Download Disorders of myelination and Neuronal storage disease

Disorders of myelination and
Neuronal storage disease
Leukodystrophies
Demyelinating disease
Metabolic neuronal storage disease
Diseases of myelin can be
divided into two broad groups:
• Dysmyelinating diseases
• Demyelinating diseases
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.
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
Diseases of myelin
• Leukodystrophies (congenital)
• Metachromatic Leukodystrophy
• Krabbe’s disease
• Adreno-Leukodystrophy (ALDLorenzo)
• Alexander disease
• Multiple sclerosis (acquired)
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).
Hallmarks:
• Lysosomal abnormalities--diagnosis
based on enzyme defect, frequently
recessive.
• White matter involvement--storage
is not usually neuronal, symptoms
relate to white matter involvement.
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.
Metabolic Disorder
Inheritance
Abnormality
Metachromatic
leukodystrophy
Autosomal Recessive
Arylsulfatase A
deficiency
Krabbe disease
Autosomal Recessive
Galactocerebroside βgalactosidase deficiency
Adrenoleukodystrophy
Autosomal Recessive,
X-linked
Peroxisomal defects;
elevated very long chain
fatty acids
Canavan disease
Autosomal Recessive
Aspartoacylase
deficieny
Pelizaeus-Merzbacher
disease
X-linked
Mutations in proteolipid
protein
Vanishing white matter
disease
Autosomal Recessive
Translation initiation
factor; link to myelin
unclear
Alexander disease
Autosomal Recessive
Mutations in glial
fibrillary acidic protein
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.
o Due to inborn error of metabolism in
which arylsulfatase A, although
present within lysosomes, is
enzymatically inactive.
o 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).
The metachromatic material (sulfatide) stains
brown with toluidine blue, cresyl violet, thionin
or acriflavine (blue stains).
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.
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.
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.
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
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
Demyelinating diseases
• Multiple sclerosis
• MS variants:
• DeVic,
• Marburg
• Acute disseminated encephalomyelitis
(acute)
• Acute necrotizing hemorrhagic
encephalomyelitis (hyper-acute)
• Central pontine myelinolysis
• Marchiafava-Bignami
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.
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.
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.
MULTIPLE SCLEROSIS
PLAQUES OF
DEMYELINATION
MYELIN STAIN
MULTIPLE SCLEROSIS
PLAQUES OF
DEMYELINATION
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.
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 structure 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
Neuronal storage diseases
Neuronal storage diseases
• Storage material typically within
neurons
• Psychomotor retardation
• Mental retardation
• Most are lysosomal
• Most are autosomal recessive
• Enzymatic deficiencies.
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.
Tay-Sachs disease
• 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).
Hurler Syndrome
• Autosomal recessive
• Neuronal accumulation of
mucopolysaccharides
• Visceral organs can be involved
• hepatosplenomegaly
• Associated features include:
• dwarfism,
• corneal opacities
• skeletal deformities.
Gaucher disease
• Glucocerebroside in macrophages
• Autosomal recessive
• Most common of the
sphingolipidoses
• Adult.
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.
Niemann-Pick disease
• Sphingomyelinase deficiency causes
sphingomyelin accumulation within
mononuclear phagocyte system (and
neurons and glial cells)
• Autosomal recessive
• cherry red spot similar to TaySachs disease.
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.
Thank you!