Muscular dystrophy

JPC SYSTEMIC PATHOLOGY

MUSCULOSKELETAL SYSTEM

March 2019

M-M06

 

Signalment (JPC #2984049): Two-year-old male weimaraner, Canis familiaris

 

HISTORY: This dog was thin with atrophy of all muscles except those of the neck and tongue. At necropsy, neck muscles were thick, giving a “buffalo hump” appearance. The diaphragmatic muscle surrounding the central tendon was pale and 1.5 cm thick. The body muscle mass was reduced and muscles were diffusely pale.

 

HISTOPATHOLOGIC DESCRIPTION: Skeletal muscle, diaphragm: The diaphragm is diffusely thickened (up to five times normal when compared with the control tissue), with disorganized, shortened myofibers that vary significantly in size and orientation. Diffusely, myocytes undergo one of the following changes: degeneration, necrosis, rare regeneration, or hypertrophy. Multifocally, degenerate myocytes are characterized by swollen and vacuolated sarcoplasm with loss of cross-striations; necrotic myocytes exhibit shrunken, angular, hypereosinophilic, fragmented sarcoplasm, with contraction bands, pyknotic nuclei, multifocal mineralization and scattered infiltration by moderate numbers of macrophages; and regenerative myocytes contain small amounts of basophilic sarcoplasm and numerous linearly arranged internalized nuclei ("rowing") with prominent satellite cell nuclei at the cell margins. Remaining myocytes are often hypertrophic with abundant sarcoplasm and several internalized nuclei. Multifocally, there is loss of myofibers with replacement by fibrous connective tissue, often surrounding atrophied myofibers, which exhibit shrunken, hypereosinophilic sarcoplasm. Multifocally the endomysial and perimysial connective tissue is expanded by moderate amounts of collagenous connective tissue and fibroblasts (fibrosis) admixed with few lymphocytes and plasma cells. There is multifocal infiltration of adipocytes.

 

Skeletal muscle, diaphragm, unaffected age-matched control: No significant lesions.

MORPHOLOGIC DIAGNOSIS: Skeletal muscle, diaphragm: Myocyte degeneration, necrosis, regeneration, and hypertrophy, diffuse, severe, with fibrosis and mineralization, weimaraner, (Canis familiaris), canine.

 

ETIOLOGIC DIAGNOSIS: Congenital muscular dystrophy

 

CAUSE: X-linked dystrophin gene deficiency

GENERAL DISCUSSION:

·      Muscular dystrophies are a heterogenous group of hereditary disorders with signs of progressive muscular weakness

·      Lesions are characterized by ongoing muscle fiber degeneration, necrosis, hypertrophy, and regeneration +/- interstitial connective tissue proliferation

·      Progressive muscular weakness can lead to respiratory and/or cardiac failure

·      In late disease, muscle fibers are replaced by fibrosis and fat

·      Animal models have similar protein and genetic defects to the diseases in humans, creating similar pathology, but the clinical course often differs

 

PATHOGENESIS:

·      Hereditary muscular dystrophy (X-linked recessive trait)

·      Duchenne muscular dystrophy and Becker muscular dystrophy (milder form) are the most common forms of muscular dystrophy in humans and is associated with defects in the dystrophin gene

·      mdx mouse and xmd dog are animal models for Duchenne muscular dystrophy

·      Absence or genetic mutations of the gene for the cytoskeletal protein dystrophin

·      Dystrophin anchors cytoskeletal actin to extracellular laminin and is believed to maintain myocyte membrane integrity during contraction

·      Absence of dystrophin allows gaps to develop in the myocyte membrane; resulting in calcium influx and hypercontraction, degeneration, and necrosis

·      Merosin (laminin alpha 2)-deficient congenital muscular dystrophy

·      Autosomal recessive inheritance

·      Mouse homozygous recessive model dko

·      Absence of merosin, one of three laminin subunits found in basement membrane of muscle fibers and Schwann cells

·      Unique feature in the mouse model is abnormal myelination of ventral spinal nerve root fibers, aggregates of unmyelinated axons, and lack of Schwann cells

·      Hereditary muscular dystrophy in chickens

·      Autosomal dominant trait, defect in ubiquitin ligase gene (WWP1)

·      Progressive loss of type-2 (fast twitch) white muscle fiber function

·      Superficial pectoralis (large breast muscle) most severely affected

 

TYPICAL CLINICAL FINDINGS:

·      mdx mice: Minimal muscle weakness; tremors and mild incoordination; high serum creatine kinase

