Demyelinating Leukodystrophies Flashcards
What are the 3 categories of genetic metabolic diseases?
- Neuronal storage diseases
- Leukodystrophies
- Mitochondrial encephalomyopathies
What are genetic metabolic diseases?
Genetic metabolic diseases that affect nervous system preferentially; children are normal at birth but begin to miss developmental milestones
What happens in neuronal storage diseases?
Defect in catabolism of sphingolipids, mucopolysaccharides, or mucolipids leading to accumulation of substrate of enzymes in lysosomes leading to neuronal death
- Cortical involvement leads to loss of cognitive fxn and possible seizure activity
What are leukodystrophies?
White or grey matter affected?
Myelin abnormalities– diffuse involvement of white matter; deterioration of motor skills, spasticity, hypotonia, or ataxia
- Progressive loss of cerebral fxn a/w diffuse & symmetric changes on imaging (compared w demyelinating diseases)
What are mitochondrial encephalomyopathies?
White or grey matter affected?
Oxidative phos disorders (affects generation of ATP which neurons depend on)
- Involve grey matter and skeletal muscle
What gene and enzyme are affected in Tay-Sachs? What is a tell-tale sign during physical exam?
- Gene: HEXA; chromosome 15
- Enzyme: Hexosaminidase A
- GM2 gangliosides accumulate
- Cherry red spot in macula
What is defective in Krabbe disease? Which chromosome is affected?
What accumulated and what cells does this affect?
- Chromosome 14q31
- Defect in galactocerebroside b-galactosidase
- Galactocerebroside accumulation leads to alt pathway of fatty acid removal which generated galactosylphingosine
- Toxic to oligodendroglia
Clinical sx of Krabbe disease?
Histo? What might brain look like grossly?
Motor signs (stiffness & weakness) and gradually inc difficulty feeding
Loss of myelin & oligodendroglia in CNS and PNS
- Neurons and axons are relatively spared
- Aggregations of engorged macrophages (globoid cells) in parenchyma & around blood vessels
Grossly, white matter in brain may look grey/yellow d/t loss of myelin
What are the 2 forms of metachromatic leukodystrophy and what happens in each?
- Late infantile & juvenile form: Motor sx that prgoress gradually, death in 5-10 years
- Adult form: Physciatric & cognitive initially, motor later
What is metachromatic leukodystrophy?
Deficiency in Arylsulfatase A; Cerebroside sulfate accumulates which is toxic to white matter
What is the histo of metachromatic leukodystrophy?
What appears with stain?
Demyelination w resulting gliosis; macrophages in white matter that have vacuolated cytoplasm
Sulfatides bind w toluidine blue –> metachromasia
What is adrenoleukodystrophy?
Progressive disease that is caused by myelin loss of the CNS and PNS w adrenal insufficiency
- Loss of myelin, gliosis, extensive lymphocytic infiltration
- Atrophy of adrenal cortex; VLCFA accumulate in remaining cells
What gene is mutated in adrenoleukodystrophy?
ABCD1 gene– ATP-binding cassette transporter family of proteins
What is the disease course for adrenoleukodystrophy?
- Early and late onset
Early onset: More rapid course
- Young boy presents w behavioral changes & adrenal insufficiency
Late onet: Adults slowly progress
- Periph nerves predominantly
What is Pelizaeus-Merzbacher disease? What are early and late sx?
Slowly progressive widespread white matter dysfxn
- Early sx: Pendular eye movements, hypotonia, choreoathetosis, pyramidal signs
- Later sx: Spasticity, dementia, ataxia
What genetic are involved in Pelizaeus-Merzbacher disease? What is the typical prognosis?
X-linked proteolipid protein (PLP) & DM20; same genetic locus as spastic paraplegia (SPG2)
Fatal
What do you see grossly and with staining in Pelizaeus-Merzbacher disease?
Myelination lost completely in cerebral hemispheres but patches may remain
- “Tigroid” pattern in tissue sections stained for myelin
What is Canavan disease?
Accumulation of N-acetylaspartic acid w spongy degeneration of white matter
What are common sx of Canavan disease?
- Megalocephaly
- Severe mental deficits
- Blindness
- S&S of white matter injury
What causes Canavan disease and what chromosome is affected?
Chromosome 17; loss of fxn mutation in deacetylatingenzyme = Aspartoacylase
What gene mutation causes Alexander disease?
Mutation in gene encoding glial fibrillary acid protein (GFAP)
What do we see on the histo of Alexander disease?
Accumulation of rosenthal fibers (PAS +) around blood vessels, subpial, & subependymal zones
Where pattern of white matter loss do we see in Alexander disease?
Fronot-to-occipital gradient
What disease progression and sx do we see in vanishing white matter leukodystrophy?
Insidious onset in first few years of life w ataxia & seizures; course exacerbated by incurrent illness, only survive a few years after onset of sx
What mutation do we see in vanishing white matter leukodystrophy?
eIF2B reduced throughout body, primarily in white matter
What happens in vanishing white matter leukodystrophy?
Essentially shrinkage of white matter in the cortex
What is a common way that mitochondrial encephalopathies present?
Many diseases of mitochondrial oxidative phosphorylation present as muscle disease w CNS as second most commonly affected tissue
What is mitochondrial encephalomyopathy, lactic acidosis, & stroke-like episodes (MELAS)?
Recurrent episodes of acute neurologic dysfxn, cognitive changes, and then muscle weakness and the things in the name
What is the genetic mutation seen in MELAS?
MTTL1 tRNAleucine
What sx do we see with myoclonic epilepsy & ragged red fibers (MERRF)?
Myoclonus seizure disorder, evidence of myopathy
- Ataxia a/w neuronal loss from cerebellar system
What genetic mutations do we see in MERRF?
tRNA distinct from MELAS
What is Leigh syndrome?
Wide spectrum of mutations in both nuclear & mitochondrial DNA
What sx do we see in Leigh syndrome?
Early childhood: Lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extra-ocular palsies, weakness w hypotonia
- Death w/i 1-2 years
What histo do we see with Leigh syndrome?
Spongiform appearance & vascular proliferation
- Periventricular grey matter of midbrain, tegmentum of pons, periventricular regions of the thalamus & hypothalamus
What is Kearn-Sayre Syndrome?
Sporadic disorder often a/w large mitochondrial SNA deletion or rearrangement
What sx do we see w Kearn-Sayre Syndrome?
- Cerebellar ataxia
- Progressive external ophthalmoplegia (inability to move eyes & eyebrows)
- Pigmentary retinopathy & cardiac conduction defects
What is the histo seen in Kearn-Sayre Syndrome?
Spongiform change in grey & white matter; neuronal loss most evident in cerebellum
