Disorders of myelination and Neuronal storage disease

LeukodystrophiesDemyelinating diseaseMetabolic 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 (ALD-

Lorenzo)•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 AbnormalityMetachromatic leukodystrophy

Autosomal Recessive

Arylsulfatase A deficiency

Krabbe disease Autosomal Recessive

Galactocerebroside β-galactosidase 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.

oDue 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 SCLEROSISMULTIPLE SCLEROSIS

MYELIN STAINMYELIN STAIN

PLAQUES OF PLAQUES OF DEMYELINATIONDEMYELINATION

MULTIPLE SCLEROSISMULTIPLE SCLEROSIS

PLAQUES OF PLAQUES OF DEMYELINATIONDEMYELINATION

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 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

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 Tay-

Sachs 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.

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