·      Canine X-linked muscular dystrophy (xmd) Golden Retrievers: Rapid progression between 3-6 months of age and disease may stabilize at 8-12 months; limb weakness; stiff, shuffling gait and muscular atrophy; inability to open jaws; death from cardiac or respiratory failure; clinical signs similar to DMD in man; markedly elevated serum creatine kinase (CK) and asparate aminotransferase (AST)

·      Hypertrophic feline muscular dystrophy (HFMD): Dystrophin deficiency in cats manifests as muscle hypertrophy, tongue protrudes due to glossal hypertrophy

·      Dystrophic chickens: Inability to turn over when placed on back because of wing/pectoral muscular weakness (type-2 muscle)

·      Markedly elevated CK

 

TYPICAL GROSS FINDINGS:

·      mdx mice: Externally normal, with no apparent muscle wasting

·      Canine X-linked muscular dystrophy (xmd): Generalized muscular wasting, firm, thick, contracted muscles with fibrosis, splayed limbs, contracted joints; animals with fulminant neonatal disease have severe degeneration of diaphragm and other muscles with white streaks in muscle

·      Dystrophic chickens: White streaks in muscle bundles; tough or rubbery muscle

·      Dystrophin deficiency results in muscle atrophy in most dog breeds, but causes hypertrophy in the Rat Terrier breed, and in mice and cats

·      Merino sheep: affected muscles pale and may be grey, hard, and atonic

·      Vastus intermedius, soleus, anconeus, medial head of the triceps most affected

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      DMD and other muscular dystrophies: Myofiber degeneration, regeneration, endomysial fibrosis; mineralization; internalized nuclei; variation in fiber diameter with marked hypertrophy of type-1 fibers; fiber splitting; phagocytosis of muscle fibers; hyalinized fibers with loss of cross striations (hypercontracted)

·      Canine X-linked muscular dystrophy (xmd):

·      Severely affected dying pups will have massive acute muscle fiber necrosis and mineralization in affected muscles as well as tongue

·      Animals that survive neonatal period will have swollen, dark staining fibers – large dark fibers represent early stage of muscle degeneration; clusters of necrotic fibers – multifocal, polyphasic necrosis, regenerating fibers, mineralization; older affected dogs will have variation in muscle fiber size with internal nuclei

·      Cardiac muscle may have subepicardial necrosis, mineralization and fibrosis; left ventricular free wall and interventricular septum are most severely affected; may eventually result in congestive heart failure in surviving dogs

·      Immunohistochemistry for dystrophin (frozen sections) is usually negative in skeletal and cardiac muscle

·      mdx mice: Balance of myofiber necrosis and regeneration (regeneration compensates for necrosis); lack of interstitial fibrosis; regenerated fibers with central nuclei

·      Dystrophic chickens: Necrosis, hypertrophy, and regeneration in type-2 (white) muscle fibers; ringed fibers (ringbinden); interstitial fibrosis; numerous intracytoplasmic vacuoles, possibly from proliferation of transverse tubular system

·      Merino sheep: Formation of characteristic pale amphophlic central or peripheral sarcoplasmic masses; no muscle regeneration

 

ULTRASTRUCTURAL FINDINGS:

·      DMD and other muscular dystrophies: Mitochondrial and myelin body fibers in subsarcolemmal blebs; myofilament structures in disoriented arrays or swirls; swollen mitochondria and endoplasmic reticulum

·      mdx mice: Disorganized Z bands, scattered hypercontracted fibers, empty sarcolemmal tubes

 

DIFFERENTIAL DIAGNOSIS:

·      Dogs:

·      Centronuclear myopathy (Labrador retrievers)

·      X-linked myotubular myopathy (Labrador retrievers)

·      Inherited myopathy (Great Danes)

·      Myopathy of Bouvier des Flandres dogs

·      Canine dermatomyositis (Shetland sheepdog, collie, Pembroke Welsh corgi)

·      Juvenile-onset distal myopathy (Rottweiler)

·      Exercise-induced collapse (Labrador retriever)

·      Cats:

·      α-dystroglycan deficiency (Sphynx and Devon Rex cats)

·      Laminin deficiency associated muscular dystrophy

·      Nemaline myopathy

·      Polymyositis

·      Sheep:

·      Nutritional myopathy (white muscle disease) due to vitamin E/selenium deficiency; nutritional myopathies are uncommon in carnivores

·      Monensin toxicity

·      Toxic plant myopathy (Cassia - coffee senna)

·      Motor endplate disease; local myocyte degeneration only; recessive disease with abnormalities in nerve fibers and motor endplates; death at 20-25 days

·      Chickens: Deep pectoral myopathy

 

COMPARATIVE PATHOLOGY:

