Definition Refers to a group of hereditary MUSCULARprogressive diseases.

Muscular Dystrophy of DYSTROPHY affects muscular strength and action, some which first become obvious in infancy, and others which develop in adolescence or young adulthood.
The syndromes are marked 1.either generalized or localized muscle weakness 2.difficulties with walking or maintaining posture 3.muscle spasms 4.some instances, neurological, behavioral, cardiac, or other functional limitations.

PROGRESSIVE MUSCULAR DYSTROPHY

Type Onset Age (years) Clinical Features Other organ systems involved

Duchenne

Before 5

1.Progressive weakness of girdle muscles. 2.unable to walk after age 12 3.progressive kyphoscoliosis 4.Respiratory failure in 2dor 3d decade. 1.Progressive weakness of girdle muscles 2. able to walk after age 15. 1.3. respiratory failure may develop by 4th grade
Elbow contractures, humeral and perineal weakness Slow progressive weakness of shoulder and hip girdle muscles

Cardiomyopathy Mental impairment

Becker 5-25yr

early childhood to adult

Cardiomyopathy

EmeryDreifuss Limb-Girdle

Childhood to adult early childhood to adult

Cardiomyopathy Cardiomyopathy

Progressive Muscular Dystrophy

Type Congenital Onset Age (years) Clinical Features Other organ systems involved CNS and Eye abnormalities At birth or within .Hypotonia, contractures, 1st few months delayed milestones Progression to respiratory failure in some cases Before age 20 Slowly progressive weakness of face, shoulder girdle, and foot dorsiflexion Slowly progressive weakness of extraocular, pharyngeal, and limb muscles Slowly progressive weakness of face, shoulder girdle, and foot dorsiflexion

Facioscapulohu meral

Deafness Coats (eye) disease

Oculopharynge al

5th to 6th decade

______

Myotonic

Usually 2nd decade May be infancy if mother affected

Cardiac conduction defects Mental impairment Cataracts Frontal baldness Gonadal atrophy

PATHOPHYSIOLOGIC
THE EXACT MECHANISM IS UNKNOWN, BUT THERE ARE 3 THEORIES

Vascular theory: the lack of blood flow causes the typical degeneration of muscle tissue. Neurogenic theory: Disturbance in nerve-muscle interaction. Membrane theory: the cell membranes are genetically altered, causing a compromise in cell integrity. An increase in the activity of muscle proteolytic enzymes may accompany the membrane alteration. Leaving the muscle cell vulnerable to degeneration.

TYPES

Duchenne MD DMD Dystrophinopathy Xp21 Becker MD BMD Dystrophinopathy Xp21 Emery-Dreifuss MD EDMD Xq28 Dominant Emery-Dreifuss MD AD-EDMD 1q11 Limb-girdle MD type 1A LGMD1A 5q Limb-girdle MD type 1B LGMD1B 1q11 Limb-girdle MD type 1C LGMD1C p25 Limb-hirdle MD type 1D LGMD1D 6q22 Limb-girdle MD type 1E LGMD1E 7q Limb-girdle MD type 2A LGMD2A Calpainopathy 15q15 Limb-girdle MD type 2B LGMD2B Dysferlinopathy 2p13 Miyoshi myopathy MM Dysferlinopathy 2p13 Miyoshi-type MD MMD 10

MUSCULAR DYSTROPHY TYPES AND GENES

-Sarcoglycanopathy SGCA LGMD2D, SCARMD2 -Sarcoglycanopathy SGCB LGMD2E -Sarcoglycanopathy SGCC LGMD2C, SCARMD1 -Sarcoglycanopathy SGCD LGMD2F Limb-girdle MD type 2G LGMD2G Limb-girdle MD type 2H LGMD2H Limb-girdle MD type 2I LGMD2I Merosin-negative congenital MD Congenital MD with rigid spine Fukuyama congenital MD FCMD Congenital Myopathy (or ?MD) Facioscapulohumeral MD FSHD Myotonic dystrophy DM Myotonic dystrophy type 2 DM2 Oculopharyngeal MD OPMD Epidermolysis bullosa simplex MD-EBS

