myopathies and myotonic dystrophies

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

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.

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.

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.

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

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.

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

FIBRE TYPING IN SKELETAL MUSCLETYPE 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

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.

RING FIBRES

HYALINE FIBRES: Hyaline fibres are pathologically rounded and enlarged than

normal,represents early stage of necrosis.

FIBRE NECROSIS

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

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

FIBRE REGENERATION On H&E,Regenerating fibres show basophilia of their

cytoplasm

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:

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.

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

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.

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.

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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.

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.

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.

(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

Clinical Featuresclumsiness 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.

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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

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.

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.

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.

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

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.

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.

Commonest systemic manifestations

Testicular atrophy

Diabetes Mellitus

Endocrine disturbances

Cardiomyopathy

Mild dementia

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.

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

CLINICAL FEATURES

Slowly progressive humeroperoneal

weakness

Cardiomyopathy associated

conduction defects

Early contractures of achilles tendon,spine

and elbows

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.

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.

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.

CLINICAL FEATURES Prominent weakness of facial and shoulder muscles.

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.

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

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

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.

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

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.

CLINICAL FEATURES

Ptosis

Ophthalmoplegia

Dysphagia

Oesophageal motility dysfunctions.

Cardiac conduction defects,cardiomyopathy.

CONGENITAL MYOPATHIES Patients frequently afflicted at an early stage,exhibiting signs

of the floppy infant syndrome.

Weakness is more extreme proximally, hypotnia and listlessness..

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

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.

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.

NEMALINE ROD MYOPATHY

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.

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.

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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

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.

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.

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.

INFLAMMATORY MYOPATHIESInflammatory myopathies –three primary inflammatory

myopathies are-

Dermatomyositis

Polymyositis

Inclusion body myositis

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.

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.

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.

HELIOTROPE RASH

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

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.

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.

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.

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.

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.

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.

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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.

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.

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.

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..

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.

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

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.

RAGGED RED FIBRES

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

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.

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

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

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.