Muscular Dystrophies

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Muscular Dystrophies

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Duchenne Muscular Dystrophy
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Duchenne Muscular Dystrophy (DMD) (Also known as
Pseudohypertrophic)   

• Onset
• Early childhood - about 2 to 6 years.
• Symptoms
• Generalized weakness and muscle wasting affecting
  limb and trunk muscles first. Calves often
  enlarged.
• Progression
• Disease progresses slowly but will affect all
  voluntary muscles. Survival rare beyond late
  twenties.
• Inheritance
• X-linked recessive (females are carriers).

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• Other clinical features
• Cardiomyopathy Dilated Especially gt 15 years
• Mental retardation Mean IQ 88
• Night blindness
• Progression Death 15 - 25 years due to
  respiratory or cardiac failure

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Laboratory

• Serum
• CK Very high
• Troponin I Elevated above normal but not to
  levels in cardiac ischemia
• Liver enzymes High AST ALT

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• Endomysial fibrosis
• Variable fiber size Small fibers rounded
  Hypercontracted (opaque) muscle fbers
• Myopathic grouping
• Muscle fiber degeneration regeneration
• Muscle fiber internal archetecture Normal or
  immature

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• X-linked recessive inheritance
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Genetic testing

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  Southern blot analysis ?????
• Most of these PCR-based tests detect 95-98 of
  the deletions/duplications that are found by
  Southern blot analysis.
• Complex rearrangements are not always detected by
  PCR.

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Western blot of dystrophin from dystrophinopathies

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• ???? 4 DMD

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• 14 KB mRNA
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DMD

• Duchenne muscular dystrophy
• Genotype Dystrophin
• 96 with frameshift mutation
• 30 with new mutation
• 10 to 20 of new mutations are gonadal mosaic
• Onset 3 to 5 yrs

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Manifesting carriers
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Becker Muscular Dystrophy

•  Onset
• Adolescence or adulthood.
• Symptoms
• Almost identical to Duchenne but often much less
  severe.
• Can be significant heart involvements.
• Progression
• Slower and more variable than Duchenne with
  survival well into mid to late adulthood.
• Inheritance
• X-linked recessive (females are carriers).

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BMD

• Genotype Dystrophin mutations
• Deletion
• 70 of patients Usually In-frame
• 16 with frameshift mutation
• New mutations rare
• Point mutations
• gt 70 identified
• Mutations in CpG All C to T None G to A
• ? Related to direct or inverted gene repeats

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• Clinical features of myopathy
• Onset gt 7 yrs
• Weakness
• Proximal gt Distal Symmetric Legs Arms
• Slowly progressive
• Severity onset age correlate with muscle
  dystrophin levels

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May be especially prominent in quadriceps or
hamstrings

• Calf pain on exercise
• Muscle hypertrophy Especially calves
• Failure to walk 16 - 80 years

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Systemic

• Joint contractures Ankles Other
• Cardiomyopathy May occur before severe weakness
• Mental retardation

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Myotonic Dystrophy
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Myotonic Dystrophy

• Myotonic muscular dystrophy (MMD) is a form of
  muscular dystrophy that affects muscles and many
  other organs in the body.
• Unlike some forms of muscular dystrophy, MMD
  often doesn't become a problem until adulthood
  and usually allows people to walk and be pretty
  independent throughout their lives.

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Myotonic Dystrophy

• Weakness and wasting of voluntary muscles in the
  face, neck, and lower arms and legs are common in
  myotonic muscular dystrophy.
• Muscles between the ribs and those of the
  diaphragm, which moves up and down to allow
  inhalation and exhalation of air, can also be
  weakened.

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• Muscle Dystrophy

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Myotonic Dystrophy

• Myotonic muscular dystrophy is often known simply
  as myotonic dystrophy and is occasionally called
  Steinert's disease, after a doctor who originally
  described the disorder in 1909.
• It's also called dystrophia myotonica, a Latin
  name, and therefore often abbreviated "DM."

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MD

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Clinical findings

• A long, thin face with hollow temples, drooping
  eyelids and, in men, balding in the front, is
  typical in myotonic dystrophy

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MD

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Congenital MMD

• When a child with congenital MMD is born, it's
  almost always found that the mother has
  adult-onset MMD -- even though her symptoms may
  be so mild that she doesn't even know she has the
  disorder.

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• A child born with congenital myotonic dystrophy
  is likely to have facial weakness and an upper
  lip that looks "tented."
• The eye muscles may also be affected.

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Congenital Myotonic Dystrophy

• The infant form of MMD is more severe.
  Unfortunately, it can occur in babies born to
  parents who have the adult form, even if they
  have very mild cases.

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CTG repeats expansion
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DM1 Myotonin protein kinase (DMPK) protein

• The expanded area of DNA is in a gene that
  carries instructions for a protein known as
  myotonin protein kinase.
• The expanded DNA isn't in the "working" part of
  the gene -- the part that carries instructions
  telling cells to make myotonin protein kinase.
• Instead, in MD, the genetic flaw is in a part of
  a gene called the untranslated DNA, an area of
  DNA that the cell doesn't use for protein
  manufacturing.

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Anticipation

• Increased Severity with progressive generations
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• It may be that the expanded DNA section affects
  the functioning of more than one gene, or it may
  cause clumps of genetic material to build up in
  the nuclei (control centers) of cells, affecting
  many cellular functions.