17q21 4q12 13q12 5q33 17q11 9q31 19q13-3 6q22 1p35 9q31 12q13 4q35 19q13 3q 14q11

MUSCULAR DYSTROPHIES
Duchennes

Muscular Dystrophy Beckers Muscular Dystrophy Emery- Dreifuss Dystrophy Facioscapulohumeral Dystrophy Scapuloperoneal Syndrome Oculopharyngeal Dystrophy Congenital Muscular Dystrophies Kearns-Sayre Syndrome Myotonic Dystrophy Limb-Girdle Muscular Dystrophies

DUCHENNES MUSCULAR DYSTROPHY

Also

called Pseudohypertrophic muscular dystrophy. X linked recessive disorder Incidence : 30 per 1,00,000 live born males No abnormality is usually obvious at birth During 2nd year , when boys begin walking , the early clumsiness is seen. Soon , the child needs to place one hand on the knee to assume an upright position when rising from the floor( GOWERS MANEUVER )

DUCHENNES MUSCULAR DYSTROPHY

The

iliotibial bands & heel cords are the first to become tight. By 5- 6 yrs of age, stair climbing becomes labored,and children use railing to pull themselves upward. At the age of 6-7 yrs , the boys often complain of sudden spontaneous falls. At 8-10 yrs of age, affected children cease to be able to climb stairs or stand up from floor and it is almost this time by which they begin to use wheel chair.

DUCHENNES MUSCULAR DYSTROPHY

Contractures of hips,knees & ankles become severe when relatively untreated child spends much of the day in wheelchair. Hips & Knees are locked at 90 degrees & feet turn downward & inward in an exaggerated position of equinovarus. With , development of severe scoliosis, resp fn becomes compromised . Cardiac inv : degeneration & fibrosis of posterolateral wall of lt.ventricle Mental impairment is common. IQ is 1 SD below the mean.

DUCHENNES MUSCULAR DYSTROPHY

By 16-18 yrs , pts are predisposed to fatal pulmonary infections. Affected children die either from resp.failure or cardiomyopathy that is resistant to treatment. Other causes : aspiration & acute gastric dilatation.

DUCHENNES MUSCULAR DYSTROPHY

Duchenne dystrophy is caused by a mutation of the gene that encodes dystrophin, a 427-kDa protein localized to the inner surface of the sarcolemma of the muscle fiber . It is localized to the short arm of the X chromosome at Xp21. The most common gene mutation is a deletion.

DIAGNOSIS

DNA studies looking for deletion in dystrophin gene - the least invasive test to confirm the diagnosis. 30 % of pts in whom deletion is not found , Muscle Biopsy is required to establish absence of dystrophin. Serum.CK levels markedly elevated (>10000 mU/ml ) EMG myopathic changes Muscle Biopsy : variation in the size of the fibres, fibrosis, groups of basophilic fibres & opaque / hypercontracted fibres (hyaline fibres) Western blot analysis of muscle biopsy specimens, revealing abnormalities on the quantity and molecular weight of dystrophin protein. Immunocytochemical staining of muscle with dystrophin antibodies can be used to demonstrate absence or deficiency of dystrophin localizing to the sarcolemmal membrane.

TREATMENT

Physical Therapy : aim : to keep joints as loose as possible. Commenced at 3-4 yrs of age , when parents are taught to stretch childs heel cords, hip flexors, iliotibial bands on daily basis. Night splints can be considered Bracing : appropriate use of bracing delay childs progression to wheelchair by approx 2yrs Surgery : Reconstructive surgery of the leg often accompanies bracing. The purpose : to keep leg extended & prevent contractures of iliotibial bands & hip flexors . Percutaneous tenotomies of Achilles tendon, knee flexors, hip flexors and iliotibial bands. Pharmacological : Prednisolone improves muscle strength & fn ( 3 yrs . Deflazacort synthetic steroid .

