Leukodystrophies Flashcards
Krabbe’s Dx
Lysosomal disorder. Globoid cell leukodystrophy.
AR, presents in childhood or infancy
glactocerbroside-B-galactosidase deficiency (Chr 14q31)
Multinucleated PAS+ macrophages/globoid cells
EM: straight or curved tubular inclusions
Metachromatic leukodystrophy
Lysosomal disorder.
AR, very rarely AD; progressive motor disability in infancy, behaviour, education, ang gait problems in childhood, psychosis and behaviour in adults
arylsulfatase A deficiency (Chr 22)
LFB+ and PAS+ macrophages in white matter, neuronal storage in basal ganglia, dentate nucleus, and brain stem; metachromasia with acidified cresyl violet stain; sulfatides stored in kidney tubules
EM: prismatic inclusions, tuffstone inclusions, zebra-like bodies
Adrenoleukodystrophy
Peroxisomal disorder
X-linked (carrier females also show manifestations)
Mutation in ATP-binding cassette transporter reduces the capacity to form the coenzyme A derivative of VLCFA (Chr Xq28); can present in infancy, childhood or adulthood
Perivascular inflammation, Sudan+ and PAS+ macrophages
EM: needle-like trilamellar inclusions; also swollen striated adrenocortical cells
Neonatal adrenoleukodystrophy
Peroxisomal disorder
AR, defective peroxisomal assembly results in absent or severely reduced numbers of peroxisomes and loss of multiple peroxisomal functions; defectin peroxisome receptor-1 (PXR1) in some pts. (Chr 12p13)
Perivascular inflammation, Sudan+ and PAS+ macrophages (same as adrenoleukodystrophy) + cerebral malformations
EM: needle-like trilamellar inclusions; also swollen striated adrenocortical cells
Pelizaeus-Merzbacher Dx
Myelin structural protein dx
X-linked (occasional female cases); may be rapidly fatal or slowly progressive in the 3rd decade
Deficient or abnormal myelin proteolipid protein, results from mutations/deletions/amplifications ox Xq21.33-22
Path: Flaky/tigeroid pattern with residual myelin around blood vessels; all central myelin affected, myelin in peripheral nerves spared; often have cerebellar cortical degeneration; U-fibers relatively spared.
Cockayne’s dx
Defective DNA repair
Cause unknown; causes dysmorphic features and prematures aging
Path: discontinuous myelin loss (mimics tigroid pattern in Pelizaeus-Mazerbacher), vasocentric calcification in cortex and basal ganglia; profound microcephaly
Alexander’s Dx
Astrocytopathy
Sporadic
Non-conservative de novo dominant gain of function mutation in the GFAP gene
Path: Enlarged brain but declines to normal weight by age 2; white matter is diffusely discolored, soft and cavitated especially in frontal lobes; diffuse demyelination with rarefaction of white matter, abundant rosenthal fibers in perivascular, subpial and subependymal regions; small inclusions similar to Rosenthal fibers present in the astrocytic cell bodies around the nucleus are unique to Alexander’s; cerebellum usually less affected
Canavan’s dx
Amino-acidopathy- Defective asparoacylase activity
AR; macrocephaly and increased brain wt initially but become less apparent after several years
Path: poor distinction between gray and white matter; gelatinous extensive vacuolized /spongy white matter that does not cavitate, subcortical U fibers ARE involved, abundant Alzheimer type II astrocytes in cortex. No sudanophilia.
EM: swollen astrocytes contain very long mitochondria with ladder like cristae (unique to Canavan’s).
“The caravan people with big spongy heads climb ladders to attack the U fibers”
Leukoencephalopathy with Vanishing White Matter
AKA Childhood Ataxia with central hypomyelination syndrome (CACH)
Astrocytopathy
AR; EIF-2B subunit mutations (also cause ovarian failure-ovarioleukodystrophy)
Path: massive cavitations of white matter, excessive number of oligodendroglia not only confined to affected WM, but also in well myelinated tracts. abnormally shaped astrocytes or decreased numbers of astrocytes
“The white matter may vanish, but counterintuitively the oligos survive and proliferate”
Aicardi-Goutieres Leukoencephalopathy
AKA Leukodystrophy with microcephaly and calcifications
Autoimmune?
AR, mutations in TREX1 and three subunits of ribonuclease H2 enzyme complex lead to overproduction of a-interferon
Path: Calcifications in white matter and basal ganglia, microcephaly, flaky myelin loss, subtle meningeal and parenchymal inflammation
“Gotye AGregates calcifications in small spaces with his TREX wand”
Orthochromatic leukodystrophy with pigmented macrophages
AKA van Boagaret and Nissen dx
AR; presents in 2nd to 4th decades
White matter looks green 2/2 massive lipofuscin deposition in astrocytes and microglia
EM: multilamelar inclusions and fingerprint bodies in macrophages
“Bogaert and Nissen wer terrible bank robbers leaving behind fingerprints and green money pigment”
