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What are Neuromuscular Disorders

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Neuromuscular disorders affect some aspect of the lower motor neuron pathway ... Lower motor: * Anterior horn cell downwards. Lower Motor neuron. Anterior Horn Cell ... – PowerPoint PPT presentation

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Title: What are Neuromuscular Disorders


1
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  • ?????? ??????????????? ?????? ?????? ????? ??"?
  • ???? ????? ???????

2
What are Neuromuscular Disorders?
  • Neuromuscular disorders affect some aspect of the
    lower motor neuron pathway
  • This is distinct from disorders such as cerebral
    palsy, traumatic brain injury which affect the
    brain /spinal cord i.e. the upper motor neuron

3
Upper and Lower Motor neurons
  • Upper motor
  • Brain and spinal cord
  • Lower motor
  • Anterior horn cell downwards

4
Lower Motor neuron
  • Anterior Horn Cell
  • Nerves
  • Neuromuscular Junction
  • Muscle

5
Anterior Horn Cell
  • Poliomyelitis
  • Spinal Muscular Atrophy

6
Nerves
  • Peripheral nerve lesions
  • Neuropathies
  • e.g. Hereditary motor and sensory neuropathy

7
Neuromuscular Junction
  • Myasthenia Gravis
  • Congenital Myasthenia

8
Muscle
  • Muscular dystrophies
  • Myotonic disorders
  • Metabolic myopathies
  • Congenital myopathies
  • Inflammatory myopathies

9
Features of Lower Motor Neuron Lesions
  • Muscle wasting
  • Fasciculation
  • Decreased tone
  • Weakness
  • Decreased or absent reflexes

10
Anterior Horn Cell
  • Spinal Muscular Atrophy
  • Severe (Type 1)
  • (Werdnig-Hoffman disease)
  • Intermediate (Type 2)
  • Mild (Type 3)
  • (Kugelberg-Welander disease)

11
Spinal Muscular Atrophy
  • Usually autosomal recessive
  • Progressive weakness and wasting
  • Second most common neuromuscular
  • disease in children

12
Muscular Dystrophies
  • About 20 types of muscular dystrophy
  • All are caused by faulty genes
  • Inheritance may be x-linked, autosomal dominant
    or autosomal recessive
  • All result in progressive muscle weakness due to
    a breakdown in muscle

13
Examples of Muscular Dystrophies
  • X-Linked
  • Duchenne Muscular Dystrophy
  • Beckers Muscular Dystrophy
  • Recessive
  • Autosomal Recessive Limb Girdle Muscular
    Dystrophy
  • Dominant
  • Fascio-Scapulo-Humeral Dystrophy

14
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15
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16
Myotonic Disorders
  • Muscles are slow to relax after contracting
  • Slow relaxation often occurs after long periods
    of rest
  • Examples
  • Myotonic Dystrophy
  • Myotonia Congenita

17
Metabolic Myopathies
  • Most present in childhood
  • Caused by disorders of
  • Glycogen storage
  • Muscle lipids
  • Mitochondria

18
Congenital Myopathies
  • Present at birth with generalised weakness and
    hypotonia
  • Examples include
  • Central core disease
  • Multicore disease
  • Nemaline Myopathy

19
Inflammatory Myopathies
  • Prolonged inflammation of many muscles
  • Caused by auto-immune response ? Initiated by
    viral infection
  • Can be successfully treated with drugs e.g.
    steroids
  • Examples
  • Polymyositis
  • Dermatomyositis

20
Patterns of Weakness in Neuromuscular Disease
  • Muscle weakness presents in different ways in
    different neuromuscular diseases
  • Proximal / Distal
  • Selective / Non-selective
  • Symmetrical / Asymmetrical

21
Muscular Dystrophies
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    ???????? ?? ???? ???????? ???????????? ?????????
    ?????
  • ????? ??? ?????? ????? ????? ???? ???????
    ????????
  • ????????? ????? ???????? ????? ????? ???? ???
    ????, ??? ??? ?? ?????? ??????? ???.