BECKERS MUSCULAR DYSTROPHY

Less severe form of X-linked recessive muscular dystrophy results from allelic defects of the same gene responsible for Duchenne dystrophy Incidence : 3 per 1,00,000 live born males. The pattern of muscle wasting in Becker muscular dystrophy closely resembles that seen in Duchenne. Proximal muscles, especially of the lower extremities, are prominently involved. As the disease progresses, weakness becomes more generalized Hypertrophy of muscles, particularly in the calves, is an early and prominent finding.

BECKERS MUSCULAR DYSTROPHY

Pts first experience difficulties b/w age 5 -15 yrs Onset can also occur in 3rd or 4th decade or even later. Pts with Becker dystrophy walk beyond age 15, while patients with Duchenne dystrophy are typically in a wheelchair by the age of 12. Frequent complaint in teenagers with BMD is leg cramps & muscle pains Significant proportion of these pts have cardiomyopathy . Some present with heart failure only . Others : hyper CK emia, myalgia without weakness & myoglobinuria.

DIAGNOSIS & TREATMENT

Western

blot analysis of muscle biopsy: reduced amount or abnormal size of dystrophin Mutation analysis of DNA from peripheral blood leukocytes Quantification of dystrophin in muscle as in BMD , dystrophin may not be absent but reduced in amount / abnormal in size. Treatment : less aggressive physiotherapy , corticosteroids , bracing genetic counscelling

EMERY DREIFUSS DYSTROPHY

Emerin deficiency( a lamina associated structural protein ) X linked recessive disease Responsible gene on long arm of X chromosome, close to centromere Clinical features : Wasting & weakness of upper arms, shoulders, ant.compartment muscles in legs. Associated contractures,early in elbows, posterior part of neck, paraspinal muscles & achilles tendon Elbow contractures are characteristic Slowly progressive Cardiac complications frequent Conduction block, atrial paralysis , sudden cardiac death Female carriers may develop cardiac abn at a later age. Severity of cardiac complications increase with age

EMERY DREIFUSS DYSTROPHY

EMERY DREIFUSS DYSTROPHY DIAGNOSIS & TREATMENT

Diagnosis

: DNA Studies : to demonstrate defect in the gene Skin Biopsy : to demonstrate absence of emerin Muscle Biopsy EMG S.CK elevated ECG repeated at regular intervals Treatment Cardiac pacemaker Supportive care for the neuromuscular disability

FACIOSCAPULOHUMERAL DYSTROPHY
Autosomal dominant disease Responsible gene end of long arm of chromosome 4 Genetic abnormality deletion Severity of illness related to size of deletion: smallest fragments severe disease Onset : childhood / young adulthood

FACIOSCAPULOHUMERAL DYSTROPHY

Clinical features : Facial weakness is the initial manifestation inability to smile,whistle,fully close the eyes Weakness of shoulder girdles usually brings pt to medical attention Loss of scapular stabilizer muscles makes arm elevation difficult. Scapular winging with attempts at abduction & forward movement of arms. Biceps & triceps severely affected with relative sparing of deltoid muscles. Weakness worst for wrist extension Weakness of ant.compartment muscles of legs footdrop Weakness of hip flexors , quadriceps , ankle dorsiflexors + But plantar flexors strength is preserved Children might lose ability to walk by 9-10 yrs.

ACIOSCAPULOHUMERAL
Extreme

DYSTROPHY

lumbosacral lordosis seen when child walks / stands. Associated with labile htn, nerve deafness and coats disease. Diagnosis : DNA studies EMG Muscle Biopsy: tiny fibres scattered throughout / scattered inflammatory cellular cellular foci associated with muscle fibres S.CK levels: elevated

FACIOSCAPULOHUMERAL DYSTROPHY
Treatment : Supportive If pt unable to lift arms above head surgical stabilization of scapula Ankle-foot orthoses footdrop Surgical transposition of posterior tibial tendon to dorsum of foot for pts with marked intorsion of foot while walking

