MUSCLES DISORDERS Definition: Diseases involving the muscle fibers (myogenic) Unlike: neuronopathies: secondary to LMN Heterogenous etiology, genotype,

MUSCLES DISORDERSMUSCLES DISORDERS

Definition:

Diseases involving the muscle fibers (myogenic)Unlike: neuronopathies: secondary to LMN Heterogenous etiology, genotype, phenotype…

Devastating evolution…No specific treatment for most of them

Myoblasts fusing to form large multi-nucleate muscle cells

white = fast (speed)

red = slow (endurance)

They move independently.

If so how do the individual myosin heads avoid interfering with each other?

They move together like oars on a 8 oar rowing shell, or the multiple oars of a Roman ship

How do the myosin heads coordinate How do the myosin heads coordinate to slide the actin filament?to slide the actin filament?

ATP dependent Calcium pump = Ca++ ATPase pumps calcium from the cytoplasm surrounding the sarcomers back into sarcoplasmic reticulum

Clinical: Muscle weakness: main feature

Gower’s sign (proximaly dominating deficit)

Contractures +/- severe: advanced stagesPain: in inflamm. Disorders onlyAtrophy (+/- pseudohypertrophy in X-linked) Deformity: advanced diseaseDTR: normal, diminished or absentTone: slightly or normal Other systems may be involved

Common Features:Common Features:


Laboratory Investigations:

CBC, LFT.. Normal ESR: high in inflammatory only U&E: abnormalities in some endocrinopathies and

periodic paralysis C.K & aldolase: generaly: raised (normal in few

sittings: metabolic, endocrine…) Lactic acid Genetic study: location & type of chromozomal

abnormalities:


Neurophysiology

NCS: normalEMG:

– Spontaneous activities +/- in inflammatory disorders

– Interferential tracing

– MUPs: small A Short D

polyphsics


Pathology

+/- Severe reduction in the muscle fibersMuscles fibers are replaced by fat orfibrosisCentralized nucleiFibrosis+ Inflammatory infiltrate in inflamm disordersType / I type II Electron microscopy:

– abnormal mithochondries in mithochondriopathies

ETIOLOGY / CLASSIFICATIONETIOLOGY / CLASSIFICATION

Inherited myopathies– Muscular dystrophies – Congenital myopathies– Inherited channelopathies – Periodic paralysis – Inherited metabolic myopathies

Disorders of glycolysis

Disorders of oxidative metabolism

Lipid myopathies

Mitochondrial myopathies

Acquired myopathies

Inflammatory myopathies

Acquired metabolic myopathies

Toxic myopathies

Hereditary transmitted (Muscles Dystrophies)

X- linked:-Duchenne ( cardiac involv..)

-BeckerEmery-Dreifuss (+ severe cardiomyopathy)

Non-X linek:

Limb Girdle Facio-scapulo-humoral

Scapulo-peroneal

Scapulo-humeral

Ocular-pharyngeal….

Inflammatory muscle disorders :

Autoimmune:

Primary dysautoimmune or complicating systemic diseases: SLE..– Polymyositis – Dermatomyositis

Paraneoplastic

Viral

Infective: toxoplasmosis,trichinosis..

Toxic & drug induced muscle disorders.

Muscle DystrophiesMuscle Dystrophies

Muscular DystrophyMuscular DystrophyDuchenne/

BeckerEmery-Dreifuss,

CongenitalLimb-Girdle,

Distal Myopathy

Onset 2-6 years Childhood to early teens, infancy

Late childhood-middle age

Muscle groups affected

Life expectancy Rarely beyond 20’s varies Middle age +

Inheritance X-linked recessive X-linked recessive, autosomal dom & rec.

Autosomal dominant & recessive

Genetic linkage Dystrophin Emerin, lamin, merosin, etc.

Calpain-3, Dysferlin, Caveolin-3, α-sargoglycans, etc.

