What are Neuromuscular Disorders

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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

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Upper and Lower Motor neurons

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

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Lower Motor neuron

• Anterior Horn Cell
• Nerves
• Neuromuscular Junction
• Muscle

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Anterior Horn Cell

• Poliomyelitis
• Spinal Muscular Atrophy

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Nerves

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

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Neuromuscular Junction

• Myasthenia Gravis
• Congenital Myasthenia

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Muscle

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

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Features of Lower Motor Neuron Lesions

• Muscle wasting
• Fasciculation
• Decreased tone
• Weakness
• Decreased or absent reflexes

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Anterior Horn Cell

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

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Spinal Muscular Atrophy

• Usually autosomal recessive
• Progressive weakness and wasting
• Second most common neuromuscular
• disease in children

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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

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Examples of Muscular Dystrophies

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

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Myotonic Disorders

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

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Metabolic Myopathies

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

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Congenital Myopathies

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

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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

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Patterns of Weakness in Neuromuscular Disease

• Muscle weakness presents in different ways in
  different neuromuscular diseases
• Proximal / Distal
• Selective / Non-selective
• Symmetrical / Asymmetrical

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Muscular Dystrophies

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Duchenne Muscular Dystrophy
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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

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

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

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?????? ? ???????? X
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• X-linked recessive inheritance
• ?? 30 ????? ??????? ????

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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.

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Western blot of dystrophin from dystrophinopathies

• ????? 1,2 BMD
• ???? 3 NORMAL
• ???? 4 DMD

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

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

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DMD

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

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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 involvement.
• Progression
• Slower and more variable than Duchenne with
  survival well into mid to late adulthood.
• Inheritance
• X-linked recessive

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BMD

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

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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 joints
• 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 does not become a problem until adulthood
  and usually allows people to walk and be
  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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  Muscular 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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• 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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  ?????? ?? ???????)
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CMD

• ????????? ??? Floppy baby
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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
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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 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

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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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Myotubular Myopathy

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

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• Pes equinovarus
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• Severe 2 to skewed X-inactivation

65
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Prenatal Diagnosis

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  ?? ??? ????

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Congenital Muscular Dystrophies

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• "floppy" infants
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Congenital Muscular Dystrophies

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????????

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• 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.

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CMD

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

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Merosin

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• ???? ?? laminin alpha 2
• Chromosome 6q22
• Recessive
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Merosin (laminin a2-chain)

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

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Merosin deficient MD

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

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

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Prenatal Diagnosis

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  ????? ?????

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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.

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SMA

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  ???? ????????.
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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.

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SMA

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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.

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SMA type 1 Werding Hoffman Infantile Muscular
Atrophy

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Type II (Chronic)

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  ???????
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Type III Mild Kugelberg-Welander or Juvenile
Spinal Muscular Atrophy

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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

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

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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

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  ???????????? SMN1 tel ? SMN2 cent
• ???? ?? ??????? ????????????

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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.

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• 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

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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

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• 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

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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

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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

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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

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LIMB-GIRDLE MUSCULAR DYSTROPHIES

• Pediatric Neuromuscular Clinic
• Metabolic-Neurogenetic Service
• Wolfson Medical Center

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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.

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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.

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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.

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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.

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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

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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.

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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.

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Biopsy

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

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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

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

118
Autosomal Recessive LGMD
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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.

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Calpainopathy (LGMD2A)
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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

129
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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131
Telethoninopathy (LGMD 2G )
132
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)

133
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.

134
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.

135
Autosomal Dominant LGMD
136
Myotilinopathy (LGMD 1A)
137
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.

138
Myotilinopathy

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

139
Laminopathy (LGMD 1B)
140
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.

141
Caveolinopathy (LGMD 1C)
142
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.

143
LGMD 1D

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

144
LGMD 1E

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