SCAPULOPERONEAL SYNDROME
Autosomal

dominant disease / X linked recessive pattern Weakness of shoulder muscles & ant.compartment of lower legs early symptoms Weak ankle dorsiflexors but strong plantar flexors Facial weakness minor Often , pt present with foot drop & shoulder weakness Treatment : ankle foot orthoses and other supportive treatment

OCULOPHARYNGEAL DYSTROPHY
Autosomal dominant disorder Hallmark of illness presence of small intranuclear tubulofilaments. These occur as palisading filamentous inclusions Clinical Features : Begins at 30-40 yrs with weakness of eye muscles & mild ptosis Ptosis asymmetrical initially, as muscles weaken, both lids become severe ptotic , eye movements are diminished in all directions. Later , pt develops difficulty in swallowing. Death starvation , emaciation pneumonia following aspiration

OCULOPHARYNGEAL DYSTROPHY

Diagnosis : Muscle Biopsy : muscle fibres contain rimmed vacuoles By electron microscopy : membranous whorls, accumulation of glycogen & other nonspecific debris related to lysosomes EMG typical myopathic S.CK Elevated Tensilon test & repetitive nerve stimulation test for abn fatigue of evoked potential to differentiate from myasthenia gravis Treatment : Supportive Swallowing difficulties : initially managed by taking soft diet. Later nasogastric tube , gastrostomy.

CONGENITAL MUSCULAR DYSTROPHIES

A group of diseases that often appear at birth with hypotonia & severe trunk & limb weakness. Contractures of joints are prominent particularly at ankle, knees & hips MR may be present MRI brain increase in signal from the white matter in many pts. All are autosomal recessive They are 1. Merosin deficiency 2. Fukuyama type muscular dystrophy 3. Walker-Warburg disease 4. Muscle-eye-brain disease of Santavuori

MEROSIN DEFICIENCY

Laminin alpha 2 , formerly known as merosin found in basement membrane It is found in muscle as well as skin & nerve. Onset in infancy Severe weakness of trunk & limbs and hypotonia at birth. Extraocular muscles & face spared Prominent contractures of feet & hips MR may be + MRI increased signal from white matter in T2 weighted images Lab invg : S.CK Elevated EMG Slowed nerve conduction velocities Diagnosis : demonstration of alteration of laminin alpha 2 in muscle muscle / skin biopsy demonstration of abn gene on chr 6

FUKUYAMA TYPE MUSCULAR DYSTROPHY

Autosomal recessive disease Responsible gene chr 9q31-33 Clinical features : Normal at birth Some are floppy, joint contractures in 70% pts by age of 3 months hip & knee Children severely mentally retarded Weakness is diffuse & disabling child never learns to walk Diagnosis : S.CK elevated Muscular biopsy : dystrophic changes with variability in size of fibres and fibrosis CT Scan presence of lucencies in frontal areas

WALKER- WARBURG SYNDROME MUSCLE-EYE-BRAIN DISEASE

Combination

of muscular dystrophy, lissencephaly,cerebellar malformations and severe retinal and eye malformations Walker-Warburg - death within first 2 yrs. eye changes severe microphthalmia, coloboma, cong.cataract, glaucoma, corneal opacities, retinal dysplasia, hypoplastic vitreous, optic atrophy Muscle-eye-brain disease milder illness, high myopia, preretinal membrane / gliosis, but severe eye stuctural abn of eye are not present

KEARNS-SAYRE SYNDROME

Belongs to the group Mitochondrial myopathies Due to large deletion in mitochondrial DNA. Severity depends on ratio of mitochondria with deletions to normal mitochondria It is almost always a sporadic disease Clinical features : Progressive external ophthalmoplegia May start in childhood / adult life progress to total immobility of eyes. Associated with retinitis pigmentosa Presence of mitochondrial abn in striated muscle & other tissues Cerebellar incoordination & nerve deafness MR + short stature Cardiac conduction defects sudden cardiac death