Source: www.mdausa.org

X-linked: DystrophinopathiesX-linked: Dystrophinopathies

Groupe of hereditary myopathies Pathophysiology: defective or absent Dystrophin Dystrophin:

– Has integral role in sarcolemmal stability– Consist in 2 globular heads with flexible rod-shaped center

– Associated in a complex with sarcoglycans & dystroglycans (transmembrane proteins & glycoproteins)

– Coding gene: on Chromosom X short arm : Xp21 location

– Function loss: cascade of events (including loss of other

components of dystrophin-associated glycoprotein complex, sarcolemmal breakdown with attendant Ca ion influx phosphlipase activation, oxidative cellular injury) and ultimately myonecrosis

X- Linked: Ducenne, Beker..X- Linked: Ducenne, Beker..

X- linked, recessive transmissionAffects malesFemales are CarrierOnset: 2-5 years in Duchenne, end 1st decade in

Becker)Proximal muscles: mainly , (early)Severe disease (+ other systemes: cardiac..) death in the 2d decade

DUCHENNE MDDUCHENNE MDprogressive skeletal muscle weakness.Absence of the dystrophin protein weakens the

connections between proteins in the muscle fibers & the cell membrane. (?the cell membrane becomes weaker & ruptures)

As a result: ions such as Ca can move in & out of the ruptured cell membrane contraction at the damaged site the muscle fibers will break the muscle will begin to waste away.

Prevalence of DMDPrevalence of DMD(1)(1)

Affects one in 3500 to 5000 newborn males

1/3 of these with previous family history

2/3 sporadic

Clinically: onset of DMDClinically: onset of DMD

Delayed developmental milestones

Loss of motor skills

Characteristic gait

Calf “hypertrophy” (pseudohypertrophy)

Clumsiness/frequent falls

Symptoms of DMDSymptoms of DMD

Muscle weakness: Difficulty in walking/running

Difficulty climbing stairs or hills

& Difficulty in rising (Gower’s sign)

DIAGNOSIS: Clinical,

Lab Invest.: CPK

Neurophysiol. (EMG): myogenic changes

Muscle biopsy

Genetic study (Immunoblot homogenate allow diffenrentiation between Duchenne & Becker)

Asymptomatic female Foetus diagnsis possible (as early as 8 weeks)

DMD: where is the Gene?DMD: where is the Gene?The gene for dystrophin production sits on the X

chromosome.

If a normal gene for dystrophin is present, then the protein will be made.

If the gene is missing or altered, dystrophin may not be produced at all or only in abnormal forms, resulting in Duchenne muscular dystrophy

Dystrophin connects the

myofibrils to a complex of proteins

in the muscle cell membrane.

This in turn connects to the

extracellular matrix protein

laminin, stabilizing the

membrane

Spectrin connects the actin cytoskeleton in Red Blood Cells to the membrane

What is Utophin?What is Utophin?

Utophin is a protein that acts the same as dystrophin where the nerve cells meet muscular tissue.

Dystrophin and Utophin both help to protect muscle tissue through wear and tear.

Dystrophin works as a shock absorber to the muscles. Utophin does also

What is the connection between What is the connection between Dystrophin and UtophinDystrophin and Utophin??

Studies done on mice showed that if there is

an abnormally high amount of Utophin in the

body, the symptoms of MD reverse.

Dystrophinopathies. Dystrophic muscle Dystrophinopathies. Dystrophic muscle

Dystrophinopathies: dystrophin stainingDystrophinopathies: dystrophin staining

Normal Normal dystrophindystrophin

Intermediate dystrophin Intermediate dystrophin BeckerBecker MD MD

Duchenne dystrophyDuchenne dystrophy

Treatments for DMDTreatments for DMD

To improve breathing:– O2 therapy

– Ventilator

– Scoliosis surgery

– Tracheotomy

Treatments (cont.)Treatments (cont.)

To improve mobility:– Physical therapy

– Surgery on tight joints

– Prednisone

– Non-steroidal medications

– Wheelchair

Treatments (cont.)Treatments (cont.)

