MS and the leukodystrophies Flashcards
What are leukodystrophies?
Diseases relating to white matter.
Which diseases can mutations in the PLP1 gene cause?
Pelizaeus Merzbacher disease and spastic paraplegia type 2
Which chromosome is the PLP1 gene on?
X chromosome.
What are the most common types of mutations in the PLP1 gene?
Duplications.
What does dysmyelination mean?
Myelin never formed.
What does demyelination mean?
Myelin formed and it breaks.
What are the symptoms of Pelizaeus Merzbacher disease?
Impaired motor development Nystagmus (abnormal eye movements) Ataxia Choreoathetosis (abnormal movements of upper limbs) Cognitive impairment.
What causes pelizaeus merzbacher disease?
Widespread hypomyelination of CNS.
What are spastic paraplegias characterised by?
Degeneration of distal ends of long spinal cord axons.
What do pyramidal neurons do?
Pyramidal neurons are a type of neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract.
Which transgenic animals have been made for Pelizaeus Merzbacher disease?
Plp1 gene knockout mice
Plp1 overexpressing mice and rats.
What happened in the plp1 knockout mouse?
Subtle abnormalities only.
Oligodendrocyte numbers are normal.
Neurological signs >15 months.
Develop a late onset axonal pathology
- axonal swellings, small diamater axons
- distal degeneration of long spinal axons.
What is the age of onset in X-ALD?
Childhood and adolescent onset.
What is the pathophysiology of X-ALD?
Adrenal atrophy
Extensive demyelination
Perivascular accumulation of lymphocytes and plasma cells in the CNS
Accumulation of very long chain fatty acids in adrenal cortical cells and microglia.
Markedly shortened lifespan.
What does AMN stand for?
Adrenomyeloneuropathy
What is the mode of inheritance of AMN?
X-linked recessive
What happens in AMN?
Neuropathological changes confined to spinal cord and peripheral nerves.
Begins with stiffness or clumsiness and legs and gait disturbances progress slowly over years.
Urinary disturbance and sexual dysfunction.
Neuropsychologic function is normal or minimally impaired.
What does ALD stand for?
Adrenoleukodystrophy
Is there any gene therapy to stop ALD?
Tranduced haematopoietic stem cells of two patients with ABCD1 gene and transplanted back into the patients.
Low levels of ABCD1 expression in peripheral blood cells.
Progressive cerebral demyelination stopped in both patients and the levels of very long chain fatty acids in the plasma as indicators for disease activity decreased.
What is metachromatic leukodystrophy (MLD)?
Lysosomal storage disorder caused by deficiency in arylsulfatase A (ASA).
What is the mode of inheritance of MLD?
Autosomal recessive.
What is a substrate of ASA?
3-O sulfogalactosylceramide.
What percentage of myelin lipid is made up of sulfatide?
4-5%
What does accumulation of sulfatide cause?
Demyelination.
What does the ASA gene do in relation to sulfatide?
Cleaves sulfatide.
How many known mutations have been found in the ASA gene?
About 130
Which therapeutic approaches have been tried in ASA knockout mice?
Adenovirus associated virus based vectors ASA
Lentivirus vectors expression wild type ASA
What is multiple sclerosis?
A chronic inflammatory/demyelinating disease
What is the prevalence of MS in Scotland?
1 in 500 people.
What is the female to male ratio of MS?
2-3:1 (increasing)
What is the concordance of MS in monozygotic twins?
30%
How is MS diagnosed?
Recurring neurological incidencts OR Incident followed by MRI OR Progressive neurological problems + MRI + spinal cord lesions Or Oligoclonal bands in CSF
90% of patients IgG or IgM
What are the genetic associations with MS?
HLA genes
IL2R
IL7
What are the environmental factors associated with MS?
EBV infection
Vitamin D
What is the progression of MS?
Most patients present with adult onset relapsing remitting disease (RRMS).
Within ten years, half of RRMS evolves into secondary progressive MS (SPMS)
Twenty percent present with primary progressive disease (PPMS)
Five percent develop MS in childhood.
What is the pathophysiology of MS?
Immune mediated - loss of self tolerance to CNS myeline
Triggers inflammation in CNS
Inflammation results in demyelination
Results in axonal injury
Accumulation of axonal deficits = disability.
What are MS lesions?
Inflammatory demyelinating plaques around the blood vessels.
What are the four different patterns of demyelination?
I and II: close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively.
III and IV: suggestive of primary oligodendrocyte dystrophy, reminiscent of virus-encephalomyelitis, respectively.
What are the symptoms of MS?
Weakness Numbness Loss of balance Muscle spasms Vision problems Slurred speech Difficulty swallowing Reduced mental sharpness Loss of bladder control Fatigue Pain Lhermitte's symptom (electrical sensation running down spine or limbs on neck flexion) Uhtoff phenomenon (transient worsening of symptoms and sign when core body temp. increases e.g. after hot bath or exercise)
Describe intrathecal immunoglobulin (Ig) synthesis.
Derived from clonal expanded B cells sequestered in CNS.
Most obvious manifestation - oligoclonal Ig bands in CSF
Recognises many different self and pathogen derived antigens
Specificity profile varies between patients
Seen in >95% of patients and persists life long.
Predicts a poor prognosis.
What is the immunopathology of MS?
Ig and/or complement deposition in >50% of lesions
Defines pattern II lesions
Myelin-specific autoantibodies associated with myelin debris
Presence correlates with a positive response to plasma exchange
Demyelinating autoantibodies present in sera of some patients.
How many susceptibility loci have been targeted in MS?
> 150
What is rituximab?
CD20 specific antibody
Complement-dependent cytotoxicity
Antibody-dependent cell mediated cytotoxicity
Induces B cell apoptosis.
What is the effect of B cell depletion on MS?
Reduces inflammatory activity in the CNS.
Reduces relapse frequency
Have you done further reading?
GO AND DO IT.
