Muscular Dystrophies

1. Muscular Dystrophies Dr.Vemuri Chaitanya

2. Muscular Dystrophies A group of primary muscle disorders that have a heriditary basis. They occur at all ages with varying degrees of severity . Muscular dystrophy refers to a group of hereditary progressive diseases each with unique phenotypic and genetic features

3. Muscular Dystrophies Duchenne�s Muscular Dystrophy Becker�s Muscular Dystrophy Emery- Dreifuss Dystrophy Facioscapulohumeral Dystrophy Scapuloperoneal Syndrome Oculopharyngeal Dystrophy Congenital Muscular Dystrophies Kearns-Sayre Syndrome Myotonic Dystrophy Limb-Girdle Muscular Dystrophies

4. Duchenne�s 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( GOWER�S MANEUVER )

6. Duchenne�s 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.

7. Duchenne�s 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.

8. Duchenne�s 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.

9. Duchenne�s 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.

11. 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.

12. Treatment Physical Therapy : aim : to keep joints as loose as possible. Commenced at 3-4 yrs of age , when parents are taught to stretch child�s heel cords, hip flexors, iliotibial bands on daily basis. Night splints can be considered Bracing : appropriate use of bracing � delay child�s 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 .

13. Becker�s 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.

14. Becker�s 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.

15. 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

16. 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

17. Emery � Dreifuss Dystrophy

18. Emery � Dreifuss DystrophyDiagnosis & 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

19. 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

20. 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.

23. Facioscapulohumeral Dystrophy Extreme 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

24. 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

25. 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

26. 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

27. 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.

28. 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

30. 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

31. 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

32. Walker- Warburg SyndromeMuscle-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

33. 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

34. 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

35. 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

36. Myotonic Dystrophyclinical 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

39. Myotonic Dystrophyclinical 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

40. Myotonic Dystrophyclinical 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.

41. Myotonic DystrophyTreatment Supportive 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.

42. 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

43. 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

44. 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

45. Autosomal dominant LGMDS LGMD1C : Onset � early childhood proximal weakness, gower�s 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

46. 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

47. 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

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

49. 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

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