To improve mobility:– Physical therapy

– Surgery on tight joints

– Prednisone

– Non-steroidal medications

– Wheelchair

Advances in Gene TherapyAdvances in Gene Therapy

Researches have developed "minigenes," which carry instructions for a slightly smaller version of dystrophin, that can fit inside a virus

Researchers have also created the so-called gutted virus, a virus that has had its own genes removed so that it is carrying only the dystrophin gene

Problems with Gene TherapyProblems with Gene Therapy

Muscle tissue is large and relatively impenetrable

Viruses might provoke the immune system and cause the destruction of muscle fibers with the new genes

Other MDOther MD

Limb Girdle MDLimb Girdle MD

Common featuresCommon features– Expression in either male or female sex – Onset usually in the late first or second decade of

life (but also middle age) – Usually autosomal recessive and less frequently

autosomal dominant – Involvement of shoulder or pelvic-girdle muscles

with variable rates of progression – Severe disability within 20-30 years – Muscular pseudohypertrophy and/or contractures

uncommon

Molecular genetics revolutionized LGMD classification

Rrecent classification (clinical and molecular characteristics) – autosomal dominant (LGMD1) – autosomal recessive (LGMD2) – The list continues to expand– Genetic linkages have been identified for 6 autosomal

dominant and 11 autosomal recessive LGMDs, – Myofibrillar myopathies share several phenotypic

characteristics with the LGMDs.

Limb Girdle MDLimb Girdle MD

LGMD may show an autosomal recessive (autosomal dominant forms reported)

or sporadic method of inheritance.

Some forms of LGMD dramatically affect young adults, while other types progress so slowly that they are not detected until much later in life.

LGMD protein defects occur in several pathways

proteins associated with the sarcolemma

proteins associated with the contractile apparatus

Various enzymes involved in muscle function.

Autosomal recessive LGMDAutosomal recessive LGMD

This childhood form

Affects both males and females

First decade of life. In general

The course is of gradual progression over years.

Distribution of weakness is typically in the pelvis (80-90% of cases)

later in life, involvement of the shoulder girdle (30%)

No hypertrophy of the calves (contrast to other forms of MD

CPK: elevated (2-3 times)

The inheritance pattern is strongly autosomal recessive with consanguinity

Positive family history often is reported.

The abnormal gene is linked to chromosome arm 15q.

Autosomal recessive LGMDAutosomal recessive LGMD

Pelvifemoral atrophy Pelvifemoral atrophy (Leyden-Mobius)(Leyden-Mobius) Most heterogeneous of all limb-girdle dystrophies. 60-70% of cases are sporadic (few cases: familial)Symmetric or asymmetric involvement of the pelvic

girdle. Late onset : second to sixth decades. Slow progression clinical arrest (ambulate into 70s)

The survival rate: seventh decade of life.CPK: vary from normal to significant elevation. No identified gene yet.

Scapulo-humeral dystrophy (Erb) Scapulo-humeral dystrophy (Erb)

Involves mainly the upper extremities. Autosomal recessive in some cases. starts later in life (second to the fifth decades), “Benign” (years before it is diagnosed). Weakness generally is asymmetric: may spare the

deltoid, supra-spinatus, and infra-spinatus muscles. lower extremities involvement very late in life show The progression: very slow (normal life

expectancy). Minimal, disability

Late-onset autosomal myopathyLate-onset autosomal myopathy

Third to the fifth decades of life.

The course is benign

Upper & lower extremity weakness :little functional impairment.

Patients: ambulate well into their 6th and 7th decade

Affects males and females.

OculopharyngealOculopharyngeal

Late onset

Ocular and bulbar symptoms

Slowly progressing

autosomal-recessive disease

Severe proximal weakness at birth (or within 6/12) Slowly progressive or nonprogressive. Contractures are common

central nervous system (CNS) abnormalities can occur.

