Inherited Leukodystrophies

Question 1

inherited leukodystrophies in general

Answer 1

heterogenous group of inherited, metabolic demyelinating neurodegenerative diseases of the central nervous system

Question 2

leukodystrophies presentation

Answer 2

commonly have an initial period of normal development followed by progressive neurological deterioration
common symptoms include bilateral and symmetric spasticity, weakness, and ataxia
can present at any age, ranging from infancy to adulthood
some present with demyelination of peripheral nerves (metachromatic leukodystrophy, Krabbe disease)

Question 3

leukodystrophy MRI

Answer 3

variable
universally show changes in the cortical white matter, appreciated as T2-sequence hyperintensity
particular dystrophies may also have white matter contrast enhancement
if only particular regions involved, this can point you in the right direction to a particular disease

Question 4

leukodystrophy treatment

Answer 4

adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe’s disease can be treated with stem cell transplantation

Question 5

Alexander disease due to

Answer 5

mutation in the glial fibrillary acidic protein (GFAP) gene

Question 6

Alexander disease: infantile

Answer 6

<3 years of age with developmental regression, macrocephaly, and spasticity
seizures often a main feature

Question 7

Alexander disease

Answer 7

also has juvenile and adult forms

Question 8

Alexander disease imaging

Answer 8

frontal-predominant white matter demyelination affecting the subcortical U-fibers with prominent contrast enhancement

Question 9

Alexander disease pathology

Answer 9

Rosenthal fibers which are densely compacted eosinophilic glial intermediate filaments made of glial fibrillary acidic protein (GFAP)
rosenthal fiber deposition leads to demyelination

Question 10

metachromatic leukodystrophy due to

Answer 10

autosomal recessive disease due to deficiency of arylsulfatase A enzyme from a mutation in the ARSA gene

Question 11

metachromatic leukodystrophy presentation

Answer 11

infancy, childhood/juvenile, or adulthood depending on severity of gene dysfunction

Question 12

metachromatic leukodystrophy: infants

Answer 12

vision loss, spastic ataxia, and seizures
death usually 2-4 years after onset

Question 13

metachromatic leukodystrophy: juvenile

Answer 13

similar symptoms to infants but slower rate of progression
vision loss, spastic ataxia, and seizures

Question 14

metachromatic leukodystrophy: adults

Answer 14

behavior changes, psychosis, dementia

Question 15

metachromatic leukodystrophy imaging

Answer 15

extensive white matter demyelination with sparing of the cortical U fibers

Question 16

metachromatic leukodystrophy other presentations

Answer 16

a demyelinating sensorimotor polyneuropathy often present in most cases

Question 17

X-linked adrenoleukodystrophy

Answer 17

X-linked mutation in the gene ABCD1 which is responsible for the function of peroxisomes leading to impaired very-long-chain fatty acid (VLCFA) oxidation
blood and urine studies can show increased levels of VLCFAs
within the same family, same genetic mutation can have variable phenotypes

Question 18

X-linked adrenoleukodystrophy: presentation

Answer 18

adrenal failure, testicular atrophy, hyperactivity, ataxia, vision/hearing loss, and seizures

Question 19

X-linked adrenoleukodystrophy: adrenal insufficiency

Answer 19

seen in 50-80% of patients and can cause hyperpigmentation
intermittent adrenal testing may be needed as well a corticosteroid supplementation during times of stress/illness

Question 20

X-linked adrenoleukodystrophy: imaging

Answer 20

posterior predominant white matter demyelination with sparing the frontal lobes and subcortical U fibers and contrast enhnacement

Question 21

X-linked adrenoleukodystrophy: adrenomyeloneuropathy variant

Answer 21

primarily affects the spinal cord leading to lower extremity weakness and spasticity

Question 22

Canavan disease

Answer 22

mutations to the ASPA gene leading to deficiency of aspartoacylase

Question 23

Canavan disease: presentation

Answer 23

infancy with neonatal hypotonia, macrocephaly, dysphagia, vision loss, and seizures

Question 24

Canavan disease: imaging

Answer 24

diffuse T2 hyperintensities involving all white matter including U-fibers

Question 25

Canavan disease: pathology

Answer 25

accumulation of N-acetylaspartate leading to cellular edema and spongiform degeneration

Question 26

Krabbe disease

Answer 26

due to deficiency of the enzyme galactocerebrosidase

Question 27

Krabbe disease: presentation

Answer 27

infantile form presents with an exaggerated startle, fevers, behavioral regression, optic atrophy, and hypertonicity
death occurs within a few years of diagnosis
juvenile and adult forms less progressive than infantile form
seizures are frequent

Question 28

Krabbe disease: imaging

Answer 28

white matter changes sparing the U fibers

Question 29

Krabbe disease: pathology

Answer 29

large globoid cells which are PAS-positive multinucleated macrophages with galactocerebroside present

Question 30

Pelizaeus-Merzbacher disease

Answer 30

due to a mutation of X-linked proteolipid protein (PLP1) gene which is involved in myelin protein integrity
dysfunction leads to hypomyelination

Question 31

Pelizaeus-Merzbacher disease: presentation

Answer 31

nystagmus, ataxia, and tremor at various ages based on the severity of the mutation

Question 32

Pelizaeus-Merzbacher disease: pathology

Answer 32

diffuse absence of myelin with preserved myelin islets around blood vessels called “tigroid demyelination” (either striped or spotted appearance of the white matter)

Question 33

cerebrotendinous xanthomatosis

Answer 33

autosomal recessive disease due to mutation of the CYP27A1 gene leads to the disruption of bile acid synthesis and lipid storage dysfunction
serum cholesterol levels are often normal, but serum cholestanol levels are high

Question 34

cerebrotendinous xanthomatosis: presentation

Answer 34

systemic organ dysfunction with sterol accumulation in the central nervous system, skin, eyes, tendons, lungs, and bones
CNS symptoms include cerebellar ataxia and cognitive decline

Question 35

cerebrotendinous xanthomatosis: imaging

Answer 35

diffuse atrophy and white matter changes preferentially affecting the cerebellum

Question 36

adult-onset leukoencephalopathy

Answer 36

due to a mutation of the colony-stimulating factor 1 (CSF-1R) gene (autosomal dominant)

Question 37

adult-onset leukoencephalopathy: presentation

Answer 37

symptoms of dementia, psychiatric problems, parkinsonism, and seizures typically develop between ages 30 and 50

Question 38

adult-onset leukoencephalopathy: pathology

Answer 38

axonal spheroids with white matter destruction