22
Duchenne Muscular Dystrophy
23
Duchenne Muscular Dystrophy (DMD)
  • 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

24
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25
????? ??????? ?? ????
26
?????? ??????? ??????
  • Cardiomyopathy Dilated especially gt 15 years
  • Mental retardation mean IQ 88
  • Night blindness
  • Progression Death 15 - 25 years due to
    respiratory or cardiac failure

27
Laboratory
  • Serum
  • CPK Very high
  • Troponin I elevated above normal but not to
    levels like in cardiac ischemia
  • Liver enzymes high AST ALT

28
??????? ????
  • Endomysial fibrosis
  • Variable fiber size small fibers rounded
    hypercontracted muscle fibers
  • Myopathic grouping
  • Muscle fiber degeneration regeneration

29
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30
?????????
  • ??? ???? ????? ?????? ????? ?????. ??????????
    ????? ???? ??????? ?????? ?? ???

31
?????? ? ???????? X
32
???? ??????
  • ??? ?????? ?????????? ???? ?? ???????? X
  • ????? ?? ?????? ??? ???? ??? ?? ?????? ?? ?????.
  • X-linked recessive inheritance
  • ?? 30 ????? ??????? ????

33
Genetic testing
  • ?? 65 ??????? ?? ????? ?? ?????????? ???????
    ????? Southern blot analysis
  • Most of the 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.

34
Western blot of dystrophin from dystrophinopathies
  • ????? 1,2 BMD
  • ???? 3 NORMAL
  • ???? 4 DMD

35
?? ??????????
  • 79 ??????? ?? ????????? ??????
  • ????? ? 3685 ?????? ?????
  • 7 ???????????

36
????? ??????????
  • ????? ??????? ???? ??? ?? ???????. ??????????
    ???? ????.
  • ????? ????? ?? ????? ???? muscular dystrophy
    ??????? ???? ?? ??? ????????? ????
  • ?????????? ???? ????? ?????? ????? ??????? ????
    ???????? ?????

37
DMD
  • Duchenne muscular dystrophy
  • Genotype Dystrophin deficiency
  • 96 with frameshift mutation
  • 30 with new mutation
  • 10 to 20 of new mutations are gonadal mosaic

38
Becker Muscular Dystrophy
  •  Onset
  • Adolescence or adulthood.
  • Symptoms
  • Almost identical to Duchenne but often much less
    severe. Can be significant heart involvement.
  • Progression
  • Slower and more variable than Duchenne with
    survival well into mid to late adulthood.
  • Inheritance
  • X-linked recessive

39
BMD
  • Genotype Dystrophin mutations
  • Deletion
  • 70 of patients Usually In-frame
  • Point mutations
  • gt 70 identified

40
  • 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

41
May be especially prominent in quadriceps or
hamstrings
  • Calf pain on exercise
  • Muscle hypertrophy especially calves
  • Failure to walk 16 - 80 years

42
?????? ?????
43
Systemic
  • Joint contractures ankles other joints
  • Cardiomyopathy may occur before severe weakness
  • Mental retardation

44
Myotonic Dystrophy
45
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 does not become a problem until adulthood
    and usually allows people to walk and be
    independent throughout their lives.

46
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.

47
????????
  • ??? ????? ????? ?? ?????
  • ???? ??? ????????? ???
  • ??????? ?????? ????? ?????? ?? ????? ??
  • ???????? ???? ???????? ???? ???? ???? ????
    Muscular Dystrophy

48
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."

49
MD
  • ????? ?????? ????? ????? ?????
  • ?? ??? ?????? ???? ?? ???????? ??? ????? ?????
    ???? ?????
  • ?? ???? ???? ??? ????? ??????????? ????? ???????
    ???? ?????

50
?????? ???????
  • A long, thin face with hollow temples, drooping
    eyelids and in men, balding in the front, is
    typical in myotonic dystrophy

51
MD
  • ?? ?????? ?????- ??????? ??.?.? ?????? ????
  • ????? ?????? ???????
  • ?????? ?????? ??????
  • ?????? ?????? ??????????? (????? ???????? ??
    ?????? ?? ???????)
  • ?????? ????? ????? ??? ??????
  • ???? ??"? ???
  • ????? ??????

