This document provides an overview of myopathies and muscular dystrophies. It begins with an introduction to inherited muscle diseases and their common presentations. It then discusses the key differences between muscular dystrophies, which involve muscle membrane or supporting proteins, and myopathies, which involve genetic defects in the muscle contractile apparatus. The document outlines best practices for muscle biopsy collection and preparation. It provides details on interpreting muscle biopsy specimens and fiber typing. Several specific myopathies and dystrophies are then described in depth, including Duchenne and Becker muscular dystrophies, myotonic dystrophy, Emery-Dreifuss muscular dystrophy, and facioscapulohumeral dystrophy. Clinical features, pathogenesis

1. MYOPATHIES AND MUSCULAR
DYSTROPHIES
 BY DR.GARGI TIGNATH
 GUIDED BY DR.SHILPI DOSI.

2. INTRODUCTION:
Inherited myopathies and muscular dystrophies are a diverse group of
muscle diseases presenting with common complaints and physical signs:
weakness, motor delay,respiratory and bulbar dysfunction.
 MUSCULAR DYSTROPHIES are diseases of muscle membrane or
supporting proteins. Muscular dystrophies – literally means “deficient
nutrition” .
 Generally characterized by pathological evidence of ongoing muscle
degeneration and regeneration.
 Inherited diseases result in progressive muscle injury in patients who
usually appear normal at birth.
 Congenital muscular dystrophies are progressive, early-onset diseases.
 Some are associated with central nervous system manifestations.

3.  MYOPATHIES are caused by genetic defects in the contractile
apparatus of muscle. .
 Defined by distinctive histochemical or ultrastructural changes on
muscle biopsy. .
 often have a perinatal or early childhood presentation .
 result in relatively static deficits.

5. COLLECTION AND PREPARATION OF MUSCLE
BIOPSY SPECIMEN
 1.Muscle biopsy should be performed by persons skilled in
biopsy technique,with knowledge of specimen submission and
procedure.
 2.specimen should be obtained from a muscle in which
disease process is active and evolving.

6. PREPARATION OF MUSCLE SAMPLE
 Two separate specimens are routinely requested
First specimen-before excision,
maintained in an isometric state
by introducing it into a muscle
clamp.
Prevent contraction
artifact,caused by cutting the
muscles and immersing into
fixative
Second specimen-msg
about1x0.5x0.5,for the
preparation of frozen
section.
Freezing must proceed
with extreme rapidity
Acceptable sample size-0.5cm in
diameter,1cm in length
Serial frozen sections are routinely
stained with
H&E,RTC,ATPase,NADH-TR

8. INTERPRETATION OF MUSCLE BIOPSY SPECIMEN
 Normal myocyte-
 Multinucleated syncytium cell with a shape resembling
elongated cylinder,polygonal or multifaceted in crossection.
 Sarcolemmal nuclei are orderly located peripherally with 4 to 6
fibres in transverse section.
 Proximal powerful muscle -85 to 90 micro meter.20 micro
meter smaller,distal or occular muscle.
 Fibre size greater in males than females.

9. Normal skeletal muscle has relatively uniform polygonal
myofibers with peripherally placed nuclei that are tightly packed
together into fascicles separated by scant connective tissue

10. FIBRE TYPING IN SKELETAL MUSCLE
TYPE 1 TYPE 2
Color Red White
Adenosine tri
phosphatase activity
at PH-9.4
low high
Oxidative enzyme
content
high low
phosphorylase low high
Lipid content high low

11. OBSERVATION IN ROUTINE PARAFFIN
SECTIONS
 1.Nuclear changes-nuclei in crossectionsnof normal muscle
are peripheral or subsarcolemmal in 97 to99% of fibres.
Nuclear
internalization is
seen in
neuromuscular
disease.

12. RING FIBRES

13. HYALINE FIBRES:
Hyaline fibres are pathologically rounded and enlarged than
normal,represents early stage of necrosis.

14. FIBRE NECROSIS
Initial sign of necrosis in
LM,acutely necrotic fibres
first stains more eosinophilic
than pales to a wan shade of
pink.

