Myelination And Demyelination Of PNS and MS Flashcards
Oligodendrocyte
Myelin-producing cells of the CNS
Oligodendrocyte progenitor cell
Undifferentiated , immature precursor cells, which proliferate and differentiate into mature, myelin-producing oligodendrocytes
Dysmyelination
Abnormal to delayed myelin formation resulting from errors in metabolism
myelin
Lipid rich layer surrounding nerve cell axons
What are the functions of myelin
Protection, metabolic support to neurons
Fast signal conduction (saltatory conduction)
Describe leukodystrophies
Grou of rare, cerebral white matter disorders caused by abnormal myelin formation in the brain and spinal cord
Genetic in origin
Leads to dysmelination or demyelination
Symptoms vary by disease, progression and the areas of the brain affected - typically presents with development delays or neurological deterioration, affecting cognitive, language and motor abilities
Symptoms of leukodystrophies
Development regression
Poor motor skills
Seizures
Cognitive decline
Symptoms as disease progresses: abnormal Body and muscle tone
Abnormal movements; increased difficulty or loss of ability to walk; trouble with speech; difficulty with eating; decline in vision and/or hearing; decline in mental and physical development
Examples of Leukodystrophies
Lysosomal Dysfunction
▪ Krabbe disease.
▪ Metachromatic leukodystrophy (MLD).
Peroxisomal Dysfunction
▪ Adrenoleukodystrophy (ALD).
Myelination Defects
▪ Pelizaeus-Merzbacher disease (PMD).
Astrocyte Defects
▪ Alexander’s disease (AxD)
Describe Krabbe Disease
Also known as globoid cell leukodystrophy or galactosylceramide lipidosis.
▪ Autosomal recessive lysosomal storage disorder, affecting 1 in 100,000.
▪ Galactolipids occur in cells that produce myelin, but its accumulation can be
toxic and triggers the destruction of oligodendroglia.
▪ KD results in a lack of galactocerebrosidase (GALC), which is needed for the
breakdown of lysosomal galactolipids.
▪ Increased uptake of galactolipids by microglia also transforms them to
abnormal, toxic cells known as globoid cells.
▪ Globoids promote myelin-damaging inflammation in the CNS and PNS.
▪ Leads to dysmyelination (early onset) or demyelination (late onset).
▪ Treatments: bone marrow and/or umbilical cord stem cell transplants.
▪ Improves development, QOL and life expectancy.
Symptoms of Krabbe Disease
Feeding difficulties
Seizures
Developmental delays, regression
Fevers without infection
Irritability
Poor head control
Hypertonic
Deaf/blindness
Walking difficulties (late onset)
Poor hand coordination (late onset)
Describe metachromatic leukodystrophy
▪ Autosomal recessive lysosomal storage disorder, affecting 1 in 40,000.
▪ Onset can occur during late infancy (<2 yrs, rapid disease progression),
juvenile (3-16 yrs) or adulthood (16+ yrs, slow disease progression).
▪ MLD is caused by mutations in the ARSA or PSAP (less common) genes.
▪ ARSA encodes for cerebroside-sulfatase, which is needed to breakdown
lipids called sulfatides.
▪ Sulfatides accumulate in MLD and interfere with the production of myelin by
destroying oligodendroglia (CNS) and schwann cells (PNS).
▪ Leads to dysmyelination (infant-juvenile onset) or demyelination (adulthood
onset).
▪ Treatment: Stem cell transplants.
Symptoms of MLD
Memory loss
Loss of motor skills
Poor muscle function/paralysis
Loss of bowel and bladder function
Gallbladder problems
Deaf/blindness
Seizures
Emotional and behavioural issues
Describe adrenoleukodystrophy
▪ X-linked recessive peroxisomal disorder, affecting 1 in 17,000.
▪ Forms of ALD: Childhood onset (4-10 yrs, rapid disease progression),
Addison’s disease and adrenomyeloneuropathy (slow disease progression).
▪ Affects males more severely than females.
▪ ABCD1 encodes for the adrenoleukodystrophy protein, which is required for
the breakdown of very long-chain fatty acids (VLCFAs).
▪ In ALD, VLCFAs accumulate in the brain and adrenal glands and results in
neuroinflammation.
▪ This inflammatory response damages the myelin sheath and leads to
cerebral demyelination (white matter loss).
▪ Treatments: Stem cell transplants, adrenal insufficiency treatment,
medication or physical therapy.
Describe the symptoms of ALD
▪ Learning disabilities
▪ Seizures
▪ Dysphagia (swallowing difficulties)
▪ Deaf/blindness
▪ Poor coordination/balance
▪ Fatigue
▪ Progressive dementia
▪ Muscle weakness
▪ Stiff gait when walking (late onset)
▪ Bladder and bowel dysfunctions (late onset
Describe pelizaeus-merzbacher disease (PMD)
▪ X-linked recessive dysmyelinating disease, affecting 1 in 200,000.
▪ Forms of PMD: Classic (common, 1+ yrs) and connatal (more severe, <1 yr).
▪ PMD is caused by mutations in the PLP1 gene, which encodes the proteins
PLP1 and DM20 in the CNS.
▪ PLP1 and DM20 are the main proteins found in myelin.
