Leukodystrophies

Feature	Demyelination (Acquired)	Dysmyelination (Leukodystrophy)
Mechanism	Loss of normally formed myelin	Genetically defective myelin formation or maintenance
Myelin	Initially normal, then destroyed	Never properly formed or maintained
Course	May be relapsing or monophasic	Progressive, often relentless
Examples	MS, ADEM, PML, NMOSD	Krabbe, MLD, ALD, Alexander, Canavan, PMD
Inheritance	Not Mendelian (complex genetic risk)	Mendelian: most AR; Alexander = AD; ALD/PMD = X-linked
Age of onset	Typically adolescence/adulthood	Often infancy or early childhood (adult forms exist)

Disease	Inheritance	Gene / Protein	Chromosome	Enzyme / Defect	Pathology Hallmark	MRI Pattern	Onset
MLD	AR	ARSA	22q13.33	Arylsulfatase A	Metachromatic granules	Periventricular, symmetric	Late infantile (1–2 yr)
Krabbe	AR	GALC	14q31.3	Galactocerebrosidase	Globoid cells	Periventricular, posterior	Infantile (3–6 mo)
ALD	X-linked	ABCD1	Xq28	Peroxisomal VLCFA transporter	Perivascular lymphocytes	Posterior/parieto-occipital	Boys 4–8 yr
Alexander	AD	GFAP	17q21.31	Glial fibrillary acidic protein	Rosenthal fibers	Frontal predominance	Infantile (<2 yr)
Canavan	AR	ASPA	17p13.2	Aspartoacylase	Spongiform degeneration	Diffuse, subcortical U-fibers early	Infantile (3–6 mo)
PMD	X-linked	PLP1	Xq22.2	Proteolipid protein 1	Tigroid pattern	Diffuse hypomyelination	Infancy
VWM/CACH	AR	EIF2B (1–5)	Various	Eukaryotic initiation factor 2B	Cystic white matter	Vanishing white matter	Childhood (2–6 yr)
CTX	AR	CYP27A1	2q35	Sterol 27-hydroxylase	Xanthomas, cholestanol deposits	Cerebellar white matter	Childhood–adult

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