15. FIBRE REGENERATION
 Fibre necrosis acts as stimulant for fibre regeneration
1.When necrosis is segmental
regeneration starts from
sprouts of sarcoplasm at
viable segments adjacent to
damaged sarcoplasm
2.Satellite cells second source of
regeneration following injury to
muscle cells
Two routes
transforms into
myocyte

16. FIBRE REGENERATION
 On H&E,Regenerating fibres show basophilia of their
cytoplasm

17.  Inclusion :-
May be located within sarcolemmal nuclei or with in the sarcoplasm.
 Nuclear inclusions are faintly pink to wine coloured in H&E stain.
 Pink or red inclusions may also be seen in the sarcoplasms of rimmed
vacuoles.
 Inflammation:-
o Inflammatory cells expand in the endomysial spaces in acute,more
severe disease.
o Most of them are mononuclear cells-mature lymphocyte,Plasma
cells form minor part.
 Fibrosis and fatty infiltration:

18. DUCHENNE MUSCULAR DYSTROPHY (DMD) AND
BECKER MUSCULAR DYSTROPHY (BMD)
 Dystrophinopathies are the most common form of muscular
dystrophy.
 Two most important disease manifestations linked to
mutations in the dystrophin gene.
Duchenne muscular dystrophy .
 Incidence of about 1 per 3500 live male births
 severe progressive phenotype.
 Follows an inexorable fatal course.

19.  DMD becomes clinically evident by the age of 5 years;
 Most patients are wheelchair-bound by the time they are
teenagers and dead of their disease by early adulthood.
 Becker type of muscular dystrophy is less common and much
less severe.
 charecterised by later onset disease,milder phenotype.
 Synthesis of truncated version of dystrophin-presumely retains
some function.
 Female carriers have unfavourable inactivation of “x”
chromosome.-have milder symptoms

20. PATHOGENESIS
 Both DMD and BMD are caused by loss-of-function mutations in the
dystrophin gene located on the short arm of the X chromosome
(Xp21).
 Dystrophin - very large protein (427 kD mol. wt) found in skeletal
and cardiac muscle, brain, and peripheral nerves; it is a part of
the dystrophin-glycoprotein complex
 Dystrophin gene spans roughly 2.4 megabases (about 1% of the X
chromosome), making it one of the largest human genes.
 Enormous size -explains vulnerability to sporadic mutations that
disrupt dystrophin production.
 most common mutations are deletions, followed by frameshift and
point mutations.

21.  Dystrophin-glycoprotein complex stabilizes the muscle cell during
contraction and may be involved in cell signaling through
interaction with other proteins.
 Defects - makes muscle cells vulnerable to transient membrane
tears during contraction -lead to calcium influx -disrupt intracellular
signaling.
 The result is myofiber degeneration that with time outpaces
the capacity for repair.
.

23. MORPHOLOGY
 Histologic alterations in skeletal muscles affected by DMD and
BMD are similar, except that changes are milder in BMD..
 Hallmarks of these as well as other muscular dystrophies are
ongoing myofiber necrosis and regeneration.
 Segmental myofibre degeneration and regeneration,associated with
atrophic myofibres.
 Fasicular architecture is preserved at this stage,no inflammation
except for the presence of myophagocytosis
Muscle biopsy specimens from patients with DMD show a
complete absence of dystrophin,’BMD have mutations that permit
some dystrophin.

24.  Progressive replacement of muscle tissue by fibrosis and
fat.
 As a result of ongoing repair -muscles typically show marked
variation in myofiber size and abnormal internally placed
nuclei.
 Both DMD and BMD also affect cardiac muscles, which
show variable degrees of myofiber hypertrophy and interstitial
fibrosis.

25. Myopathic conditions often are associated with segmental
necrosis and regeneration of individual myofibers.
Necrotic cells (B1-B3) are infiltrated by variable numbers of
inflammatory cells.
Regenerative myofibers (B4, arrow) are characterized by
cytoplasmic basophilia and enlarged nucleoli.

26. (C)-Clusters of both atrophic myofibers (grouped atrophy) and fiber-type
grouping
(D)-patchy areas in which myofibers share the same fiber type, are
features of neurogenic remodeling.
The ATPase reaction shown in this is one method of distinguishing
between fiber types, as type I fibers stain more lightly than type II fibers.
Note loss of the “checkerboard” pattern

27. Clinical Features
clumsiness and an inability to keep up with peers due to
muscle weakness.
weakness typically begins in the pelvic girdle and next involves
the shoulder girdle.
Enlargement of the calf muscles, termed pseudohypertrophy, is
an important early physical finding.(due to fatty infiltration and
reactive fibrosis.
The increased muscle bulk initially stems from myofiber
hypertrophy, but as myofibers progressively degenerate, an
increasing part of the muscle is replaced by adipose tissue and
endomysial fibrosis.