Biopsy: signs of dystrophy, a marked in endomysial and perimysial connective tissue, and fiber size variability with small round & immature fibers, less commonly, necrosis

No distinguishing features (as in congenital myopathies)

Congenital Muscular DystrophyCongenital Muscular Dystrophy

Congenital Muscular DystrophyCongenital Muscular DystrophyThe pathophysiology of CMD depend on specific

associated genetic defect (known with 4 of the CMDs)

Functions of the disrupted proteins: defined in 2:– Deficiency of laminin-alpha2 (merosin), a skeletal

muscle extracellular matrix protein that binds the dystrophin-associated glycoprotein complex (see Picture 1)

– Deficiency of integrin-alpha7 beta1, a skeletal muscle membrane protein that binds laminin-2

The pathophysiology of the other CMDs is unknown

Muscular dystrophyMuscular dystrophyCongenital

Duchenne, Becker

Emery-Dreifuss

Limb girdle

Distal myopathy : Miyoshi (1967, 1986)– Locus 2p13.3– DYSF gene mutation (Bashir et al ; Liu et al, 1998)

Type 2B limb girdle myopathy:– Firstly described in Palestinian families (Mahjneh et al,

1992)– Chromosome 2p linked (Bashir et al, 1994)

Both MM and LGMD phenotype in the same family (Illiaroshkin et al ; Weiler et al, 1996)

DysferlinopathiesDysferlinopathies

Distal myopathy : Miyoshi (1967, 1986)– Locus 2p13.3– DYSF gene mutation

(Bashir et al ; Liu et al, 1998)

Type 2B limb girdle myopathy:– Firstly described in Palestinian families

(Mahjneh et al, 1992)– Chromosome 2p linked

(Bashir et al, 1994)

Both MM and LGMD phenotype in the same family

(Illiaroshkin et al ; Weiler et al, 1996)

Geographical distributionMM identified in Japan LGMD (Palestinian, Lybian Jews)

Dysferlin mutation 1/3000 Lybian Jews (Argov et al, 2000)

Most frequent distal myopathy (except Scandinavia)LGMD2B= second cause of LGMD (Tagawa et al)Dysferlinopathies : about 25% of unindentified

muscular dystrophy

Dysferlinopathies: EpidemiologyDysferlinopathies: Epidemiology

Dysferlin is located to muscle cell membranes, and is missing in patients with severe limb girdle muscular dystrophy

Model

for the

function

of

Dysferlin

in

muscle

repair

AR inheritance Normal developmental milestones, sport possible prior to

first symptoms Onset between 15 – 35 y (young adults) LL : distal, proximo-distal, or proximal wk calf involvment

++ UL : biceps atrophy, moderate scapular involvment Facial, bulbar muscles = spared Normal cardiac and respiratory function CK (10 to 123 N) Unspecific myopathic pattern, necrosis, no vacuoles Various severity

Dysferlinopathies: Common traitsDysferlinopathies: Common traits

Distal myopathy– Posterior leg (Miyoshi myopathy)– Anterior leg compartment

Proximal myopathy « limb girdle » (LGMD2B)

High CPK

Polymyositis-like

Exercise intolerance

Dysferlin

Myotonic DystrophyMyotonic Dystrophy

Myotonic dystrophy Autosommal dominant disorder with highly variable

expression of the disease phenotypeThe molecular abnormality is an expansion of a

CTG nucleic acid triplet repeat sequence on the nineteenth chromosome

The muscle weakness can be mildMarked facial weakness, ptosisGreater distal weakness

Difficulty in releasing hand grip. At the bedside, myotonia

Frontal balding: usually more prominent in men

Premature cataracts, arrhythmias, diabetes, and testicular atrophy

Myotonia can be a disturbing symptom or does not

In disabling myotonia, quinine, Phenytoin, henytoin

Mexiletine should not be used if cardiac manifestations

Myotonic dystrophyMyotonic dystrophy

Type 1 (most common, 98%)– an expansion of CTG repeats in the DMPK gene on

chromosome 19– Prevalence in West: 13.5 per 100,000

Type 2– an expansion of CCTG repeats in the ZNF9 gene on

chromosome 3

Type 3 ?

