Leukodystrophies

Question 1

Leukodystophies are progressive white matter diseases, typically representing hereditary inborn errors in metabolism
-Referred to as “Dysmyelinating diseases” - myelin is chemically or structurally abnormal

Question 2

Metachromatic Leukodystrophy:
-Inheritance
-Genetic Defect

Answer 2

-AR

-Arylsulfatase A

Question 3

Krabbe Disease:
-Inheritance
-Genetic Defect

Answer 3

-AR

-Galactocerebrosidase

Question 4

Adenoleukodystrophy:
-Inheritance
-Genetic Defect

Answer 4

-X-linked recessive

-ABCD1 transporter (Xq28)

Question 5

Alexander Disease:
-Inheritance
-Genetic Defect

Answer 5

-Autosomal DOMINANT (New Mutation)

-GFAP

Question 6

Canavan Disease:
-Inheritance
-Genetic Defect

Answer 6

-AR

-Aspartoacylase

Question 7

Vanishing White Matter Disease:
-Inheritance
-Genetic Defect

Answer 7

-AR

-Translation initiation factor elF2B subunits

Question 8

Retinal Vasculopathy with Cerebral Leukodystrophy:
-Inheritance
-Genetic Defect

Answer 8

-Autosomal DOMINANT

-TREX1

Question 9

Metachromatic Leukodystrophy (Arylsulfatase A; AR):
-Clinical (infant, kid & adult forms)
-Pathologic features
-Lab findings

Answer 9

-Infant: Hypotonia, weakness
-Kid: Behavioral/intellect, gait issues
-Adult: Psychiatric

-Metachromatic Acidified Cresyl Violet-Stained inclusions in Oligos & Macrophages
-EM: Prismatic inclusions
-PNS demyelinating neuropathy

-Low arylsulfatase A activity in fibroblast cultures

Question 10

Krabbe Disease (Galactocerebrosidase; AR):
-Clinical
-Pathologic features

Answer 10

-Infantile onset w/ progressive Motor and Mental Retardation, Blindness, Hyperirritibility, Myoclonus, and Neuropathy

-CNS: Multinucleated Globoid Cells (monocytic-lineage)
-PNS: Demyelinating neuropathy
-EM: Macrophages w/ tubular inclusions

Question 11

Adenoleukodystrophy (ABCD1 transporter; X-linkedR):
-Clinical
-Pathologic features

Answer 11

-Variable Adrenal Dysfunction
-Adrenomyeloneuropathy variant presents as progressive paraparesis, bowl and bladder dysfunction

-Parieto-Occipital lobe WM affected
-Perivascular CD8 T-cell infiltrate
-EM: Striated Trilaminar Lipid Inclusions in Macrophages, Schwann, Adrenal Cortial, and Testicular Leydig cells

Question 12

Alexander Disease (GFAP; AD):
-Clinical
-Pathologic features

Answer 12

-Megalencephalic with Seizures and Spasticity

-Numerous ROSENTHAL Fibers (perivascular, parenchymal, subpial)

Question 13

Canavan Disease (Aspartoacylase; AR):
-Clinical
-Pathologic features
-Lab findings

Answer 13

-Irritability (Early); Hypotonia, Blindness, Seizures, Megalencephaly (Late)

-Intramyelinic vacuolation
-EM: Myelin splitting at intraperiod line; Astrocytes have Atypical Mitochondria

-Increased N-acetylaspartic acid in Urine, CSF, and Plasma
-Cultures skin fibroblasts with deficient Aspartoacylase activity

Question 14

Vanishing White Matter Disease (elF2B subunits; AR):
-Clinical
-Pathologic features

Answer 14

-Childhood or Adolescent onset of Hypotonia, Seizures, Vomiting and Diarrhea - Worsening with fever or head trauma
-Early Preservation of intellect

-Foamy Oligos containing myelin-oligodendrocyte protein (MOG)

Question 15

Retinal Vasculopathy with Cerebral Leukodystrophy (TREX1; AD):
-Clinical
-Pathologic features

Answer 15

-Middle Age onset - Headache, Memory impairment, Seizures, Motor, Sensory and Cerebellar Signs

-Necrosis, Calcification, Vasculopathy w/ fibrinoid necrosis and hyalinization (resembles radiation-induced encephalopathy)