness)
̶ Muscle atrophy (decrease of the muscle mass)
̶ Decreased deep tendon reflexes (and exteroceptive reflexes) (hyporeflexia)
̶ Decreased muscle tone (flacidity)
̶ Fasciculations
̶ Muscle cramps
̶ Pure motor dysfunction (no positive/negative sensory symptom unless there is a
combination with some other disease – polyneuropathy, CTS… )
̶ In some diseases (typically ALS) both UMN a LMN signs are combined
32
METHODS USED TO CONFIRM UMN/LMN LESIONS
̶ LMN: NCS/EMG – nerve condution studies are typically normal (the decrease of
CMAP amplitudes is possible) – performed mostly to exclude other explanatory
diagnosis
̶ Needle EMG shows the reinnervation potenials (polyphasic MUPs, broad, and
high in amplitude, reduced number of MUPs that have an increased firing rate),
frequently combined with denervation potentials (fibrilations and PSW) and/or
fasciculations
̶ UMN: besides clinical examination, motor evoked potentials (MEP) using the
transcranial magnetic stimulation can be used.
̶ Genetic testing is relevant in inherited diseases (SMA, SBMA, familial ALS)
33
SPINAL MUSCULAR ATROPHY
̶ a group of disorders caused by degeneration of anterior horn cells – LMN only!!!
̶ Almost all cases are genetically determined, with most being AR due to homozygous
deletions of the survival motor neuron gene in chromosome 5.
̶ The incidence of infantile to juvenile AR SMA is estimated to be 1 in 6000 newborns
̶ Clinical picture in type I: hypotonia, severe generalized muscle weakness, deep
tendon reflexes are absent, weak cry - floppy” baby.
̶ Intercostal muscles are severely weakened (causing respiratory distress)
̶ In type II or III, delayed motor milestones are first hints to diagnosis, otherwise similar
SMA TYPE AGE AT ONSET SURVIVAL/PROGNOSIS INHERITANC
E
DEFECTIVE GENE
Infantile SMA (WerdnigHoffmann)
– type 1
Birth to 6 mo Death by 2 yr old, never able to sit without support,
unable to lift their heads when placed prone
AR SMN gene
Intermediate SMA – type 2 Before 18 mo No walking, adulthood AR SMN gene
Juvenile (Kugelberg-Welander)
– type 3
After 18 mo Adulthood AR SMN gene
Adult-onset SMA
(pseudomyopathic SMA)
After 20 yr (Most > 30 yr) Slow progression of mucle weakness, proximal or
distal
AR, AD
“Sporadic”
SMN gene, distal overlap with
HMN-5
No need to know it in detail – just that this disease exist and may start in various age ☺
34
SPINAL MUSCULAR ATROPHY
̶ Patients with SMA have normal or above-average intelligence.
̶ They attend school, and when they reach adulthood often live
and work outside the home (Stewen Hawking?).
̶ The diagnosis mainly based on a typical clinical picture
̶ Most important test is a molecular genetic analysis to identify homozygous
deletions in the SMN gene on chromosome 5q
̶ In unclear cases, EMG can confirm suspition and support the indication of molecular
genetic analysis
̶ Serum CK may be elevated up to 10 times normal levels in SMA type 3 but is
typically normal in the infantile and intermediate types.
Nathan Yates, M.S., is an adjunct
economics and finance professor at
Southern New Hampshire University.
35
̶ Treatment: multidisciplinary approach: Physical therapy (to maintain active mobility and
independence and prevent the development of contractures and kyphoscoliosis), occupational therapy,
orthopedic evaluation (frequent scoliosis), and emotional support
̶ To assist in breathing, non-invasive ventilation (BiPAP) is frequently used (tracheostomy
in more severe cases). Nutrition via a feeding tube or gastrostomy.
̶ Nusinersen is used to treat spinal muscular atrophy. It is an antisense nucleotide that modifies the
alternative splicing of the SMN2 gene. It is given directly to the central nervous system using an
intrathecal injection (initially 6x /year, later 3x/ year – price $750,000 in the first year, than $375,000
each year). It was approved in the US in 2016 and in the EU in 2017.
̶ Onasemnogene abeparvovec (Zongelsma) is a gene therapy treatment which uses selfcomplementary
adeno-associated virus type 9 (scAAV-9) as a vector to deliver the SMN1
transgene. As an intravenous formulation, it was approved in 2019 in the US to treat those below 24
months of age (price: $2.125 million, only one administration is needed).
SPINAL MUSCULAR ATROPHY
36
AMYOTROPHIC LATERAL SCLEROSIS
̶ Charcot's disease, motor neuron disease, and, in the US, Lou Gehrig's disease
̶ neurodegenerative disorder of undetermined etiology that primarily affects the motor neuron cell
populations in the motor cortex, brainstem, and spinal cord.
̶ Genetic predispositon (in familial and to lesser extent in sporadic), association with FTD in some mutations.
̶ Presents with a progressive pure motor weakness (leading in therminal phase to respiratory
failure), typically spreading from one part of the body (one extremity) with slow generalization.