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Facioscapulohumeral muscular dystrophy (FSHD)

• An autosomal dominantly inherited myopathy with a
  characteristic pattern of muscular wasting and
  weakness involving primarily face and shoulder
  girdle muscles.
• Later on, foot dorsiflexors, lower abdominal
  muscles and the pelvic girdle are affected.
• Extramuscular manifestations such as neurosensory
  hearing loss and retinal
• vasculopathy are described.
• Clinical severity and age of onset may vary
  widely between and within affected families

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• A deletion of an integral number of 3.3 kb KpnI
  repeats (D4Z4) in the subtelomeric region of
  chromosome 4 (4q35) is associated with the
  disease.
• The deletion leads to a reduction of D4Z4 repeats
  below a critical number on the FSHD-causing
  allele.
• The number of remaining D4Z4 repeats on the FSHD
  allele seems to be directly related to the age at
  onset and progression of the
• disease with low repeat numbers causing a more
  severe disease

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• The locus for autosomal dominant
  facioscapulohumeralmuscular dystrophy (FSHD1A)
  has been mapped to the telomeric region of the
  long arm of chromosome 4 (4q35)in about 98 of
  cases.
• The gene responsible, however,has not been
  identified to date.

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• In healthy subjects, 4q35- probe p13E-11
  (D4F104S1) detects polymorphic EcoRI
  DNA-fragments of 35300 kb consisting of multiple
  copies of a 3.3 kb KpnI unit.
• In FSHD patients p13E-11/EcoRI fragments are
  found to be shortened to sizes of 1035 kb by the
  loss of integral KpnI copies.
• In affected families, shortened fragments are
  transmitted between generations without
  alteration in size.

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• Diagnostic difficulties arise from atypical
  clinical presentations and from an overlap in
  D4Z4 numbers between controls and FSHD
  individuals.
• Thus, a molecular genetic test result with a
  borderline D4Z4 number has its limitations for
  the clinician wanting to differentiate between
  the diagnosis of FSHD and a myopathy presenting
  with FSHD-like symptoms.

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There is no definite D4Z4 diagnostic cut-off
point separating FSHD, FSHD-like myopathies and
controls. (J Neurol (2003) 250 932937)

• A broad myopathic spectrum with four phenotypes
  (typical FSHD, facial sparing FSHD, FSHD with
  atypical features, non-FSHD muscle disease) was
  found in the borderline region.
• The expected correlation of D4Z4 repeat number
  and clinical severity was not found.
• Therefore the molecular test is of limited help
  to differentiate FSHD from FSHD like muscle
  disorders when the D4Z4 number is n 8.

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Channelopathies

• Ion channels are membrane-bound proteins that
  perform key functions in virtually all human
  cells.
• Such channels are critically important for the
  normal function of the excitable tissues of the
  nervous system, such as muscle and brain

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Channelopathies

• Some proteins are tissue specific, while others
  are widely distributed throughout the body.
• The resting membrane potential of excitable cells
  is entirely due to the presence of such ion
  channels.

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• It had been suspected that genetic dysfunction of
  such critical membrane- bound proteins would be
  lethal.
• However, during the past few years there has been
  an explosion in the discovery of disease-causing
  mutations in genes coding for ion channel
  proteins and these disorders are known as
  channelopathies.
• We now recognize both genetic and autoimmune
  channelopathies affecting a range of tissues.

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CLASSIFICATION OF ION CHANNELS

• two broad categories depending on their mode of
  activation
• voltage gated
• ligand gated.

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Most ion channels have a similarbasic structure.

• All voltage gated ion channels have a large pore
  forming subunit, which sits within the membrane.
• The pore forming subunit (also called the
  a-subunit) contains a central aqueous pore
  through which the relevant ion passes in response
  to voltage change induced activation, also known
  as gating.

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• A computer representation based on x-ray
  crystallography measurements shows a voltage
  gated potassium channel.
• Ions flow through the empty region in the middle.

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• The structural topology of all voltage gated ion
  channels is remarkably conserved through
  evolution.
• To date, most genetic neurological
  channelopathies affecting the peripheral nervous
  system (PNS) and central nervous system (CNS) are
  caused by a-subunit mutations, resulting in
  dysfunction of voltage gated ion channels.

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Malignant hyperthermia syndromes
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Central nervous system

• In the last few years an increasing number of
  genetic CNS channelopathies have been described.
• There is increasing evidence that the discoveries
  made will be relevant to common neurological
  diseases such as migraine and epilepsy.
• Ion channel dysfunction is important in common
  neurological disease.
• It has been shown that a particular epilepsy
  phenotype know as generalized epilepsy with
  febrile seizures is more common than previously
  realized and that it frequently associates with
  mutations in brain ion channel genes

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Familial hemiplegic migraine

• Familial hemiplegic migraine is a form of
  migraine with aura which is inherited in an
  autosomal dominant manner.
• Patients experience typical migraine headaches
  but in addition there are paroxysmal neurological
  symptoms of aura including hemianopia,
  hemisensory loss, and dysphasia.
• Hemiparesis occurs with at least one other
  symptom during familial hemiplegic migraine aura
  the weakness can be prolonged and may outlast the
  associated migrainous headache by days.
• Coma has also been described with severe attacks.
  
• Persistent attention deficits and memory loss can
  last weeks to months.

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• Triggers include emotion or head injury.
• The age at onset for familial hemiplegic migraine
  is often earlier than typical migraine,
  frequently beginning in the first or second
  decade.
• The number of attacks tends to decrease with age.
  
• About 20 of families have cerebellar signs
  ranging from nystagmus to progressive, usually
  late onset cerebellar ataxia.

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• Genetic studies have established that many cases
  of familial hemiplegic migraine are caused by
  missense mutations in the P/Q-type voltage gated
  calcium channel gene, CACNA1A.
• The presynaptic location of this calcium channel
  allows it to function as a key controller and
  modulator of the release of both excitatory and
  inhibitory neurotransmitters throughout the CNS.
• It is suspected that a disturbance in this
  control is important in the genesis of familial
  hemiplegic migraine

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skeletal muscle channelopathies

• The four genes known to cause the periodic
  paralyses

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