28. Cardiac muscle damage and fibrosis –lead to
heart failure and arrhythmias, which may prove
fatal.
cognitive impairment - sometimes seen , may
be severe enough to manifest as mental
retardation
high serum creatine kinase levels at birth and
persist through the first decade of life due to
ongoing muscle degeneration, but falls as muscle
mass is lost during disease progression.
Death -results from
• respiratory insufficiency,
• pneumonia
• cardiac decompensationat

29. BMD becomes symptomatic later in childhood or adolescence and
progresses at a slower and more variable rate.
Many patients live well into adulthood and have a nearly normal life
span.
Cardiac involvement can be the dominant.

30. OTHER X-LINKED AND AUTOSOMAL
MUSCULAR DYSTROPHIES
 Other forms of muscular dystrophy share some features
with DMD and BMD but have distinct clinical, genetic, and
pathologic features.

31. Myotonic dystrophy :
 Autosomal dominant multisystem disorder.
 Affects 1 in 10,000 individual.
 Age of onset from infancy to later childhood-2nd and 3rd decade
 Myotonia,a sustained involuntary contraction of muscles,a key feature
of the disease.
 Congenital myotonia-leads to severe manifestations in infancy.

32. PATHOGENESIS:
 Mutation in MyD gene located on chromosome no.19 -
Expansion of CTG Triplet repeats.
 Toxic gain of function,caused by triplet repeats.
 Triplet repeats in the 3’ –non coding region of the myotonic
dystrophy protein kinase gene(DMPK) gene.
Mis splicing of other RNA transcripts,CLC1
Chloride channnel
CLC1 deficiency responsible for myotonia
Plays important role in RNA splicing
Inhibits this muscle like -1 function
Expanded CTG repeats in DMPK m-RNA
Transcript
Bind and sequester protein –called as muscle blind
like protien-1

33. MORPHOLOGY
 Muscle biopsy studied at early stage-shows :
 multitude of pyknotic internal nuclei,selective atrophy of type
1 fibres and ring fibres.
 In chronic long standing disease-
 Fibre destruction.
 Regeneration.
 Reactive fibrosis.

34. CLINICAL FEATURES:
 Patients often complain of stiffness and difficulty releasing
their grip, for instance, after a handshake.
 Disease often manifests in late childhood with gait
abnormalities due to weakness of foot dorsiflexors,
 With subsequent progression -weakness of the intrinsic
muscles of the hands and wrist extensors,
 Atrophy of the facial muscles and ptosis.

35.  Commonest systemic manifestations
 Testicular atrophy
 Diabetes Mellitus
 Endocrine disturbances
 Cardiomyopathy
 Mild dementia

36. INVESTIGATIONS
 Membrane instability can be elicited by vigrous voluntary
muscle contraction or by percussion with a reflex hammer.
 EMG-to substantiate myotonia when it is clinically silent.

37. EMERY DREIFUSS MUSCULAR DYSTROPHY
 Caused by mutations in genes that encode nuclear lamina proteins..
Present in the inner face of nuclear membrane
Provides shape and mechanical stability of nucleus during
contraction, influence gene expression by affecting chromatin
organisation in the nucleus.
PROTEINS AFFECTED
EMERIN LAMININ A/C
TWO FORMS
1.X-LINKED FORM EMD1
2.AUTOSOMAL FORM
EMD2

38. CLINICAL FEATURES
Slowly progressive
humeroperoneal
weakness
Cardiomyopathy
associated conduction
defects
Early contractures of
achilles tendon,spine
and elbows

39. FASCIOSCAPULOHUMERAL DYSTROPHIES
 Milder myopathy that principally involves-
 Voluntary musculature of face, shoulder and upper
extremities.
 Autosomal dominent
 Age of onset-2nd and 3rd decade.
 Incidence-1 in 20,000
 Gene involved-q35 subtelomeric region of chromosome 4.