52
CMD
  • ????????? ??? Floppy baby
  • ????? ?????? ??????? ?????? ?????? ???????
  • ????? ??? ?? ????? ?????
  • ??? ???????? ????? ????????
  • ?????? ????? ?? ???? ????
  • ????? ????? ??????
  • ???? ?????
  • ???? ????? ?? ????? ??????

53
  • 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.

54
?????
  • ????? ?????????? ?????????

55
??????? ????
  • ??????? ?? ????????, ??????? ???????

56
???
57
CTG repeats expansion
58
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 is not in the "working" part of
    the gene
  • Instead, in MD, the genetic flaw is in a part of
    a gene called the untranslated DNA

59
Anticipation
  • Increased severity with progressive generations
  • ????? ?? ?????? ?? ????? ?????????? ??? ???????
  • ????? ?? ????? ????? ????????????
  • 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.

60
Myotubular Myopathy
  • Centronuclear myopathy
  • X-linked (MTM 1)   l Myotubularin
  • Chromosome Xq27.3-q28 Recessive  

61
?????? ???????
  • ??????? ???? ????? ??? ??????
  • ? 50 ?????????????
  • ?????? ???????? ?? ???? ???????? ???? ???????
  • ????????? ??? ?????
  • ??????
  • ????? ???
  • ?? ????? ?? ????? ??????

62
????????
  • ???? ???? 5 ? ??????
  • ???? ????? ?? ???? ???? ???? ?????? ???????????
  • ????? ??????
  • 80 ???? ??????? ??????? ?????? ?????

63
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64
??????
  • ??????, ????? ?? ????? ?????
  • ?????? ???? ?????????????
  • Pes equinovarus
  • ????? ?????? ??????????
  • Severe 2 to skewed X-inactivation

65
??????? ????
  • ??????? ???????
  • ????? ?????? ?????

66
Prenatal Diagnosis
  • ???? ???? ????? ?????????? ???? ????? ???????
    ????? ?????
  • ???? ????? ?? ??????? ?????? ?????? ???? ??????
    ?? ??? ????

67
Congenital Muscular Dystrophies
  • ????????? ??? ????????
  • "floppy" infants
  • ???? ???????? ???? ????
  • ???? ??? ?? ?? ?????
  • ????? ?????? ????

68
Congenital Muscular Dystrophies
  • ????? ???? ?????
  • ????? ?????? ????? ?????? ??? ??? ??????
  • ????? ???????????
  • ??? ?????? ????? ???????

69
????????
  • ??? ???? ??????? ?????
  • It is important to note that just because the
    muscle weakness in CMD starts earlier, CMD is not
    automatically more severe than other forms of
    muscular dystrophy.
  • The degree and rate of progression of muscle
    weakness varies with different forms of CMD and
    from one child to the next.

70
CMD
  • 3 major groups
  • merosin-negative
  • merosin-positive with out CNS involvement
  • merosin-positive with neuronal migration disorders

71
Merosin
  • ????? ????? ????? ????? ?????? ?? ??? ?????
  • ???? ?? laminin alpha 2
  • Chromosome 6q22
  • Recessive
  • ????? ??? ???????, ???? ?????

72
Merosin (laminin a2-chain)
  • Location
  • Basement membrane
  • Muscle, Skin, CNS Peripheral nerve (Schwann
    cells)
  • Binds to a-Dystroglycan in basal lamina

73
?????? ?????
74
Merosin deficient MD
  • ????? ??????? ????? ????? ???????
  • ?????? ??? ???? ????? ?? ????? ??? ?????? ?????
    ????? ??? 3
  • ???????????
  • ?????? ?????
  • ???????
  • ???????????? ????? ???
  • ?????? ?????? ?????

75
?????? ???
  • Laboratory
  • CK Moderately high
  • MRI of CNS White matter changes (Increased
    signal on T2) Cortex usually normal

76
??????? ????
  • ?????????? ??????
  • ????? ???? ????

