Muscular dystrophies

MUSCULAR DYSTROPHIES

By,K.PRIYANGACRRI

Muscular dystrophy refers to a group of hereditary progressive diseases each with unique phenotypic and genetic features.

TYPES :

Classification

Sex-linked: DMD, BMD, EDMDAutosomal recessive: LGMD, infantile

FSHDAutosomal dominant: FSHD, distalMD,

ocular MD, oculopharyngeal MD.

DUCHENNE MUSCULAR DYSTROPHY

Also called Pseudo Hypertrophic muscular dystrophy

X LINKED RECESSIVE disorder INCIDENCE : 1 in 5200 live births MALES

PATHOGENESIS

single gene defectXp21.2 regionabsent

dystrophin(Kunkel discovered dystrophin gene)

Guillaume Benjamin Amand Duchenne

(French neurologist, 1860s)

PATHOGENESIS

CLINICAL FEATURES

Apparent by ages 3 and 5 years Frequent falls while playing,running, jumping and hopping By 5 years , muscle weakness is obvious- Gowers' maneuver, toe

walking is associated with a lordotic posture. Loss of muscle strength is progressive (proximal limb muscles and the

neck flexors and leg involvement more) By 8 and 10 years -walking may require the use of braces By 20 yrs -wheelchair dependent. Progressive scoliosis often develops associated with pain which impairs

pulmonary function.

Contd..

By 1 6 一 1 8 years , predisposed to fatal pulmonary infections. Other causes of death include aspiration of food and acute gastric dilation.

Cardiac cause of death is uncommon despite the presence of a cardiomyopathy in almost all patients. CCF and arrhythmias are rare

Intellectual impairment is common

GOWER’S MANEUVER :

LAB DIAGNOSIS :

Serum CK levels : elevated between 20 and 100 times normal.

EMG : features typical of myopathy.

Muscle biopsy : muscle fIbers of varying size as well as small groups of neιrotic and regenerating fIbers. Connective tissue and fat replace lost muscle fIbers.

Biopsy of muscle tissue or mutation analysis on peripheral blood leukocytes by Western blot analysis

Immunocytochemical Staining : dystrophin antibodies can be used to demonstrate absence or defIciency of dystrophin localizing to the sarcolemmal membrane.

TREATMENT :

PREDNISOLONE – 0.75mg/kg given daily for a period of 3 yrs but often reduced due to side effects

Physical therapy Assisted devices Surgery

Peter Emil Becker (German doctor, 1950s)

BECKER’S MUSCULAR DYSTROPHY

Less severe form of X-linked recessive muscu1ar dystrophy It is 10 times less frequent than Duchenne. Proxima1 muscles especially of the 1ower extremities are

prominently invo1ved then it becomes more generalized. Hypertrophy of muscles of ca1ves is an early and prominent finding Patients with Becker dystrophy wa1k beyond age 15 Menta1 retardation may occur Cardiac invo1vement occurs in Becker dystrophy and may result in

heart failureLAB DIAGNOSIS : Western blot ana1ysis of muscle biopsy

shows reduced amount or abnorma1 size of dystrophin Genetic testing revea1s de1etions or duplications of the dystrophin

gene in 65% of patients

EMERY-DREIFUSS MUSCULAR DYSTROPHY

X-linked recessive Xq28 Emerin protein

CLINICAL FEATURES : Prominent contractures in early childhood and teenage years often preceding muscle weakness. Muscle weakness affects humeral and peroneal muscles at first and later

spreads to a limb-girdle distribution. Cardiomyopathy is potentially life threatening and may result in sudden

death.

LAB DIAGNOSIS : Serum CK may be elevated two- to tenfold. o EMG is myopathic.o Muscle biopsy usually shows nonspecific dystrophic features， Immunohistochemistry reveals absent Emerin

TREATMENT : Supportive care Stretching of contractures Manage cardiac complications

LIMB GRIDLE MUSCULAR DYSTROPHY

Autosomal recessive at chromosome 15q

Autosomal dominant at 5q

CLINICAL FEATURES : Age of onset: 3rd decade Initial: pelvic/shoulder muscles

(proximal to distal) Similar distribution as DMD

LAB DIAGNOSIS : Same as DMD/BMD carriers Moderately elevated CPK Normal dystrophin

FASCIOSCAPULOHUMERAL MUSCULAR DYSTROPHY/Landouzy Dejerine MDo Etiology : Autosomal dominant - Gene defect (FRG1) Chromosome 4q35 Epidemiology - Female > male

Clinical manifestation : Age of onset: late childhood/ early adult No cardiac, CNS involvement Winging scapula –ANGEL WING APPEARANCE Markedly decreased shoulder flexion & abduction Horizontal clavicles Rare scoliosis

“Popeye” appearance Lack of facial mobility Incomplete eye closure Pouting lips Transverse smile Absence of eye and forehead

wrinkles

OCULOPHARYNGEAL MUSCULAR DYSTROPHY

Autosomal dominant Age of onset: 3rd decade Characterized by progressive external ophthalmoplegia and

Ptosis Pharyngeal involvement – Dysarthria,Dysphasia,Repetitive

regurgitation,Frequently choking The molecular defect is a subtle expansion of a modest

polyalanine repeat tract in a poly-RNA-binding protein (PABP2) in muscle.

TREATMENT : Cricopharyngeal myotomy may improve swallowing, although it does not prevent aspiration. Eyelid crutches can improve vision when ptosis obstructs vision

MYOTONIC DYSTROPHY/Dystrophia myotonica

Myotonic dystrophy type 1 (DM l )- classic disease originally described by Steinert

Myotonic dystrophy type 2 (DM2) -proximal myotonic myopathy (PROMM).CLINICAL FEATURES : o Hatchet-faced Appearance - temporalis,masseter and facial muscle

atrophyo Neck muscles and sternocleidomastoids and distal limb muscles are involved

early- SWAN NECK APPEARANCEo Weakness of wrist extensors ,finger extensors and intrinsic hand muscleso Ankle dorsiflexor weakness may cause footdrop.. o Palatal pharyngeal and tongue involvement produce a dysarthric

speech ,nasal voice and swallowing problems. o Diaphragm and intercostal muscle weakness resulting in respiratory

insufficiency.

Contd…

o Myotonia which usually appears by age 5 years DEMONSTARTED by percussion of the thenar eminence,the tongue and wrist extensor

muscles. It causes a slow relaxation of hand grip after a forced voluntary closure. o Cardiac disturbances occur commonly in patients with DMl . ECG

may show first-degree heart block .Complete heart block and sudden death can occur. CCF occurs infrequendy but may result in cor pulmonale secondary to respiratory failure. Mitral valve prolapse also occurs commonly

o TREATMENT : Phenytoin and Mexiletine Cardiac pacemaker Ankle foot prosthesis

CONGENITAL MUSCULAR DYSTROPHY Etiology -Autosomal

recessive

SUMMARY

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