40. PATHOGENESIS
 Over expression of gene called DUX4,located in region of q35
subtelomeric repeats on chromosome no.4.
 Normal gene locus near or with in FRG1 gene.
 Inherited single nucleotide polymorphisms(SNPs),at positions
immediately 3’ of DUX4 coding sequence.

41. MORPHOLOGY:
 Muscle biopsy specimen reveals-
 1.Many atrophic fibres in the absence of significant fibre
necrosis or regeneration.
 2. Numerous Moth eaten fibres.-seen in oxidative enzyme
reactions.
 3.presence of inflammation-small foci of perivascular mature
lymphocytes,seperates this dystrophy from others,seen in
early stages.

42. CLINICAL FEATURES
 Prominent weakness of facial and shoulder muscles.

43. LIMB GIRDLE MUSCULAR DYSTROPHY
 Six autosomal dominant+fifteen autosomal recessive entities.
 Incidence-1 in 25,000 to 50,000 individuals.
 Age of onset-late adolscence or young adulthood
 All forms are characterized by muscle weakness-that
preferentially involves-proximal muscle groups.

44. PATHOGENESIS
 Genes encoding:
1. Structural component-adhalin or α sarcoglycans of dystrophin
glycoprotien complex(gene locus-17q12)-type 2A
2. α dystroglycan,a component of dystrophin glycoprotien
complex
3. “z “ disks of sarcomeres,Z-Band associated protein
telethonin(gene locus on chr17q11-12).
4. Vesicle trafficking and cell signalling
5. Protease caplain 3 (calcium activated protease)and laminin a/c-
Type 2A

45. MORPHOLOGY
 Marked nuclear internalization
 Variability in fibre diameter,that is accentuated by fibre
hypertrophy.
 Hypertrophy with fibre splitting.
 Mild chronic inflammation.
 IHC-immunostains show upregulation of MHC class 1 antigen
on muscle fibres membranes.
 Rimmed vacuoles are seen in telothinin and titin deficiency

47. CLINICAL FEATURES
 Involvement of proximal axial muscles.
 Pseudohypertrophy noticed in 1/3rd of patients.
 Late onset disease named as titinopathy, is a distil organ
involvement with predominant lower leg involvement.

48. OCULOPHARENGEAL MUSCULAR
DYSTROPHIES
 Late onset myopathy,begins in middile life and has benign
outcome
 Pathogenesis:GCG repeats in the polyA binding protein
gene on chromosome 14q11-13.
 six triplet repeats,dominantly inherited disorder.
 small CGC,expanded segments are found in the affected
region of PAPB2

49. MORPHOLOGY:
 Muscular reveals
 Mild dystrophic change
 Nuclear internalization.
 Fibre atrophy and interstitial fibrosis
 Presence of rimmed vacuoles.
 On EM-muscle tissue reveals-nuclear inclusions ,composed of
unbranched tubulofilamentous structures with outer diameter
of 8.5nm.
 Inclusions contains-protien PAPB2.

50. CLINICAL FEATURES
 Ptosis
 Ophthalmoplegia
 Dysphagia
 Oesophageal motility dysfunctions.
 Cardiac conduction defects,cardiomyopathy.

51. CONGENITAL MYOPATHIES
 Patients frequently afflicted at an early stage,exhibiting signs
of the floppy infant syndrome.
 Weakness is more extreme proximally, hypotnia and
listlessness..

52. CENTRAL CORE DISEASE.
 Lack of muscular vitality ,noted in infancy
 Gene Locus-q13.1 band of chromosome19.
 17 mis-sense mutations in RYR1 Gene.
 Muscle involvement is likely to be mild,proximal and non
progressive.
 In biopsy specimen-a multiplicity of muscle fibres harbors a
single,centrally located defect or core.
 More than one core per fibre may be seen.
 Predominance of type 1 fibre is seen

54. MULTICORE MYOPATHY
 Gene locus-19q13 and RYR1
 congenital non progressive myopathy .
Morphology:
 Characterized by type 1 fibre predominance and minute
corelike structures in the majority of muscle fibres.
 Often globular or sometime disk like in longitudnal sections.
 C/F-
 generalized weakness and hypotonia,
 facial and extraoccular muscles are also involved in some
patients.

