Metachromatic leukodystrophy is one of the LSDs causing the most problems with regard to accurate patient identification. Arylsulfatase A (ASA) activity is measured in individuals of any age with evidence of weakness, mental regression, psychiatric problems, or white matter changes on magnetic resonance imaging. Low ASA activity could indicate a diagnosis of MLD. However, owing to the high frequency of the so-called pseudodeficiency (Pd) allele, this diagnosis must be confirmed by additional studies. The major cause of pseudodeficiency is a mutation in the polyadenylation signal that results in only about 10% of the normal amount of ASA messenger RNA.4 About 1 in 7 individuals in the general population are heterozygous for this polymorphism. Therefore, about 1 in 200 individuals, whether completely normal or with neurologic problems, is homozygous for this mutation and has low (5%-15% of normal) ASA activity. These low ASA values overlap those found in patients confirmed to have MLD (MLD/MLD) and in carriers of MLD who have 1 MLD-causing mutation and 1 Pd allele (MLD/Pd). Further complications arise because MLD-causing mutations have been found on the Pd allele.5 Since the Pd allele is so common, additional mutations have occurred on the same copy of the ASA gene. However, the accurate diagnosis of suspected patients is not difficult when proper samples are analyzed. First, ASA activity should be measured in leukocytes, and if low, DNA can be isolated from the remaining sample, and the presence of the Pd allele can be determined by polymerase chain reaction–based testing. If the Pd allele is not present and the clinical features suggest a leukodystrophy, the diagnosis of MLD is almost certain. If it is present, MLD must still be considered, and a first morning voiding of urine should be analyzed for sulfatides. If excess sulfatides are being excreted, the diagnosis of MLD is confirmed. It is very important to obtain ASA values from the parents of all patients identified. About 1 in 14 of the healthy parents has ASA activity near that of their affected child due to the frequency of the Pd allele. This is critical to know if the couple requests prenatal testing in subsequent pregnancies. The inheritance of the Pd allele (without an additional mutation) from one parent and an MLD-causing mutation from the other results in low ASA activity in any fetal sample (chorionic villi, cultured trophoblasts, and amniotic fluid cells) received for testing. Having information regarding ASA values and the presence of the Pd allele in the parents results in accurate pregnancy prediction. In addition, patients with multiple sulfatase deficiency have low activity for all sulfatases, including ASA, and excrete sulfatides plus glycosaminoglycans in urine. However, the parents of these patients do not have carrier levels of any sulfatases. It should also be noted that there are some patients who have normal ASA activity but have defects in a sphingolipid activator protein known as saposin B. The few individuals who have been identified clinically resemble those with juvenile MLD. Such patients excrete excess sulfatides in urine, and molecular analysis of the saposin gene can usually identify a mutation(s) in the saposin B region.