Inherited Leukodystrophies Flashcards
inherited leukodystrophies in general
heterogenous group of inherited, metabolic demyelinating neurodegenerative diseases of the central nervous system
leukodystrophies presentation
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)
leukodystrophy MRI
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
leukodystrophy treatment
adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe’s disease can be treated with stem cell transplantation
Alexander disease due to
mutation in the glial fibrillary acidic protein (GFAP) gene
Alexander disease: infantile
<3 years of age with developmental regression, macrocephaly, and spasticity
seizures often a main feature
Alexander disease
also has juvenile and adult forms
Alexander disease imaging
frontal-predominant white matter demyelination affecting the subcortical U-fibers with prominent contrast enhancement
Alexander disease pathology
Rosenthal fibers which are densely compacted eosinophilic glial intermediate filaments made of glial fibrillary acidic protein (GFAP)
rosenthal fiber deposition leads to demyelination
metachromatic leukodystrophy due to
autosomal recessive disease due to deficiency of arylsulfatase A enzyme from a mutation in the ARSA gene
metachromatic leukodystrophy presentation
infancy, childhood/juvenile, or adulthood depending on severity of gene dysfunction
metachromatic leukodystrophy: infants
vision loss, spastic ataxia, and seizures
death usually 2-4 years after onset
metachromatic leukodystrophy: juvenile
similar symptoms to infants but slower rate of progression
vision loss, spastic ataxia, and seizures
metachromatic leukodystrophy: adults
behavior changes, psychosis, dementia
metachromatic leukodystrophy imaging
extensive white matter demyelination with sparing of the cortical U fibers
metachromatic leukodystrophy other presentations
a demyelinating sensorimotor polyneuropathy often present in most cases
X-linked adrenoleukodystrophy
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
X-linked adrenoleukodystrophy: presentation
adrenal failure, testicular atrophy, hyperactivity, ataxia, vision/hearing loss, and seizures
X-linked adrenoleukodystrophy: adrenal insufficiency
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
X-linked adrenoleukodystrophy: imaging
posterior predominant white matter demyelination with sparing the frontal lobes and subcortical U fibers and contrast enhnacement
X-linked adrenoleukodystrophy: adrenomyeloneuropathy variant
primarily affects the spinal cord leading to lower extremity weakness and spasticity
Canavan disease
mutations to the ASPA gene leading to deficiency of aspartoacylase
Canavan disease: presentation
infancy with neonatal hypotonia, macrocephaly, dysphagia, vision loss, and seizures
Canavan disease: imaging
diffuse T2 hyperintensities involving all white matter including U-fibers
Canavan disease: pathology
accumulation of N-acetylaspartate leading to cellular edema and spongiform degeneration
Krabbe disease
due to deficiency of the enzyme galactocerebrosidase
Krabbe disease: presentation
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
Krabbe disease: imaging
white matter changes sparing the U fibers
Krabbe disease: pathology
large globoid cells which are PAS-positive multinucleated macrophages with galactocerebroside present
Pelizaeus-Merzbacher disease
due to a mutation of X-linked proteolipid protein (PLP1) gene which is involved in myelin protein integrity
dysfunction leads to hypomyelination
Pelizaeus-Merzbacher disease: presentation
nystagmus, ataxia, and tremor at various ages based on the severity of the mutation
Pelizaeus-Merzbacher disease: pathology
diffuse absence of myelin with preserved myelin islets around blood vessels called “tigroid demyelination” (either striped or spotted appearance of the white matter)
cerebrotendinous xanthomatosis
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
cerebrotendinous xanthomatosis: presentation
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
cerebrotendinous xanthomatosis: imaging
diffuse atrophy and white matter changes preferentially affecting the cerebellum
adult-onset leukoencephalopathy
due to a mutation of the colony-stimulating factor 1 (CSF-1R) gene (autosomal dominant)
adult-onset leukoencephalopathy: presentation
symptoms of dementia, psychiatric problems, parkinsonism, and seizures typically develop between ages 30 and 50
adult-onset leukoencephalopathy: pathology
axonal spheroids with white matter destruction