56. NEMALINE ROD MYOPATHY
 Mutation in five thin filament genes,including slow α-
tropomyosin(TPM3) and nebulin(NEB).
 May be dominant or recessive trait.
 More prevalent in females
 C/F-
 weakness is more prominent in facial and proximal limb
muscles..
 Facial dysmorphism is seen face is elongated,the jaw is
prognathic and palate is highly vaulted.
 Morphology:Selective atrophy of oxidative fibres,majority of them
show rods.

57. NEMALINE ROD MYOPATHY

59. CONGENITAL FIBRE TYPE DISPROPORTION
 Occurs in families,but mechanism of inheritance has not been
confirmed.
 Detactable at birth,paucity of motor activities and diminished
muscle tone
 Deterioration of muscle function tends to continue through out
first decade and then ceases or even undergo reversal.
 C/F-skeletal deformities-hip dislocation,kyphoscoliosis and
joint contractures.
 Morphology:atrophy of type 1 fibre and hypertrophy of type 2
,glycolytic fibres may be rare as a predominance of type1.

61. CENTRONUCLEAR MYOPATHY
 Dominant or recessive or x linked.
 Abnormal gene MTM1,located in chromosome Xq27-28.
 MTM1-encodes myotubularin with an active site of tyrosine
phosphatase
 Disease may be expressed fully in infancy or remain dormant
from childhood to 7th decade of life..
 C/F-involvement of appendicular muscles with facial asthenia
and extraocular palsies.
 .

62.  Morphology:
 central or paracentral nucleus seen in most of the fibres
resembling fetal myoyube stage of development.
 The nuclei exceed the normal size,have a vesicular chromatin
network,sarcoplasm surrounding the central nucleus has
disruptrd appear as a clear vacuole in frozen sections

64. MYOFIBRILLAR MYOPATHY
 Protein surplus myopathies,accumulation of intermediate
filaments including,desmin,actin,myosin,αβ crystalline and
myotilin with in fibres..
 Often adult onset,autosomal dominent.
 slowly progressive condition.
 Best known type is desmin myopathy.

65. DESMIN MYOPATHY
 Onset usually in childhood or early adulthood
 Mis-sense mutation or deletion involves the desmin gene
located on 2q35
 Mutation in CRYAB gene on chromosome no.11q21-
23,encodes for αβ crystalline ,a cytoplasmic heat shock
protein.
 Frozen sections stained with RTC-
smudged.,basophilic,purple filamentous areas in the
sarcoplasm of some fibres..these are unstained in NADH-TR
reactions,but are highlightened in immunostains for desmin.

67.  On EM:electron dense accumulation that are both granular and
filamentous.
 2nd feature of desmin myopathy-cytoplasmic bodies-they are
filamentous and feature adark center surrounded by loosely
arranged radiating fibrils.
 Hyaline bodies are the mark of hyaline body myopathy-contains
myosin
 Gene located on chromosome 14q,mutations of MYH7 myosin
gene.
 Round ,well circumscribed and subsarcolemmal.
 Opaque compared with surrounding normal sarcoplasm.
 On EM:contains filamentous material.

68. INFLAMMATORY MYOPATHIES
Inflammatory myopathies –three primary inflammatory
myopathies are-
 Dermatomyositis
 Polymyositis
 Inclusion body myositis

69. DERMATOMYOSITIS
 Systemic autoimmune disease ,which typically presents with
proximal muscle weakness and skin changes.
 Pathogenesis:
 Damage to small blood vessels-contribute to muscle injury.
 Vasculopathic changes-telengectasias in nail folds,eyelids and
gums.
 Dropouts of capillary vessels in skeletal muscle.
 Biopsies from skin and muscle show-MAC{C5b-9}.
 Various autoantibodies in association to B lymphocyte and
plasma cells infiltrate is seen in muscle.

70. ANTIBODIES INVOLVED IN
PATHOGENESIS ARE:
 Anti-Mi2 Abs-against Helicase -implicated in nucleosomal
remodelling.-associated with heliotropic rash and gottorons
papule.
 Anti jo 1Abs- against enzyme histidyl t-RNA synthetase-
associated with interstitial lung disease,non erosive
arthritis,skin rash.
 Anti P-155/p-140 Abs- associated with several transcriptional
regulators.-paraneoplastic and juvenile cases of DM.