▪ A lack of PLP1 and DM20 leads to dysmyelination – poor myelin
development (hypomyelination).
▪ Nervous system function impaired.
▪ A different mutation of the PLP1 gene can also lead to spastic paraplegia
type 2 (SP2).
▪ No treatment available.
Symptoms of PMD
Hypotonia
Nystagmus
Delayed motor skills
Muscle stiffness
Ataxia
Poor cognitive abilities
Poor cognitive vilifies
Speech difficulties
Feeding difficulties
Joint deformities
Seizures
Describe Alexander’s disease AxD
▪ Autosomal dominant disease, affecting 1 in 1,000,000.
▪ Onset can occur during infancy (onset <2 yrs, more severe), juvenile (onset
4-10 yrs) or adulthood (onset 16+ yrs, rarest).
▪ AxD is caused by a mutation in the astrocyte gene GFAP (glial fibrillary acidic
protein).
▪ GFAP is involved in the structural development of cells, providing lipids to
oligodendrocytes during myelin formation.
▪ In AxD, abnormal structures called Rosenthal fibres accumulate within
astrocytes, preventing normal cell functions.
▪ This affects the development and structural integrity of myelin, and leads to
white matter impairments.
▪ No treatment available.
Symptoms of AxS
E nlarged brain and head size
▪ Seizures
▪ Stiffness
Developmental delays
▪ Feeding difficulties
▪ Speech abnormalities (juvenile-adult)
▪ Swallowing difficulties (juvenile-adult)
▪ Ataxia (poor balance) (juvenile-adult)
▪ Vomiting (juvenile-adult)
Liss of motor control
Consequences of demyelination
Alterations in axonal signalling
Neuronal and axonal loss
Physical abnormalities in function - dependent on area affected
Causes of demyelination
Inflammation/immune related
Infections
Hypoxia-ischaemic injury eg stroke
TBI
Metabolic diseases
Toxin induced eg vitamin B12 deficiency, cyanide
Genetics eg MLD
What are the mechanisms of demyelination
Immune mediated or autoimmune
Myelin antigens (MOG, MBP, PLP, MAG)
Possible mechanism: molecular mimicry
Describe immune mediated demyelination
Immune-mediated demyelination commonly occurs in MS pathology.
It is a pro-inflammatory immune response from both infiltrating and CNS-resident
immune cells.
Cells Involved:
▪ T cells (CD4s and CD8s) (infiltrating/resident)
▪ B cells (infiltrating/resident)
▪ Macrophages (infiltrating)
▪ Microglia (resident)
▪ Reactive astrocytes (resident)
Describe demyelination
Naturally occurring process in the CNS
Involves recruitment, proliferation, and differentiation of OPCs into mature myelin-producing oligodendrocytes
Newly formed myelin is thinner
Describe the mechanisms involved in demyelination
Removal of myelin debris by microglia
Recruitment and proliferation of OPCs
Differentiation of OPCs into mature oligodendrocytes
Mature oligodendrocytes produce myelin
Myelin wraps around exposed axons
Demyelination can also occur in the ..
PNS
Exemplars of demyelinating diseases of the PNS
▪ Guillain-Barre syndrome (GBS).
▪ Inflammatory demyelinating polyradiculoneuropathy (CIPD).
▪ Multifocal motor neuropathy (MMN).
▪ Charcot-Marie-Tooth disease (CMT).
Describe Guillain-Barré syndrome
Symptoms:
▪ Paresthesia (pins and needles)
▪ Weakness
▪ Ataxia and difficulty walking
▪ Difficulty swallowing and/or breathing
▪ Double vision
▪ Loss of bowel and bladder function
▪ Rapid heart rate
▪ Low or high blood pressure
▪ Affects 1-2 in 100,000.
▪ Forms of GBS: Acute inflammatory demyelinating polyradiculoneuropathy
(AIDP), Miller Fisher syndrome (MFS) and Acute motor axonal neuropathy
(AMAN).
▪ Cause of GBS is unknown but has been linked to gastrointestinal infections
and the Zika virus.
▪ GBS is an autoimmune disease - T cells/B cells/macrophages attack myelin-
producing Schwann cells.
▪ Acute demyelination occurs (only in AIDP).
▪ Complete recovery is possible with Schwann cell remyelination.
▪ Treatments: Plasma exchange and immunoglobulin therapy.
Describe chronic inflammatory demyelinating polyneuropathy (CIDP)
Symptoms:
▪ Paresthesia (pins and needles)
▪ Gradual weakening of arms and legs
▪ Loss of reflexes
▪ Ataxia and difficulty walking
▪ Fatigue
▪ Affects 5-7 in 100,000.
▪ Immune-mediated pathology is similar to GBS, but the disease is chronic.
▪ No virus or infection found to precede CIPD (cause unknown).
▪ Forms of CIDP: Progressive (continuously worsens), recurrent (on/off
symptoms) and monophasic (disease occurs for 1-3 yrs).
▪ Is an autoimmune disease - T cells/B cells/macrophages attack myelin-
producing Schwann cells.
▪ Treatment needed to improve condition.
▪ Treatments: Corticosteroids, high-dose intravenous immune globulins (IVIG)
or plasma exchange.