77
????? ???????
  • Merosin (Laminin a2) staining
  • Usually absent 95 with absent merosin have gene
    mutation
  • Partial merosin loss milder disability or later
    onset

78
Prenatal Diagnosis
  • ???? ????? ?????? ?????? ?"? ????? ?? ???????
    ????? ?????

79
Spinal Muscular Atrophy
  • In 1850, the first form of the disorder was
    identified in adults by two French physicians,
    François-Amilcar Aran and Guillaume Duchenne.
  • Toward the end of the 19th century, two German
    doctors, Guido Werdnig and Johann Hoffmann,
    described the disease in children.
  • In the early 1950s, Eric Klas Henrik Kugelberg
    and Lisa Welander, identified still another form
    of the disease.

80
SMA
  • ????? ????? ????????? ????????? ??????? ??????
    ???? ????????.
  • ????? ????? ???? ??? ??????

81
SMA
  • Progressive degeneration and loss of the anterior
    horn cells (i.e., lower motor neurons) in the
    spinal cord and sometimes in the brainstem
    nuclei,
  • Causes lower motor neurons in the base of the
    brain and the spinal cord to disintegrate,
    preventing them from delivering electrical and
    chemical signals that muscles depend on for
    normal function.

82
SMA
  • ??????? ??? ??????? ?? ??????
  • ??? ????? ?????? ?? ?????
  • ??????????? ????? ????? ??? ??????

83
SMA
  • SMA type 1 Werding Hoffman
  • SMA type 2
  • SMA type 3 Kugelberg Welander
  • Autosomal recessive
  • Types 1, 2 and 3 appear to be variants of the
    same condition, because they all appear to arise
    from a defect in the same gene on chromosome 5.
  • It is possible that different defects in the same
    gene may give rise to the different types of
    SMA.

84
SMA type 1 Werding Hoffman Infantile Muscular
Atrophy
  • ????? ???? ????? ??? ??? 3 ?
  • ????? ?????? ?????
  • ????? ?????? ???????
  • ????? ??????? ????? ?????

85
????? ???????
  • ?????? ????? ??????? ?????
  • ????????? ??? ???? ??????
  • ???????????
  • ?????????? ????? ???? ??????
  • ?? ????? ???????
  • ??????? ?? ????? ????? ???? ????? ????

86
Type II (Chronic)
  • ????? ???? ??? ??????
  • ?????? ???? ??? ?? ???????
  • ????? ?????? ?????????? ??????? ???? ??????
    ???????
  • ????? ?????
  • ??? ??????

87
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88
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89
Type III Mild Kugelberg-Welander or Juvenile
Spinal Muscular Atrophy
  • ????? ???? 18 ????? ??? ?????
  • ?????? ???? ?????? ?? ?????
  • ????? ??? ????
  • ??? ??????????

90
The diagnosis of SMA after the neonatal period
  • Poor muscle tone and symmetric muscle weakness
    that spares the ocular muscles and only involves
    the facial muscles and diaphragm late in the
    course
  • Delayed acquisition of motor skills
  • Anterior horn involvement evident as tongue
    fasciculations (seen in only 65 of patients) and
    absence of deep tendon reflexes
  • Normal reaction to sensory stimuli
  • Normal intellect

91
??????? ????
  • Grouped atrophy
  • Small muscle fibers are often rounded
  • Pyknotic nuclear clumps are not present.
  • Large muscle fibers are hypertrophied

92
SMN-survival motor neuron
  • ????? ?"? ??????? ? SMN gene (chromosomal
    locus 5q11-q13)
  • The SMN region is unusually complex, with
    repetitive sequences, pseudogenes,
    retrotransposable elements, deletions, and
    inverted duplications

93
  • ??????? ?? ??? ?????? ?? SMN ?? ?? ???
    ???????????? SMN1 tel ? SMN2 cent
  • ???? ?? ??????? ????????????