̶ In most typical cases presents with the combination of UMN and LMN (increased deep tendon
reflexes and Babinsky sign in atrophic limb represent very typical sign), frequent bulbar involvement.
̶ Fasciculations are a typical phenomenon (but not exclusive for ALS!!!)
̶ Some patients may have:
̶ UMN onset (Primary lateral sclerosis)
̶ LMN onset (Progressive muscular atrophy
̶ Bulbar onset (Progressive bulbar palsy)
̶ dyspnea at onset
+ later usually develop signs of
involvement of the other parts
of the motor system
37
AMYOTROPHIC LATERAL SCLEROSIS
̶ Median survival 2-4 years from the diagnosis
̶ The diagnosis is based on a typical clinical picture (slow spreading of the pure motor
symptoms/signs, not explained by spondylogennic disease or any other diagnosis) – revised
ElEscorial criteria
̶ NCS/EMG can confirm the diagnosis (pure motor axonal lesion, reinnervation +
denervation changes and fasciculations present in upper and lower extremities, trunk and
also in cranial nerve distribution) and/or exclude other possible causes
̶ Treatment multidisciplinary:
̶ Physical therapy (to maintain active mobility and independence and prevent the
development of contractures and kyphoscoliosis), emotional support
̶ To assist in breathing, non-invasive ventilation (BiPAP) is frequently used (tracheostomy in
more severe cases). Nutrition via a feeding tube or gastrostomy.
̶ Riluzole prolongs survival by 2-5 months, edaravon partly efficient
MAIN SOURCE OF INFORMATION
̶ https://www.mayoclinic.org/diseases-conditions/
̶ https://neuromuscular.wustl.edu/ (some pictures are also taken from this page)
̶ https://ghr.nlm.nih.gov
̶ Paganoni S, Amato A. Electrodiagnostic evaluation of myopathies. Phys Med Rehabil Clin N
Am. 2013;24(1):193-207. doi: 10.1016/j.pmr.2012.08.017
̶ Murray B, Mitsumoto H. CHAPTER 78 – Disorders of Upper and Lower Motor Neurons. In
Bradley WG, Daroff RB, Fenichel GM, Jankovic J. Neurology in Clinical Practice, 5th ed.
London: Elsevier 2008.
̶ Amato AA, Brooke MH. CHAPTER 83 – Disorders of Skeletal Muscle. In Bradley WG, Daroff
RB, Fenichel GM, Jankovic J. Neurology in Clinical Practice, 5th ed. London: Elsevier 2008.
CONGENITAL MYOPATHIES
̶ There are different types of congenital myopathies (just to get some idea, no need to know in detail), some of
which include:
̶ Central core disease. This condition causes muscle weakness and developmental problems. Some people
may develop a significant reaction to general anesthesia (malignant hyperthermia).
̶ Centronuclear myopathies. These rare conditions cause muscle weakness in the face, arms, legs and eye
muscles, and breathing problems.
̶ Congenital fiber type disproportion myopathy. Small fibers are found on muscle tissue during a biopsy.
This condition causes muscle weakness in the face, neck, arms, legs and trunk.
̶ Nemaline myopathy. Nemaline myopathy is one of the more common and causes muscle weakness in the
face, neck, arms and legs, and sometimes scoliosis. It may also cause breathing and feeding problems.
̶ Multiminicore disease. This condition has several subtypes and often causes severe muscle weakness in
the arms and legs, and scoliosis.
̶ Myotubular myopathy. This rare condition, which occurs only in males, causes muscle weakness,
floppiness and breathing problems.
̶ Other myopathies. Other rare myopathies include autophagic vacuolar myopathy, cap disease, congenital
myopathy with arrest of myogenesis, myosin storage myopathy and zebra body myopathy
MYOTONIC DYSTROPHY (MD)
̶ The muscle weakness associated with type 1 particularly affects the lower legs, hands, neck, and
face. Muscle weakness in type 2 primarily involves the muscles of the neck, shoulders, elbows,
and hips.
̶ The two types of myotonic dystrophy are caused by mutations in different genes.
̶ Myotonic dystrophy type 1 is caused by mutations in the DMPK gene (DM1 protein kinase),
while type 2 results from mutations in the CNBP gene (CCHC-type zinc finger nucleic acid
binding protein, also called ZNF9). The specific functions of these genes are unclear. The
protein produced from the DMPK gene may play a role in communication within cells. It
appears to be important for the correct functioning of cells in the heart, brain, and skeletal
muscles. The protein produced from the CNBP gene is found primarily in the heart and in skeletal
muscles, where it probably helps regulate the function of other genes.
̶ Type 1 myotonic dystrophy results from a mutation in the DMPK gene known as a trinucleotide
repeat expansion (50-5000 repeats, while it´s only 5 to 34 in healthy individuals)
̶ Type 2 myotonic dystrophy results from a mutation in the CNBP gene known as a
tetranucleotide repeat expansion (75-11000, in most healthy people no more than 26)