71. CLINICAL FEATURES:
 Muscle weakness-slow in onset,symmetrical,often
accompanied by myalgias.
 Typically affects proximal muscle first,getting up from a chair
and climbing steps becomes difficult.
 Fine movements controlled by distil muscles-affected only late
in the disease.
 Various charecteristic rashes seen in DM-
 Liliac coloured discoloration of upper eyelid-HELIOTROPE
RASH with periorbital oedema.
 Scaling erythematous eruptions or duskey red patches over
the knuckles,elbow and knees.-GOTTRON PAPULES.

72. HELIOTROPE RASH

74.  Dysphagia-oropharengeal/oesophageal muscles-occur in 1/3rd of
the affected muscles.
 10%-patients have interstitial lung disease.
 Cardiac invovement is also common.
 JUVENILE AND ADULT FORMS OF DM:
 Avg.age of juvenile dermatomyositis is -7 yrs
 Adult-4 to 6 th decade
 Childhood disease-calcinosis and lipodystrophies
 Less likely associated with myositis specific antibodies,cardiac
involvement interstitial lung disease or underlying malignancy

75. MORPHOLOGY:
 Muscle biopsies-infiltrate of
mononuclear inflammatory cells-most
pronounced in perimysial connective
tissue and around blood vessels.
 Distinctive pattern of myofibre atrophy-
accentuated at the edges of fasicles
 Perifasicular atrophy
 Segmental fibre necrosis and
regeneration.
 IHC-Infiltrate rich in cd4 T helper cells
and deposition of C5b-9 in capillary
vessels.
 Electron microscopy-tubuloreticular
endothelial cell inclusions.

77. POLYMYOSITIS:
 Adult onset inflammatory myopathy that shares myalgia and
weakness with dermatomyositis but lacks its distinctive
cutaneous features.
 Symmetrical proximal muscle involvement.
 Inflammatory involvement of heart and lungs.
 Similar antibodies as dermatomyositis.

78. PATHOGENESIS:
 Uncertain,but believed to be immunologic
 CD8 positive cytotoxic T cells are prominent part of
inflammatory infiltrate in affected muscle.-mediators of tissue
damage.
 Unlike DM,vascular injury doesnot play a major role.
 Cytoplasmic inclusions,containing proteins-beta
amyloid,TDP-43 and ubiquitin.
 In chronic disease –endomysial fibrosis and fatty replacement.

79. MORPHOLOGY:
 Mononuclear inflammatory cells infiltrate
are present,endomysial in location.
 Myofibres with otherwise normal
morphology appear to invade by
mononuclear inflammatory cells.
 Degenerating necrotic,regenerating and
atrophic myofibres.
 Typically found in random and patchy
distribution.
 Perifasicular atrophy is absent.

80. INCLUSION BODY MYOSITIS
 It is a disease of late adulthood,typically affects patients older
than 50 yrs.
 Antibody to Cn1a has been recently been described.
 Most common inflammatory myopathy in patients>65 yrs.
 Men> women.

81. CLINICAL FEATURES
 Slowly progressive muscle weakness-more severe in
quadriceps.
 Distil upper extremities(acral muscle).-extensor compartment
of arm.
 Dysphagia from oesophageal and pharengeal muscle
involvement.

82. MORPHOLOGY:
 Inclusion body myositis has features similar to those of
polymyositis-
 Patchy, often endomysial mononuclear infiltrate CD8 T cells
rich.
 Focal invasion of normal appearing myofibres by inflammatory
cells.
 Admixed degenerating and regenerating fibres.

83.  Features typical of inclusion body
myositis:
 Abnormal cytoplasmic inclusions
described as “rimmed vacuoles.
 Tubulofilamentous inclusions in
myofibres,seen by electron
microscopically.
 Cytoplasmic inclusions containing
protiens typically associated with
neurodegenerated diseases like beta
amyloid,TDP-43 and ubiquitin.
 Endomysial fibrosis and fatty
replacement,reflective of a chronic
course.