Inflammatory MyopathiesInflammatory Myopathies- Age: young/adult- +/- Skin rash- Main feature: weakness + Muscle pain

+tenderness Investigations- High C.K.- EMG- Muscle biopsy

Diagnosis: Treatment Immune suppressive = steroids

Polymyosite

Maladie hépatique

CMT

Myopathie

métabolique

BMD

FSH

0 2 4 6 8 10 12 14 16

Err

an

ce d

iag

nosti

qu

e

Nombre de patients

Metabolic myopathies Metabolic myopathies

Thyroid disease Hypothyroid or hyperthyroid ophthalmopathy periodic paralysis Pituitary and adrenal disease Cushing's syndrome Steroid myopathy Adrenal insufficiency Primary hyperaldosteronism Acromegaly Hyperparathyroidism Hypoparathyroidism

MYASTHENIA GRAVISMYASTHENIA GRAVIS


DEFINITION: Disorder of the NMJ (postsynaptic membr)

Forms: Transient neonatal (~10% of neonate myasthenic mothers)

– Different prognosis, effective treatment

Congenital myasthenia Common myasthenia gravis

– Any age: 2 pics: 20-30 (F > M) & 60-70 M > F)– Usually progressing (remission are possible but: relapse later)


CLINICAL FEATURES - Onset: insidious- Fluctuating weakness: with exercise- Fatigability (worsening with exercise & improvement in rest)

- Precipitating factors: Infection, Pregnancy, stress, hot temperature, drugs: muscle relaxants, BZDZ,phenytoin antibiotics (neomycin)

Clinical presentation: - Ocular: – ptosis, diplopia opthalmoplegia- Bulbar: dysphagia, dysphonia, +/-facial weakness- Generalized: +/-respiratory muscles weakness risk of

death


Clsassification: Osserman classification

I ocular

II (A & B): mild to moderate generalised, ++/- drug response, no crises

III Acute fulminant + crises, risk of death, high mortality

IV late severe MG

Associated disorder:-- Dysthyroidism- Rh. Arthritis, P. anaemia, SLE

The Spectrum of autoimmune Diseases

Hashimoto’s thyroiditis Pernicious anaemia Insulin dependent diabetes

Myasthenia gravis Multiple sclerosis

Ulcerative colitisRheumatoid arthritis

Systemic lupus erythematous

Systemic Organ specific

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Neuromuscular junction transmission autoimmune disorder (Post synaptic membrane)

Destruction of the Ach. receptors on the post synaptic membrane by the AB insufficient muscle fibers contraction

Ach.receptor Anti-bodies: – circulating: level can be done– Origine: thymus (hyperplasia, thymoma)

association of HLA, A1 + B8.

Auto reactive T cell

Genetically predisposed

Tr

IL-6, etc

B cell

CD8

Tissue damage

Cytokines

Cytokines

Diagnosis Clinical presentation, excrcise test, rest test Tensilon Test: 10 mg Edrophonium IV carrefullty &

slowly Investigations

Investigations Laboratory Investigations.

– Acetycholine receptor antibodies level– Straited muscle AB, other antibodies

Neurophsiology– EMG: decrement test

Imaging: Chest x-ray and chest CT scan / MRI Others: PFT…..

MANAGEMENTMANAGEMENT

Medical treatment Anticholinesterase

Immunosupressant: Steroids

Azathioprin

Plasmaphoresis

Immunoglobulins

Surgery: Thymectomy

PrognosisPrognosis

Remission ~ 30 %.– More likely in patient with short history– Less in prominent thymic hyperplasia/thymoma

Approach through suprasternal or transsternal– (extensive, large thymectomy)

Medical treatment:

may be D/C, need for low doses, same doses

or worsening + other ttt

Myasthenic crisesMyasthenic crises

Severe situationNeeds urgent managementDiferentiate from cholinergic crises

Myasthenic syndromeMyasthenic syndrome

Clinically: differencesPathophysiology: presynaptic membraneNeurophsiology: increamentPoor response to Anti Ch-esterase Etiology: paraneoplastic

Documents

MUSCLES DISORDERS Definition: Diseases involving the muscle fibers (myogenic) Unlike: neuronopathies: secondary to LMN Heterogenous etiology, genotype,