1. Disorders of myelination and Neuronal storage disease
Leukodystrophies
Demyelinating disease
Metabolic neuronal storage disease

2. Diseases of myelin can be divided into two broad groups:
Dysmyelinating diseases
Demyelinating diseases

3. Dysmyelinating Diseases
These disorders are also termed leukodystrophies, and almost all of them manifest themselves early in life and are genetically determined.
Profound disturbance in the formation and preservation of myelin so that its proper functioning is never established.

4. Demyelinating Diseases
The myelin sheath, once properly formed and functioned, is destroyed by a disease process.
The most common disease in this category is multiple sclerosis.
Other examples include:
Central pontine myelinolysis
Progressive multifocal leukoencephalopathy
Subacute combined degeneration of the spinal cord

5. Diseases of myelin Leukodystrophies (congenital)
Metachromatic Leukodystrophy
Krabbe’s disease
Adreno-Leukodystrophy (ALD-Lorenzo)
Alexander disease
Multiple sclerosis (acquired)

6. Leukodystrophies
Similar to neuronal storage diseases: Most are lysosomal storage diseases with specific enzymatic defects (metachromatic leukodystrophy, Krabbe leukodystrophy)
Different from neuronal storage diseases: White matter involvement
Storage material is toxic :
globoid cells (Krabbe disease),
accumulates in macrophages (Metachromatic leukodystrophy).

7. Hallmarks:
Lysosomal abnormalities--diagnosis based on enzyme defect, frequently recessive.
White matter involvement--storage is not usually neuronal, symptoms relate to white matter involvement.

8. Clinical findings in Leukodystrophies
Similar to neuronal storage diseases
The enzyme deficiency in Adrenoleukodystrophy, Metachromatic leukodystrophy and Krabbe
Differences: Signs and symptoms relate to white matter abnormalities (pyramidal signs)
Gait (walking) disorders
Loss of motor abilities,
Spasticity.
Peripheral nerve involvement occurs in ALD, MLD and Krabbe’s disease.

9. Metabolic Disorder
Inheritance
Abnormality
Metachromatic leukodystrophy
Autosomal Recessive
Arylsulfatase A deficiency
Krabbe disease
Galactocerebroside β-galactosidase deficiency
Adrenoleukodystrophy
Autosomal Recessive, X-linked
Peroxisomal defects; elevated very long chain fatty acids
Canavan disease
Aspartoacylase deficieny
Pelizaeus-Merzbacher disease
X-linked
Mutations in proteolipid protein
Vanishing white matter disease
Translation initiation factor; link to myelin unclear
Alexander disease
Mutations in glial fibrillary acidic protein

10. Metachromatic Leukodystrophy
Autosomal recessive
Presents in infancy,
Most common of the leukodystrophies
Both central and peripheral white matter involved
Course is progressive, usually fatal in a few years
Pathology is diffuse, confluent loss of myelin that is most advanced in the cerebrum.

11. Due to inborn error of metabolism in which arylsulfatase A, although present within lysosomes, is enzymatically inactive.
Leads to breakdown of myelin and the accumulation of galactosyl sulfatides (cerebroside) within schwann cells and oligodendrocytes
The metachromatic material (sulfatide) stains brown with toluidine blue, cresyl violet, thionin or acriflavine (blue stains).

12. The metachromatic material (sulfatide) stains brown with toluidine blue, cresyl violet, thionin or acriflavine (blue stains).

13. Krabbe Disease Globoid cell leukodystrophy
Usually appears in early months of life and progresses to death in one to two years.
Motor signs (hypertonic flexion), optic atrophy.
Autosomal recessive
Caused by deficiency of b-galactosidase. Galactocerebroside accumulates and expressed histologically by the presence of perivascular aggregates of globoid cells:
Undigested galactocerebroside in globoid cells (macrophages)
Loss of oligodendrocytes.

14. Adreno-Leukodystrophy (ALD)
Severe, bilateral, symmetric loss of myelin
Aut. Rec. & X-linked
Presents in childhood (3-10 years), lethal in a few years
High levels of very long chain fatty acids
Adrenoleukodystrophy is peroxisomal*.
*The peroxisome is a cellular organelle measuring 0.5 micron in diameter that participates in important cellular functions such as beta-oxidation of very-long-chain fatty acids (VLCFA), plasmalogen production, and bile acid synthesis.

15. Adrenoleukodystrophy (ALD)
Adrenal insufficiency
pigment, diarrhea, hypotension
Peroxisomal membrane disorder
High levels of very long chain fatty acids in tissue and fluids
Lorenzo’s oil contains short chain FA’s
VLCFA also seen in schwann cells and macrophages in the demyelinated CNS.

