Metachromatic leukodystrophy is a neurodegenerative condition with a variable rate of progression that warrants more systematic investigation. In their natural history study of 98 patients with metachromatic leukodystrophy, Dr. Kehrer et al. summarize the prominent symptoms and age of symptom onset according to various forms of the illnesses (late infantile, early juvenile, late juvenile, and adult). In younger persons (under age 6 years), motor manifestations with or without cognitive impairment were common, whereas in late juvenile and adult forms, cognitive symptoms became increasingly common. Patients with earlier disease onset experienced more rapid progression. Dr. Michell-Robinson and Lépine hypothesize that arylsulfatase A activity (the defective enzyme in metachromatic leukodystrophy) and therefore buildup of toxic sulfatide levels might be related to the severity or progression of the illness. Because some older patients may also experience rapid declines, the investigators do not believe sulfatide toxicity to be the primary mediator of disease severity. They also emphasize the importance of motor system involvement as a driver of neurologic deterioration. Although there is much more to understand about this condition, it is clear now that motor symptom manifestations typically precede rapid disease progression.