94
Molecular genetic tests of SMNT
  • Direct DNA analysis to detect a homozygous
    deletion of exon 7 of SMNT (designated D7 SMNT),
    which is used for confirmation of the clinical
    diagnosis of SMA in about 95 of patients with
    SMA and for prenatal testing.

95
  • Dosage test that determines the number of exon 7
    SMNT -containing gene copies present in an
    individual, which is used for carrier detection.
  • Such testing is clinically available in a limited
    number of laboratories

96
Genotype-Phenotype Correlations
  • Several studies have shown that the neuronal
    apoptosis inhibitory protein gene (NAIP) gene,
    which is in close proximity to the SMN gene, is
    more frequently deleted in severe SMA.
    Approximately 45 of patients with SMA1 were
    shown to have NAIP deletions, whereas only 12-18
    of patients with type II and III SMA were deleted
    for NAIP

97
  • SMN1 (SMNT telomeric SMN gene) mutations
  • Present in 95 of SMA patients
  • Carrier frequency in population 1.8
  • Incidence of disease 1 in 6,000 to 8,000 births

98
SMN1 SMN2 genes Correlation with disease
severity
  • Milder disease (SMA II or III) with Increased
    SMN2 gene copy number
  • Absence of both SMN1 SMN2 genes Lethal
  • No SMN1 gene 1 copy of SMN2 Death lt 1 month of
    age

99
5q CHROMOSOMESTypical SMN mutations in SMA
  • SMN1 Normal gene
  • SMN1 Mutation types
  • Deletion More severe SMA
  • Conversion to SMN2 gene Milder SMA
  • SMN2 gene Variations
  • More copies Correlate with milder SMA
  • SMN2 mutations alone Do not produce SMA

100
Correlation with disease severity
  • SMA type I Mostly deletions Few missense point
    mutations
  • SMA type II
  • Mutations convert SMN1 gene to SMN2
  • SMN2 gene copy number gt 3
  • Missense point mutations more common
  • SMA type III
  • SMN2 gene copy number gt 3
  • Missense point mutations more common
  • Total full length SMN protein ? Best correlation
    with SMA severity

101
LIMB-GIRDLE MUSCULAR DYSTROPHIES
  • Pediatric Neuromuscular Clinic
  • Metabolic-Neurogenetic Service
  • Wolfson Medical Center

102
Introduction
  • The limb-girdle muscular dystrophies (LGMD) are a
    group of genetically heterogeneous MD presenting
    with weakness of hip and shoulder girdle.
  • Coined by Stevenson 1953, Walton and Natrass 1954
    to account for occurrence of cases not clearly
    X-linked or FSH MD.
  • Continuing problem in classification.

103
Introduction
  • Clinical overlap with genetically distinct
    disorders e.g SMA and mitochondrial and
    metabolic myopathies may present with limb-girdle
    weakness.
  • Molecular pathogenesis known in 14 (3AD, 11AR)
    types (lt50).
  • Each type may be clinically heterogeneous.
  • Some are allelic with other forms of muscular
    dystrophy.
  • Some have unique pathogenic mechanisms.

104
Clinical Criteria
  • Onset
  • Pelvic or shoulder girdle muscles or both
    simultaneously involved.
  • Onset of weakness in distal, facial or
    extra-articular muscles should suggest
    alternative diagnoses, though these muscles may
    be involved later in the course of the disease.
  • Most individuals with LGMD begin to exhibit
    symptoms between adolescence and adulthood.

105
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106
Clinical
  • In more severe cases, symptoms manifest during
    childhood.
  • Progression
  • Progression of the weakness is inevitable but
    variable.
  • Involvement of other systems is rare. Proximal
    areas are more severely affected than those
    muscle groups distal to the body.
  • The heart and bulbar muscles are generally
    spared.

107
Clinical
  • Proximal weakness.
  • Scapular winging.
  • Gowers sign.
  • Quadriceps myopathy -atrophy of the lower portion
    of the quadriceps is most conspicuous.