KEARNS-SAYRE SYNDROME
Diagnosis : Muscle biopsy : numerous ragged-red fibres in trichrome stain against relatively normal muscle CSF protein elevated CSF folate reduced Treatment : Thiamine, folate, riboflavin, carnitine, ubiquinone, methionine

MYOTONIC DYSTROPHY
Also

known as dystrophia myotonica Composed of 2 clinical disorders with overlapping phenotypes & distinct molecular genetic defects : 1. DM1- the classic disease 2. DM2- proximal myotonic myopathy Autosomal dominant disease Responsible gene chr 19q13.3 CTG trinucleotide repeats

MYOTONIC DYSTROPHY
CLINICAL FEATURES
Hatchet-faced appearance d/t temporalis, masseter, facial muscle atrophy & weakness Frontal baldness Neck muscles, sternocleidomastoids & distal limb muscles involved early Weakness of wrist & finger extensors, intrinsic muscles of hand Ankle dorsiflexors weakness foot drop Proximal muscles remain strong all throughout the course of disease Palatal,pharyngeal & tongue inv produce a dysarthric speech, nasal voice & swallowing problems Diaphragm & intercostal muscle weakness resp insuff

MYOTONIC DYSTROPHY
CLINICAL FEATURES
Myotonia appears by age 5 yrs percussion of thenar eminence , tongue, wrist extensor muscles Myotonia causes slow relaxation of hand grip after a forced voluntary closure Cardiac disturbances common in DM1 1st degree heart block, complete heart block, sudden cardiac death MVP is common Intellectual impairment, hypersomnia, posterior subcapsular cataract, gonadal atrophy, insulin resistance, decreased esophageal & colonic motility

MYOTONIC DYSTROPHY
CLINICAL FEATURES
Congenital myotonic dystrophy more severe form of DM1 - severe facial & bulbar weakness, transient neonatal respiratory insufficiency & mental retardation DM2 distinct pattern inv of muscles proximal muscles Lab Invg : S.CK Normal / mildly elevated EMG evidence of myotonia in DM1 but more patchy in DM2 Muscle Biopsy : muscle atrophy involves type 1 fibres in 50% of cases & ringed fibres in DM1 but not in DM2.

MYOTONIC DYSTROPHY TREATMENT

treatment ankle foot orthoses to treat foot drop Breathing exercises & postural drainage in severe myotonia to ward off frequent respiratory infections. Quinine, phenytoin, procainamide, mexiletine & acetazolamide to treat myotonia Cardiac pacemaker- in pts with unexplained syncope, conduction system defects.
Supportive

LIMB-GIRDLE MUSCULAR DYSTROPHIES

Both males & females are affected Onset ranging from late in 1st decade to 4th decade Progressive weakness of pelvic & shoulder girdle musculature. Respiratory insufficiency , cardiomyopathy Presently there are 5 autosomal dominant & 10 autosomal recessive disorders

AUTOSOMAL DOMINANT LGMDS

LGMD1A Onset 3rd 4th decade muscle weakness- distal limb muscles, vocal cords, pharyngeal muscles lab: S.CK- elevated EMG Mixed myopathy/neuropathy NCS Normal gene - myotilin

AUTOSOMAL DOMINANT LGMDS

LGMD1B : Onset 1st -2nd decade proximal lower limb weakness cardiomyopathy conduction defects lab: S.CK Elevated NCS Normal EMG myopathic gene lamin A/C

AUTOSOMAL DOMINANT LGMDS

LGMD1C : Onset early childhood proximal weakness, gowers sign, calf hypertrophy, exercise related muscle cramps Lab: S.CK elevated NCS Normal EMG myopathic gene caveolin -3 LGMD1D Onset 3rd 5th decade proximal muscle weakness, cardiomyopathy, arrhythmias Lab : S.CK elevated NCS Normal EMG Myopathic locus chr7q LGMD1E childhood onset , proximal weakness Lab: S.CK Normal, NCS Normal , EMG Myopathic locus chr 6q23

