Demyelinating Leukodystrophies

Question 1

What are the 3 categories of genetic metabolic diseases?

Answer 1

• Neuronal storage diseases
• Leukodystrophies
• Mitochondrial encephalomyopathies

Question 2

What are genetic metabolic diseases?

Answer 2

Genetic metabolic diseases that affect nervous system preferentially; children are normal at birth but begin to miss developmental milestones

Question 3

What happens in neuronal storage diseases?

Answer 3

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

Question 4

What are leukodystrophies?

White or grey matter affected?

Answer 4

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)

Question 5

What are mitochondrial encephalomyopathies?

White or grey matter affected?

Answer 5

Oxidative phos disorders (affects generation of ATP which neurons depend on)
- Involve grey matter and skeletal muscle

Question 6

What gene and enzyme are affected in Tay-Sachs? What is a tell-tale sign during physical exam?

Answer 6

• Gene: HEXA; chromosome 15
• Enzyme: Hexosaminidase A
• GM2 gangliosides accumulate
• Cherry red spot in macula

Question 7

What is defective in Krabbe disease? Which chromosome is affected?

What accumulated and what cells does this affect?

Answer 7

• Chromosome 14q31
• Defect in galactocerebroside b-galactosidase
• Galactocerebroside accumulation leads to alt pathway of fatty acid removal which generated galactosylphingosine
• Toxic to oligodendroglia

Question 8

Clinical sx of Krabbe disease?

Histo? What might brain look like grossly?

Answer 8

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

Question 9

What are the 2 forms of metachromatic leukodystrophy and what happens in each?

Answer 9

• Late infantile & juvenile form: Motor sx that prgoress gradually, death in 5-10 years
• Adult form: Physciatric & cognitive initially, motor later

Question 10

What is metachromatic leukodystrophy?

Answer 10

Deficiency in Arylsulfatase A; Cerebroside sulfate accumulates which is toxic to white matter

Question 11

What is the histo of metachromatic leukodystrophy?

What appears with stain?

Answer 11

Demyelination w resulting gliosis; macrophages in white matter that have vacuolated cytoplasm

Sulfatides bind w toluidine blue –> metachromasia

Question 12

What is adrenoleukodystrophy?

Answer 12

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

Question 13

What gene is mutated in adrenoleukodystrophy?

Answer 13

ABCD1 gene– ATP-binding cassette transporter family of proteins

Question 14

What is the disease course for adrenoleukodystrophy?

- Early and late onset

Answer 14

Early onset: More rapid course
- Young boy presents w behavioral changes & adrenal insufficiency

Late onet: Adults slowly progress
- Periph nerves predominantly

Question 15

What is Pelizaeus-Merzbacher disease? What are early and late sx?

Answer 15

Slowly progressive widespread white matter dysfxn

• Early sx: Pendular eye movements, hypotonia, choreoathetosis, pyramidal signs
• Later sx: Spasticity, dementia, ataxia

Question 16

What genetic are involved in Pelizaeus-Merzbacher disease? What is the typical prognosis?

Answer 16

X-linked proteolipid protein (PLP) & DM20; same genetic locus as spastic paraplegia (SPG2)

Fatal

Question 17

What do you see grossly and with staining in Pelizaeus-Merzbacher disease?

Answer 17

Myelination lost completely in cerebral hemispheres but patches may remain
- “Tigroid” pattern in tissue sections stained for myelin

Question 18

What is Canavan disease?

Answer 18

Accumulation of N-acetylaspartic acid w spongy degeneration of white matter

Question 19

What are common sx of Canavan disease?

Answer 19

• Megalocephaly
• Severe mental deficits
• Blindness
• S&S of white matter injury

Question 20

What causes Canavan disease and what chromosome is affected?

Answer 20

Chromosome 17; loss of fxn mutation in deacetylatingenzyme = Aspartoacylase

Question 21

What gene mutation causes Alexander disease?

Answer 21

Mutation in gene encoding glial fibrillary acid protein (GFAP)

Question 22

What do we see on the histo of Alexander disease?

Answer 22

Accumulation of rosenthal fibers (PAS +) around blood vessels, subpial, & subependymal zones

Question 23

Where pattern of white matter loss do we see in Alexander disease?

Answer 23

Fronot-to-occipital gradient

Question 24

What disease progression and sx do we see in vanishing white matter leukodystrophy?

Answer 24

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

Question 25

What mutation do we see in vanishing white matter leukodystrophy?

Answer 25

eIF2B reduced throughout body, primarily in white matter

Question 26

What happens in vanishing white matter leukodystrophy?

Answer 26

Essentially shrinkage of white matter in the cortex

Question 27

What is a common way that mitochondrial encephalopathies present?

Answer 27

Many diseases of mitochondrial oxidative phosphorylation present as muscle disease w CNS as second most commonly affected tissue

Question 28

What is mitochondrial encephalomyopathy, lactic acidosis, & stroke-like episodes (MELAS)?

Answer 28

Recurrent episodes of acute neurologic dysfxn, cognitive changes, and then muscle weakness and the things in the name

Question 29

What is the genetic mutation seen in MELAS?

Answer 29

MTTL1 tRNAleucine

Question 30

What sx do we see with myoclonic epilepsy & ragged red fibers (MERRF)?

Answer 30

Myoclonus seizure disorder, evidence of myopathy

- Ataxia a/w neuronal loss from cerebellar system

Question 31

What genetic mutations do we see in MERRF?

Answer 31

tRNA distinct from MELAS

Question 32

What is Leigh syndrome?

Answer 32

Wide spectrum of mutations in both nuclear & mitochondrial DNA

Question 33

What sx do we see in Leigh syndrome?

Answer 33

Early childhood: Lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extra-ocular palsies, weakness w hypotonia
- Death w/i 1-2 years

Question 34

What histo do we see with Leigh syndrome?

Answer 34

Spongiform appearance & vascular proliferation

- Periventricular grey matter of midbrain, tegmentum of pons, periventricular regions of the thalamus & hypothalamus

Question 35

What is Kearn-Sayre Syndrome?

Answer 35

Sporadic disorder often a/w large mitochondrial SNA deletion or rearrangement

Question 36

What sx do we see w Kearn-Sayre Syndrome?

Answer 36

• Cerebellar ataxia
• Progressive external ophthalmoplegia (inability to move eyes & eyebrows)
• Pigmentary retinopathy & cardiac conduction defects

Question 37

What is the histo seen in Kearn-Sayre Syndrome?

Answer 37

Spongiform change in grey & white matter; neuronal loss most evident in cerebellum