108
Labs
  • CK is always elevated in recessive cases and may
    be used as a presymptomatic test in families
    where elevation of CK has been documented.
  • In dominant families CK is normally no greater
    than 6 times normal, while in recessive families
    in may be as high as 200 times normal.
  • Muscle CT scanning may also provide evidence of
    hypodensity of the involved muscles

109
Labs
  • Electromyography and muscle biopsy usually
    provide evidence of non-specific myopathic or
    dystrophic changes.
  • Recruitment of an excessively large number of
    motor unit action potential (MUAP)
  • Alteration in the morphology of MUAP small
    shorter and polyphasic.
  • Increase in insertional activity, fibrillation
    potentials and positive sharp waves.

110
Genetics
  • Mode of inheritance
  • The majority of LGMD cases are inherited in an
    autosomal recessive manner however several rare
    dominantly inherited subtypes have recently been
    classified at the molecular level.
  • Current estimates suggest that approximately 10
    of all patients with LGMD may have a dominant
    mutation.

111
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112
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113
Biopsy
  • Non-specific changes including
  • Variation of myofiber size with increased
    endomysial connective tissue
  • Increased central nuclei

114
Biopsy
  • Degenerating and regenerating fibers are seen but
    they are rarely prominent and usually scattered
    throughout the muscle with no tendency to group
    as in DMD. Necrotic fibers contain Trichrome ()
    material that may resemble IBM.

115
Biopsy
  • Ring fibers are frequent and can be observed in
    50 of cases.
  • In ring fibers, the normal longitudinal
    orientation of the myofibrils is lost.

116
Biopsy
  • Many fibers show a moth eaten appearance with
    stains for oxidative enzymes.
  • Focal decrease in the intermyofibrillar
    mitochondrial population, most evident in type 1
    fibers

117
  • Immunohistochemistry may be very useful
  • Differentiating from dystrophinopathy
  • 17 of suspected LGMD had a dystrophinopathy
    (Arikawa, 1991)

118
Autosomal Recessive LGMD
119
Sarcoglycanopathies
120
Sarcoglycanopathies
  • Heterotetrameric transmembrane complex .
  • Interacts with dystroglycan complex but does not
    bind dystrophin directly.
  • Plasma membrane stabilization.
  • Most frequent is a SG (17q)
  • b SG (4q) is second most common
  • g SG (13q) severe childhood autosomal recessive
    muscular dystrophy
  • d SG (5q) least common (Brazil)

121
Sarcoglycanopathies
  • Generally manifest earlier in life (3-5 years of
    age) than other LGMD.
  • Clinical presentation
  • Limb-girdle muscle weakness with atrophy,
    scapular winging. Severe cases resemble DMD.
  • Pain and cramping typical.
  • Calf hypertrophy early.
  • Ankle contractures.
  • Cardiac involvement not common.
  • Extremely elevated CK (10-100 x higher than other
    LGMD).

122
Sarcoglycanopathies
  • Primary mutations in b- or d-sarcoglycan leads to
    secondary loss of all elements in the complex.
  • Mutation in a-sarcoglycan (adhalin) leads to
    milder loss.
  • Mutation in g-sarcoglycan is least disruptive.
  • These generalizations not reliable, DNA
    confirmation recommended.

123
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124
Calpainopathy (LGMD2A)
125
Calpainopathy (LGMD2A)
  • The most common single genetic cause of LGMD
  • CAPN3 gene (15q).
  • Calpain (nonlysosomal Ca dependent protease)
    associated with sarcomere. Maintains sarcomere
    size and elasticity.
  • Function in the myofiber is not known probable
    role in membrane signaling and repair.
  • Calpain is unstable, so immunostain is not
    reliable.
  • Direct sequencing of the gene.

126
Calpainopathy (LGMD2A)
  • Usually presents in the second decade of life.
  • Gluteus maximus and thigh adductors predominately
    involved. Spares quadriceps.
  • Consistently develop heel cord contractures toe
    walking, later hips knees and elbows.
  • Abdominal laxity and hyperlordosis.
  • CK elevated but lower than seen in sarcoglycan
    disease.