AUTOSOMAL RECESSIVE LGMD

LGMD2A

: Onset 1st -2nd decade tight heel cords, contractures at elbows, wrists, fingers, rigid spine proximal & distal weakness Lab: S.CK elevated NCS Normal EMG Myopathic gene Calpain -3

AUTOSOMAL RECESSIVE LGMD

LGMD2B : Onset 2nd 3rd decade proximal muscle weakness at onset & later distal muscles Miyoshi myopathy a variant Lab: S.CK Elevated NCS Normal EMG Myopathic gene dysferlin

AUTOSOMAL RECESSIVE LGMD

LGMD2C-F : Onset childhood teenage similar to duchenne , cognition - normal cardiomyopathy uncommon Lab : S.CK- Elevated NCS Normal EMG Myopathic

AUTOSOMAL RECESSIVE LGMD

LGMD2G : Onset -10 to 15 yrs proximal & distal muscle weakness LGMD2H : onset 1st to 3rd decade proximal muscle weaknes LGMD2I : Onset 1st 3rd decade similar to duchenne , cognition normal rarely cardiomyopathy LGMD2J : Onset 1st 3rd decade proximal lower limb weakness, mild distal weakness LAB: S.CK Elevated NCS Normal EMG - Myopathic

SIGNS AND SYMPTOMS

They vary according to the type of muscular dystrophy. In general, they may include: Muscle weakness Apparent lack of coordination Progressive crippling, resulting in contractures of the muscles around your joints and loss of mobility Many specific signs and symptoms vary from among the different forms of MD. Each type is different in the age of onset, what parts of the body the symptoms primarily affect and how rapidly the disease progresses.

SIGNS AND SYMPTOMS CONT..

Dystrophinopathies These types of muscular dystrophies are due to a genetic deficiency of the protein dystrophin.

SYMPTOMS
Muscle weakness Delayed development of muscle motor skills Problems walking (delayed walking) Difficulty using one or more muscle groups (depends on the type of dystrophy) Eyelid drooping (ptosis) Drooling Hypotonia Mental retardation ( only present in some types of MD) Joint contractures (clubfoot, clawhand or others) Scoliosis

SIGNS AND TESTS

Examination and history help to distinguish the type of MD. Specific muscle groups are affected by different types of MD. Often, there is a loss of muscle mass (wasting), which may be disguised in some types of muscular dystrophy by an accumulation of fat and connective tissuethat makes the muscle appear larger (pseudohypertrophy). Joint contractures are common.

Shortening of the muscle fibers, fibrosis of the connective tissue and scarring slowly destroy muscle function. Some types of MD involve the heart muscle, causing cardiomyopathy or arrhythmias.
A muscle biopsy may be the primary test used to confirm the diagnosis. In some cases a DNA test from the blood may be sufficient.

LABORATORY TEST
Muscle biopsy: the primary test used to confirm the diagnosis. DNA test Serum CPK (creatine phosphokinase-an enzyme found in muscle) may be elevated. EMG (electromyography) may confirm that weakness is caused by destruction of muscle tissue rather than damage to nerves. ECG (electrocardiography) to monitor changes in cardiac status. Myoglobin - urine/ serum: When muscle is damaged, the myoglobin is released into the bloodstream. It is filtered out of the bloodstream by the kidneys, and eliminated in urine. In large quantities, myoglobin can damage the kidney and break down into toxic compounds, causing kidney failure.

LDH: LDH is most often measured to evaluate the presence of tissue damage. The enzyme LDH is in many body tissues, especially the heart, liver, kidney, skeletal muscle, brain, blood cells, and lungs. Creatinine : A normal (usual) value is 0.8 to 1.4 mg/dl. Creatinine is a breakdown product of creatine, which is an important constituent of muscle. A serum creatinine test measures the amount of creatinine in the blood. Greater-than-normal levels may indicate: Muscular dystrophy. Lower-than-normal levels may indicate: Muscular dystrophy (late stage) AST: The normal range is 10 to 34 IU/L. An increase has many indications, one of them being progressive MD. Aldolase: Why the test is performed? ofmuscle damage. This test is indicator