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Lecture 313: Leukodystrophies

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What are leuko-dystrophies? how different than MS?
= diffuse involvement of white matter from myelin abnormalities

Sx
- motor regression
- spasticity
- ataxia

Compare to MS
- slowly progressive (not relapsing, remitting)
- px in childhood** usually
- clear genetics, usually AR
Main leuko-dystrophies?
Krabbe disease
- galactocerebrosidase def

Metachromatic leukodystrophy
- arylsulfatase A deficiency
- also has peripheral neuropathy**

Adreno-leukodystrophy
- childhood onset
- issue with very longchain FAs, X linked**
- also adrenal insuff

Adreno-myelodystrophy
- adult from, X linked
- VLCFAs issue, adrenal insuff**
- adrenal may be only sx

Pelizaeus-Merbacher disease
- X linked** defective proteolipid protein gene
- cannot make myelin sheath

Canavan disease
- def of aspartoacylase
- build up of N-aceylaspartic acid
- macrocephaly**

Alexander disease
- mutation in glial fibrillary acid protein
--> diffuse accum of Rosenthal fibers**

Vanishing WM disease
- loss of eIF2B
- important for protein synthesis under stress**
Krabbe disease: what messed up? how px? prognosis?
Auto recessive
- glactocerebrosidase** deficiency
--> forms globoid cells** in white matter

Px
- normal at birth
- sx start at 3-6months
- irritability, spasticity, feeding difficulties
- slowed devel progress

Then
- psychomotor regression
- seizures, inc tone and extensor posturing

Death at 2yrs**
Krabbe disease: how dx? tx?
Dx
- dec serum and leukocyte galactocerebrosidase
- inc CSF protein (not always done)
- dec nerve conduction

MRI brain
- diffuse**, symmetric WM involvement

Tx
- have to do something BEFORE child is sx
- stem cell transplant
- so usually for next child
Metachromatic leuko-dystrophy: enzyme? px?
Auto recessive
- def of arlysulfatase A**

Multiple px
- infantile, most common
- juvenile
- adult forms

Infantile px
- normal until 2-4yrs
- then spasticity, ataxia, distal weakness
- loss of reflexes
- from concomitant peripheral neuropathy**

Sputtering course
- periods of rapid decline, then stable

Later
- bed ridden with spastic quadriplegia
- feeding difficulties, optic atrophy
- death before 10yrs
Metachromatic leuko-dystrophy: MRI? how dx? tx?
Dx
- absense of arylsulfatase A in WBCs
- elevated urine suflatides

MRI brain
- subcortical
- posterior predominance**
- sparing of U fibers**

Tx
- supportive
Adrenoleukodystrophy: enzyme? types?
X-linked recessive**
- inability to catabolize very longchain FAs**
- issue within peroxisomes
- variable expressivity** (even within same family)

--> loss of myelin with gliosis
- also see lymphocyte infiltration

Types
- childhood cerebral form (50%)
- adreno-myeloneuropathy (25%)
- adrenal insuff only (10%, usually men)
- expressing carriers (60% of obligate carriers)
Adreno-leukodystrophy: childhood form?
Px
- starts in boys bw 5-10yrs
- change in behavior
- decline in school performance

Then
- neuro deterioration
- gait and coordination difficulties
- vision loss and hearing
- vegetative state

Die 3yrs after disease onset (8-13yrs)

Assoc with adrenal insufficiency**
Adreno-leukodystrophy, childhood form: how dx? MRI brain?
Dx
- elevated plasma VLCFAs
- adrenal insuff**

MRI brain
- periventricular
- posterior predominance**
- leading edge enhancement

Tx
- steroids for adrenal insuff
- stem cell for pts with early sx
- dietary therapy does NOT work
Adreno-myeloneuropathy/adult form?
Px
- early adulthood**
- spastic paralysis
- peripheral neuropathy
- adrenal insuff**

MRI
- will show changes even if no sx
Pelizaeus-Merzbacher disease: issue? how px?
X linked
- defective myelin sheath
- proteolipid protein gene** messed up

Px
- early infancy or early childhood
- pendular nystagmus
- choreoathetosis (rocking back and forth)
- hypotonia
- psychomotor arrest and regression

Death by 5-7yrs
Pelizaues Merzbacher: how dx? MRI brain? tx?
Dx
- mutations in PLP-1 gene**
- normal nerve conduction (diff than Krabbe)
- normal CSF protein (diff than Krabbe)

MRI brain
- diffuse hypomyelination, scattered spread

Autopsy
- tigroid appearance** of WM on stains
- from some spared areas

Tx
- symptomatic
Canavan disease: issue? px?
= spongy degen of the nervous system

Auto recessive
- aspartoacylase def**

Px
- first 6months of life**
- psychomotor arrest and regression
- macrocephaly**
- blindness at 6-10months

Dx
- inc N-acetylaspartic acid in urine/plasma
- low aspartoacylase activ in fibroblasts

MRI brain
- diffuse inc lucency
- poor demarcation of gray and white**

Tx: symptomatic
Alexander disease: issue? px? MRI brain?
Rare
- glial fibrillary acid disorder
--> diffuse accum of Rosenthal fibers**

Px
- onset birth to early childhood
- megalencephaly (large brain)
- psychomotor regression, spasticity
- seizures
- NO optic atrophy (diff from Canavan)

MRI brain
- frontal predominance**

Tx: symptomatic
Vanishing white matter disease: issue? px?
Auto recessive
- mutation --> loss of eIF2B
- needed for protein syn during STRESS**

Px
- normal at birth
- then chronic deterioration, cerebellar ataxia
- worsens with illness, trauma, fright**

MRI brain
- white replaced with cystic CSF areas

Tx: avoid triggers
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