127
Dysferlinopathy
128
Dysferlinopathy
  • LGMD2B caused by mutations in the DYSF gene (2p).
  • Dysferlin is normally present at the plasma
    membrane probable role in membrane signaling and
    repair.
  • Mutations may lead to either LGMD2B or Miyoshi
    myopathy (can have both in same pedigree). These
    tend to resemble each other as disease advances.
  • Diagnosis relies on Western Blot analysis and
    immunostaining

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Dysferlinopathy
  • Manifests in 2nd decade of life.
  • Involves most of leg muscles but tends to spare
    shoulder girdle musculature (upper extremity
    involvement of biceps).
  • Usually do not see scapular winging or calf
    hypertrophy.
  • Diagnosis relies on Western Blot analysis and
    immunostaining (Note may frequently see
    inflammation and rimmed vacuoles on biopsy).

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Telethoninopathy (LGMD 2G )
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Telethoninopathy
  • Newly recognized form of AR LGMD
  • Described in 4 Brazilian families
  • LGMD 2G (17q)
  • Telethonin is a sarcomeric protein preferentially
    expressed in striated muscle, and accumulates in
    the Z line with alpha-actinin
  • Onset in childhood small or large calves
  • Affects upper and lower proximal muscles but also
    involves distal leg muscles early ankle
    dorsiflexion weakness.
  • Diagnosis is by immunohistochemistry (may also
    see rimmed vacuoles on biopsy)

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Other Autosomal Recessive LGMD
  • LGMD 2H seen only in Manitoba Hutterites. TRIM32
    mapped to 9q (4.4 kb from fukutin).
  • LGMD2J Titin deficient late onset distal tibial
    myopathy. Double mutants have severe limb-girdle
    pattern.

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LGMD 2I (19q)
  • Fukutin-related protein (FKRP)
  • Involved in glycosylation of a-dystroglycan.
  • Mutations cause abnormal glycosylation and
    disrupt link between dystroglycan and laminin.
  • Most are CMDs or simulate dystrophinopathy.
  • Milder LGMD with infant to adult onset.
  • Severe CMD picture with cerebellar cysts.
  • Reduced laminin alpha-2 immunostain.

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Autosomal Dominant LGMD
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Myotilinopathy (LGMD 1A)
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Myotilinopathy
  • Myotilin gene (5q).
  • Myotilin is a sarcomeric protein that binds to
    alpha-actinin and is localized to the Z-line.
  • Anticipation suggesting unstable trinucleotide
    repeat.
  • LE weakness precedes UE weakness, reduced DTRs.
  • Facial weakness in some patients.
  • Frequent heel cord contractures.

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Myotilinopathy
  • 50 of patients have a distinctive nasal,
    dysarthric speech.
  • CK elevated (2-9 fold).
  • Histology rimmed vacuoles.
  • EM rod like bodies.

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Laminopathy (LGMD 1B)
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Laminopathy
  • Mutation on chromosome 1q resulting in altered
    lamin A/C protein product.
  • Allelic with autosomal dominant Emery-Dreifuss
    muscular dystrophy
  • Onset in childhood in one half.
  • LE extremity weakness precedes UE weakness.
  • Slowly progressive.
  • Cardiac irregularities, AV conduction
    disturbances, bradycardia, syncope, sudden
    cardiac death.

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Caveolinopathy (LGMD 1C)
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Caveolinopathy
  • CAV3 3p25.
  • Caveolin is involved in membrane traffic and
    signal transduction in smooth and skeletal
    muscle.
  • Manifests in early childhood with mild to
    moderate proximal muscle weakness, calf
    hypertrophy, elevated CK.
  • May have muscle rippling or mounding with
    percussion.
  • May be asymmetric.

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LGMD 1D
  • Chromosome 6q gene not known
  • Significant cardiac pathology familial dilated
    cardiomyopathy with conduction disease and
    myopathy.
  • No testing is available

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LGMD 1E
  • Two large pedigrees map to 7q
  • Adult onset, proximal weakness, dysphagia,
    Pelger-Huet anomaly (granulocytes with abnormal
    nuclei)
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