15/02/2013

1

Inherited neuromuscular

disorders

“Bully” Whippet

mutation dysrupting myostatin's normal

role of limiting muscle growth

http://powerofthegene.com/joomla/index.php/genetically-inherited-diseases/muscular-disorders/myostatin

Clare Rusbridge 2013 ©

Weak?

What is neuromuscular disease ?

• Exercise intolerance

• Weakness

• Poor spinal reflexes

• Good proprioception

(when supported)

Devon Rex Myopathy

Thanks to

Richard

Malik

15/02/2013

2

General Proprioceptive pathways

Spinocerebellar

Involved reflex arc

Info. to cerebellum

Conscious proprioception

Proprioceptive info. to

somatosensory cortex

Postural reactions

Normal

conscious

proprioception

Hopping responses

Upper and lower motor

neuron

15/02/2013

3

Upper and lower motor neuron

UMN LMN

Motor

function

Paresis/paralysis Paresis/paralysis

Reflexes Normal/hyperactive Reduced/absent

Muscle Late, disuse atrophy

Increased tone

Early, neurogenic atrophy

Decreased tone

Upper and lower motor neuron

Localisation Thoracic limbs Pelvic limbs

Cranial to C5 UMN UMN

C6-T2 * LMN UMN

T3-L3 Normal UMN

L4-S3 * Normal LMN

Neuropathy LMN LMN

* - remember sites of intumescences

Spinal reflexes

Thoracic limb

• Biceps

(musculocutaneous)

• Extensor carpi

radialis (radial)

• Triceps (radial)

• Withdrawal

(multiple)

Pelvic limb • Patella (femoral)

• Cranial tibial (peroneal)

• Gastrocnemius (tibial)

• Withdrawal (sciatic)

• Panniculus

• Perineal

15/02/2013

4

Most useful - spinal reflexes

Patella Withdrawal (versus deep

pain perception)

Exercise intolerance

Exercise intolerance

15/02/2013

5

versus lameness

Neurological examination

Neurological examination

Muscle Junction Nerve

Spinal Reflexes N / N /

Muscle tone N / / N /

CP N N N/

Palpebral reflex N N/

15/02/2013

6

Neurological examination Exercise intolerance

Weak Diminished reflexes Muscle tone/bulk

Gait progressively worse with exercise

Stiff stilted / bunny hopping gait Poor “hopping ability” Proprioception often normal Cranial / Spinal nerves Usually normal myopathies Often reduced / atrophy May have muscle pain

Important historical clues!

• Walking ability good initially but

deteriorates with exercise

• Regurgitation / dysphagia

• Dysphonia

• Drooling saliva

• Sleeping with eyes open

• Urinary / faecal incontinence

Neuromuscular disease

15/02/2013

7

Diagnostic tests - Haematology • Neutrophillia/eosinophillia - inflammatory

myopathies

Biochemistry • Glucose - diabetes mellitus, insulinoma

• Electrolytes - hypokalaemia, hypocalcaemia

• Creatinine kinase - muscle

breakdown(dystrophy, inflammation,

metabolic imbalance)

• Liver enzymes and bile acids -

Hyperthyroidism, Protozoal infections

Dystrophin-deficient Muscular dystrophy Richard Piercy & Gemma Walmsley,

Comparative Neuromuscular Diseases Laboratory

Royal Veterinary College

• Neuromuscular weakness

• Dysphagia

• Aspiration pneumonia

• Restricted jaw mobility

• Macroglossia

• Marked elevation CK

• single exon deletion (exon

50) dystrophin mRNA

Exercise tolerance tests (limited in cat!)

• Response to IV edrophonium chloride

• Pre and post exercise lactate

• Pre and post exercise blood pH

• Pre and post exercise electrolytes

• Pre and post exercise glucose

• Post exercise rectal temperature

15/02/2013

8

Example

Other diagnostic tests • Thoracic radiographs

– Pneumonia – Protozoal diseases

– Thymoma

• Antibody titres

– Acetyl choline receptor (myasthenia gravis)

– Masticatory myositis (anti-2M antibody titre)

– Toxoplasma gondii / Neospora gondii

Other diagnostic tests

• Endocrine diseases

– Fructosamine (Diabetes mellitus)

– Insulin (Insulinoma)

– T4 (hyperthyroidism)

– T4 / TSH (hypothyroidism)

– Biochemistry and ACTH stimulation test

(Cushing’s syndrome and Addison’s

disease)

15/02/2013

9

Specific DNA tests Disease Breed Test Other info / Laboratory

Early-onset

progressive

polyneuropathy

Alaskan Malamute DNA (mouth

swabs)

University of Copenhagen

Laboklin

Genoscoper

Centronuclear

Myopathy (Hereditary

Myopathy)

Labrador retrievers DNA (mouth

swabs)

Animal Health Trust

Laboklin, Alfont University

Hypokalemic

myopathy

Burmese cat DNA Langford veterinary Services

Leonberger

Polyneuropathy

Leonberger DNA (blood,

mouth swabs)

University of Minnesota,

University of Bern

Malignant

Hyperthermia

All breeds DNA (blood,

mouth swabs)

Laboklin

Muscular Dystrophy Golden Retriever DNA (blood,

mouth swabs)

Laboklin

Myostatin Deficiency

("Bully" Whippet)/

Double Muscling

Whippet DNA (blood,

mouth swabs)

Laboklin

Myotonia congenita Schnauzer DNA (blood,

mouth swabs)

Laboklin

Pyruv ate

Dehydrogenase

Phosphate 1

Deficiency (PDP1)

Sussex Spaniels

Clumber Spaniels

DNA (mouth

swabs)

Animal Health Trust,

Laboklin

Polyneuropathy,

neuropathy

Greyhound DNA (blood,

mouth swabs)

Optigen,

Laboklin

Spinal Muscular

Atrophy

Maine Coon DNA (blood,

mouth swabs)

Antagene

Electrophysiology

• Electromyography

– Insertional activity

– Spontaneous activity

• Nerve function studies

– Conduction velocity

– Amplitude and character of cMAP

Electrophysiology

15/02/2013

10

Spontaneous activity

Nerve and muscle biopsy

Storage disease 1yo DSH, siblings (brother and sister)

Progressive neuropathy

Lipid droplets within

macrophages endoneurium &

subperineurally

Axonal degeneration

scattered myelin ovoids

no regeneration