·      Mouse:

·      A strain and SJL mouse:

·      Dysferlin gene mutation

·      Progressive degenerative changes in proximal skeletal muscle groups

·      >70% of A strain mice develop rhabdomyosarcomas over 20 months of age

·      Similar to a form of limb-girdle muscular dystrophy in humans

·      C57BL/10ScSn (mdx) mouse:

·      X chromosome mutation (mdx allele) in the dystrophin gene

·      Similar to Duchenne’s muscular dystrophy in humans

·      Other mouse models have been developed, but those listed above are naturally occurring mutations

·      Rats:

·      Dystrophin deficient strains developed that develop cardiomyopathy similar to human DMD cardiomyopathy

·      Dogs:

·      xmd in the Golden Retriever: X-linked recessive with progressive muscle weakness; lack of dystrophin; clinical and pathologic course similar to DMD; regarded as a good model for therapeutic trials; many other breeds of dogs also effected but the Golder Retriever is most characterized

·      Hereditary MD of Labrador retrievers: Typical MD lesions; atrophy, particularly of type 2 fibers, suggestive of an endocrine influence

·      Reported in 22 breeds

·      Cats:

·      Feline X-linked muscular dystrophy

·      Severe, progressive degenerative myopathy in young usually male cats

·      Thickening of tongue, esophagus, and diaphragm

·      Muscular hypertrophy – most prominent in neck and proximal limbs

·      Less endomysial fibrosis and myofiber degeneration and regeneration (as compared to dystrophic dogs); +/- myocardial lesions

·      Sheep:

·      Muscular dystrophy of Merino sheep – autosomal recessive disorder

·      Skeletal muscle has normal dystrophin expression

·      Only affects type 1 fibers

·      Equally affects both sexes; clinical signs begin around 3-4 weeks of age

·      Abnormal growth and reduced flexion of the hindlimbs

·      Variable progression – most have easily detectable hindlimb gait abnormalities by 6-12 months and are severely affected by 2-3 years of age; most die between 6-18 months of age

·      Cattle:

·      MD reported in Meuse-Rhine-Yssel breed in the Netherlands; diaphragm and intercostal muscles; large elongated segments of sarcoplasm free of myofibrils (central cores)

·      Poultry:

·      Dystrophic chickens: Autosomal dominant trait affecting type 2 muscle fibers; ubiquitin ligase gene defect

·      Japanese quail: Autosomal dominant trait of muscle weakness, stiffness, myotonia; lenticular cataracts and testicular degeneration; similar to human myotonic dystrophy

·      Mink: Autosomal recessive trait; affects especially large proximal muscles and temporal muscles

·      Man:

·      X-linked:

·      Most common forms of muscular dystrophy; caused by lack of dystrophin

·      Duchenne (DMD): Most severe/most common; death from respiratory compromise/cardiac decompensation

·      Becker: Less severe

·      Autosomal Muscular Dystrophies:

·      Limb girdle muscular dystrophies

 

REFERENCES:

1.    Baroncelli AB, Abellonio F, Pagano TB, et al. Muscular dystrophy in a dog resembling human Becker muscular dystrophy. J Comp Pathol. 2014; 150(4):429-433.

2.    Cooper BJ, Valentine BA. Muscle and tendon. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:167,173-200.

3.    Hall RL, Bender HS. Muscle. In: Latimer KS, ed. Duncan and Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Ames, IA: Wiley-Blackwell; 2011: 286-289.

4.    Leininger JR. Skeletal muscle. In: Maronpot RR, Boorman GA, Gaul BW, eds. Pathology of the Mouse. Vienna, IL: Cache River Press; 1996:638-639.

5.    Matsumotos H, et al. The ubiquitin ligase gene (WWP1) is responsible for the chicken muscular dystrophy. FEBS Letters 2008;582:2212-2218.

6.    Remmers G, Hayden DW, Jaeger MA, Ervasti JM, Valberg SJ. Postanesthetic death in a cat with myopathy. Vet Pathol. 2015; 52(1):186-188.

7.    Saito F, et al. Aberrant glycosylation of alpha-dystroglycan causes defective binding of laminin in the muscle of chicken muscular dystrophy. FEBS Letters 2005;579:2359-2363.

8.    Valentine BA. Skeletal muscle. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease, 6th ed. St. Louis, MO: Elsevier; 2017:914-922,928,944-952.

9.    Wilson K, Faelan C, Patterson-Kane JC, et al. Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification. Tox Path. 2017;45(7):961-967.

10. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. Ames, IA: John Wiley & Sons, Inc.; 2016: 105,115.


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