86. TREATMENT OF INFLAMMATORY
MYOPATHIES:
 Corticosteroids are the first line treatment for polymyositis and
dermatomyositis.
 Immunosuppressive drugs are used in steroid resistant
disease or as steroid-sparing agents –azathioprine and
methotrexate.
 Intravenous immunoglobulin,cyclophosphamide,cyclosporine,
Rituximab(antibody targets B-cell) and are third line therapies.

87. TOXIC MYOPATHIES:
 caused by prescription or recreational drugs or by certain hormonal
imbalances.
 Statins are amongst the leading culprits
 Chloroquin and hydroxychloroquin(antimalarial drugs).-causes drug
induced lysosomal storage myopathy-presents with with slowly
progressive muscle weakness
 ICU Myopathy or myosine deficient myopathy is a neuromuscular
disorder seen in patients during the course of treatment for critical
illness-in ICU with steroid therapy.
 There may be selective degradation of sarcomere myosin thick
filaments producing profound weakness..

88.  Thyroid myopathy-most commonly acute or chronic proximal muscle
weakness.
 External ophthalmoplegia,characterized by swelling of eyelids,edema of
the conjunctiva,diplopia.
 Alcohol can be myopathic,binge eating produces an -acute toxic shock
syndrome rhabdomyolysis,myoglobinuria and renal failure.

89. MITOCHONDRIAL MYOPATHIES
 Complex systemic conditions can involve many other organ
systems including skeletal muscles and other tissues rich in cell
types with high ATP requirements,particularly cardiac muscles
and neurons.
 Pathogenesis:
a) Disease results only when a certain threshold of mutated
mitochondrial DNA copies exceeded within a substantial
fraction of at risk cells.
b) Single point mutation in mitochondrial leucine-t-RNA.
c) Deletion in mitochondrial DNA

90. MORPHOLOGY
 Skeletal muscle shows abnormal aggregates of mitochondria
 Preferentially seen in subsarcolemmal area of affected of
affected myofibrils,producing an appearance of ragged red
fibres.
 Loss of particular mitochondrial enzyme,may be appreciated
by cytochrome oxidase.

91. RAGGED RED FIBRES

92. CLINICAL FEATURES
Single point mutation in
leucine t-RNA
Deletion of
mitochondrial DNA
-Mitochondrial
encephalopathy
-lactic acidosis
-stroke like
episodes
-Chronic progressive external
ophthalmoplegia
-pigmentary degeneration of
retina
-complete heart block
e.g-myoclonic epilepsy with ragged
red fibres.
-Lebers heriditary neuropathy
-Subacute necrotising encephalopathy
e.g- kearn sayre syndrome

93. ION CHHANEL MYOPATHIES
 Channelopathies are a group of inherited diseases caused by
mutations affecting the function of ion channel.
1.KCNJ2-mutations-K+ channel-andersen twail syndrome.
 Autosomal dominant
 Periodic paralysis,heart arrythmias,skeletal abnormalities.
2.SCN4A mutations-Na+ channel-several autosomal disorder.
 Myotonia to periodic paralysis
3.CACNA1S-mis sense mutation-Ca++ channel mutation-
hypokalemic paralysis.

94. 4.CLCI mutation-mutations affects chloride channel-causes
myotonia congenita.
 Its expression decreases in myotonic dystrophy.
5.RYR1 mutation:gene dysrupts the function of ryanodyn receptor-
regulates ca++ in sarcoplasmic reticulum
 Leads to congenital myopathy.
 Mutated receptor-increased ca++ influx in sarcoplasmic reticulum
leads to-hypermetabolic state ,characterized by-
-tachypnea
-tachycardia
-muscle spasms
-hyperpyrexia
-tetany

95. Diagnosis :on the basis
History and examination,
Biochemical examination
Neurophysiological assessment,
Muscle biopsy,
Genetic testing.
Treatment is focused on symptomatic management
and rehabilitation and monitoring for disease
complications

96. SPINOMUSCULAR ATROPHY/DIFFERENTIAL DIAGNOSIS OF
HYPOTONIC INFANT
 Neuropathic disorder-loss of motor neurons-leads to muscle
weakness and atrophy.
 Autosomal recessive disorder
 1 in 6000 births
 Loss of function mutation in SMN-1 gene.
 Morphology:large zones of severely atrophic myofibres,mixed
with scattered normal sized or hypertrophied fibers ,that retain
innervation from remaining motor neurons.