Diseases of the motor unit

Neuroscience and Cognition, Utrecht University 2010

Manje Brinkhuis, Lynn Kraak, Maryse Lamme, Tessa Mulder, Paulina Rowicka, Leonie Vergouw, Iris Wever

Overview

Introduction
Neurogenic vs myopathic diseases

Clinical criteria

Laboratory criteria
Amyotrophic lateral sclerosis (ALS) Duchenne myotrophy

Neurogenic diseases

Myopathic diseases

Introduction

Neurogenic diseases

Cell body Axon

Myopathic diseases

Neuromuscular junction Muscle fibers

Introduction

Pre-motor neurons

Originate from higher regions of the brain (e.g. motor cortex) Synapse on the lower motor neurons

Spasticity, overactive tendon reflexes, abnormal plantar extensor reflex

Motor neurons

Originate from spinal cord and brain stem

Directly innervate skeletal muscles

Atrophy, fasciculations, decreases muscle tone, loss of tendon reflexes

Neurogenic vs myopathic diseases

Clinical criteria
Neurogenic diseases Myopathic diseases

Weakness Wastings Loss of reflexes Fasciculations Sensory loss Hyperreflexia

++ + + + + +

++ + 0 0 0 0

Neurogenic vs myopathic diseases

Laboratory criteria
Neurogenic diseases Myopathic diseases

Cerebrospinal fluid protein Slow nerve conduction velocity Serum enzymes

+ + +/-

0 0 ++++

Neurogenic vs myopathic diseases

Laboratory criteria: muscle biopsy

Neurogenic disease

Fiber type grouping Group atrophy

http://emedicine.medscape.com/article/1189246-media, Apr 17, 2009 (18 Nov 2009)

Neurogenic vs myopathic diseases

Laboratory criteria: Electromyography

Neurogenic vs myopathic diseases

Neurogenic

Myopathic
Duchenne muscular dystrophy Myotonic dystrophy Dermatomyositosis Polymyositosis syndrome Endocrine myopathies

Amyotrophic lateral sclerosis (ALS) Guillan-Barr Chronic peripheral neuropathy

Amyotrophic lateral sclerosis (ALS)

Progressive degeneration of premotor and motor neurons
Neurogenic atrophy of muscle

Weakness of arms or legs

indicative of motor neuron disease Hyperreflexia

indicative of premotor neuron disease

http://yassermetwally.wordpress.com/

Causes
90% sporadic
Infections Toxins

Autoimmune reactions
10% genetic

SOD1 mutation

Dion et al., 2009, Nature reviews genetics

Symptoms
Difficulties in executing fine movements
Fasciculations and fibrillations in limbs Muscle weakness starts distal, progressing proximal Affection of respiratory system, typically within 5 years after onset of the disease. No cure, only one approved treatment which only slightly prolongs life (35 months)

Discussion
Kandel: ALS only affects motor neurons, not sensory or autonomic neurons. How is it possible that ALS patients die of respiratory problems? (Also claimed in Kandel)
http://yassermetwally.wordpress.com/2009/05/12/stem-cell-therapy-ofamyotrophic-lateral-sclerosis/ Dion, P.A., Daoud, H., Rouleau, G.A. Genetics of motor neuron disorders: new insights into pathogenic mechanisms, 2009, Nature Reviews genetics, Volume 10.

Pasinelli, P. and Brown, R.H. Molecular biology of amyotrophic lateral sclerosis: insights from genetics, 2006, Nature, Volume 7.

Duchenne Muscular Distrophy (DMD)

Genetic Basis
X linked recessive disease (1 in 3300 males) DMD caused by frameshift in Xp21 (which codes for dystrophin) At most 5% of the normal amount dystrophin

http://jennyndesign.com/DMD/physiology5.html

Duchenne Muscular Distrophy (DMD)

Dystrophin Functionality
Lack of dystrophin leads to dystrophy of skeletal muscles. Dystrophin is important for stabilizing plasma membrane of muscle fiber. Current view on pathophysiology Fragile membrane: contractions micro-lesions loss of calcium homeostasis cell death.

DMD Symptoms

Rapid progressive muscle weakness, which begins in the legs

Fatigue

http://www.prosensa.eu

DMD Diagnosis

Electromyography

Shorter duration and smaller amplitude of motor unit potentials Necrosis

Regeneration

Muscle biopsy

Serum creatine phosphokinase (CPK)

Deconinck et al., 2007

Very high levels

Genetic tests

DMD Possible Treatment

Exon Skipping

Restoration of open reading frame Conversion of DMD into a much milder Becker Muscular Dystrophy (BMD)

http://www.prosensa.eu/