17. Alexander Disease Loss of myelin with numerous Rosenthal fibers
refractile eosinophilic hyaline bodies found within the cytoplasm of astrocytes particularly in the subpial, subependymal, and perivascular regions.
Myelin is preserved in peripheral nervous system
Periventricular white matter of frontal lobes
Loss of myelin

19. Demyelinating disease
Acquired not congenital
Mechanism is autoimmune not metabolic
Hallmark is the plaque of abrupt demyelination
Common locations: optic nerves and chiasm and paraventricular white matter

20. Demyelinating diseases
Multiple sclerosis
MS variants:
DeVic,
Marburg
Acute disseminated encephalomyelitis (acute)
Acute necrotizing hemorrhagic encephalomyelitis (hyper-acute)
Central pontine myelinolysis
Marchiafava-Bignami

21. Multiple Sclerosis
First “attack” may be a single symptom, commonly optic neuritis:
Ophthalmoplegia
Monocular blindness.
Facial hypesthesia or trigeminal neuralgia (tic douloureux)
Bell’s palsy, hemifacial spasm, vertigo, vomiting, nystagmus, deafness, abnormal speech, intention tremor, ataxia, motor abnormalities, bowel and bladder dysfunction.

22. Hallmark: demyelinating plaques, peripheral nerves spared.
Multiple sclerosis
Temperate climates (rare in tropics with increasing frequency further from equator)
F>M (x2), mean age = 30
Pathogenesis:
genetic predisposition (HLA-DR2),
auto- immune,
viral—EPV
Hallmark: demyelinating plaques, peripheral nerves spared.

23. Pathology of MS Multiple plaques
These are sharply delineated, irregular zones of total demyelination with initial preservation of axons.
They are most numerous in the white matter of the cerebrum (periventricular), brain stem, cerebellum and spinal cord (peripheral regions).
Within the plaque, initially axons are preserved.
Microglial cells proliferate and phagocytize the myelin debris.
Later, a glial scar forms.

24. PLAQUES OF DEMYELINATION
MULTIPLE SCLEROSIS
PLAQUES OF DEMYELINATION
MYELIN STAIN

25. PLAQUES OF DEMYELINATION
MULTIPLE SCLEROSIS
PLAQUES OF DEMYELINATION

26. Demyelinating diseases
Post-infectious encephalomyelitis
perivascular demyelination with lymphocytes, ?auto-immune
headache, vomiting fever, 15-20% die
similar to “post-vaccinal encephalomyelitis”.
Central pontine myelinolysis
quadriparesis, pseudo-coma
usually in alcoholics.

27. Summary of Primary Diseases of Myelin
Because of the critical role of myelin in nerve conduction, diseases of myelin can lead to widespread and severe neurologic deficits.
Diseases of myelin can be grouped into demyelinating diseases (in which normal myelin is broken down for inappropriate reasons-often by inflammatory processes), and dysmyelinating diseases (which are metabolic disorders that include the leukodystrophies in which the underlying struc-ture of the myelin is abnormal or its turnover is abnormal).
Multiple sclerosis, an autoimmune demyelinating disease, is the most common disorder of myelin, affecting young adults often with a relapsing-remitting course with eventual progressive accumulation of neurologic deficits.
Other less common forms of immune-mediated demyelination often follow infections and are more acute illnesses

28. Neuronal storage diseases

29. Neuronal storage diseases
Storage material typically within neurons
Psychomotor retardation
Mental retardation
Most are lysosomal
Most are autosomal recessive
Enzymatic deficiencies.

30. Neuronal storage disease
In general:
Visual impairment (due to retinal pathology)
Seizures are more common (vs. leukodystrophies) due to neuronal involvement
Some show hepatosplenomegaly:
Gaucher disease
Hurler syndrome
Niemann-Pick disease.

31. Tay-Sachs disease accumulation of ganglioside in lysosomes
Hexosaminidase A deficiency
absent hexosaminidase A&B = Sandhoff’s disease.
accumulation of ganglioside in lysosomes
cherry red spot on retina
myelin figures in lysosomes on EM (membranous cytoplasmic bodies).

32. Hurler Syndrome Autosomal recessive
Neuronal accumulation of mucopolysaccharides
Visceral organs can be involved
hepatosplenomegaly
Associated features include:
dwarfism,
corneal opacities
skeletal deformities.

33. Gaucher disease Glucocerebroside in macrophages Autosomal recessive
Most common of the sphingolipidoses
Adult.

34. Many inherited disorders of metabolism can lead to accumulation of storage products in cells, as seen here with Gaucher's disease involving spleen. The large pale cells contain an accumulated storage product from lack of an enzyme.

35. Niemann-Pick disease
Sphingomyelinase deficiency causes sphingomyelin accumulation within mononuclear phagocyte system (and neurons and glial cells)
Autosomal recessive
cherry red spot similar to Tay-Sachs disease.

36. Leukodystrophy vs. Neuronal storage
Leukodystrophies: Adrenoleukodystrophy, Metachromatic leukodystrophy, Krabbe disease, Alexander disease
white matter rarefaction, motor findings, enzymatic defect.
Neuronal storage diseases: Gaucher disease, Nieman Pick, Tay Sachs, Hurler syndrome
storage material in neurons, cherry red spot, seizures, enzymatic defect.

37. Thank you!