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Arylsulfatase A (ASA) pseudodeficiency does per definitionem not lead to metachromatic leukodystrophy. It is conceivable, however, that it may contribute to the susceptibility for more common, multifactorial disorders of the nervous system. In order to examine whether there is an association with multiple sclerosis (MS), the most common demyelinating disease, we screened 160 MS patients for ASA activity and looked for pseudodeficiency genotypes using polymerase chain reaction. Four homozygotes for the ASA pseudodeficiency allele were found among the MS patients, but only one in the control sample. Further studies are necessary to validate whether ASA pseudodeficiency is associated with MS.

The clinical and biochemical characteristics of metachromatic leukodystrophy (MLD), true adult forms and late juvenile forms which are still living at adulthood, are reviewed as they both are observed in adult Neurology and Psychiatry departments. Mental deterioration is often the first symptom, evolving progressively; and dementia finally occurs. The latency before the appearance of neurological objective symptoms may be long and extend for several years. In many cases, the behavioral abnormalities are the first symptoms. Some of these forms have been diagnosed as schizophrenia. Very seldom, neurological symptoms, especially ataxia, occur without cognitive or psychiatric disturbances. Most of these cases have pyramidal and cerebellar symptoms, at diverse degrees. Seizures can also occur which is some cases can be early symptoms associated to mental deterioration. The association of central and peripheral neurological symptoms is very characteristic of MLD. The peripheral neuropathy is not generally clinically evidenced, but is rarely missing electrophysiologically. Arylsulfatase A determination should be performed for diagnosis as a first step, and confirmed by the accumulation of sulfatide, either by quantitative determinations in urine or by the sulfatide loading test. It is as yet not clear why certain forms have a rather rapid evolution in 5 years, and others have a very protracted course during decades.

Pseudodeficiency is defined as the in vitro measurement of low activity (usually under 15% of the normal mean for controls) of an enzyme in a healthy person. They may be hard to distinguish from presymptomatic people who will present with adult-onset clinical disease. The finding of healthy people with low arylsulfatase A and galactocerebrosidase activities is well documented. This confuses the laboratory doing testing and the clinician providing the sample. Therefore confirmation of a diagnosis of metachromatic leukodystrophy and Krabbe disease, as well as accurate identification of carriers, requires additional testing including 14C-sulfatide loading in cultured skin fibroblasts, examination of urine for excretion of undegraded lipids, examination of enzyme levels in additional family members including grandparents, and molecular analysis of DNA samples for known mutations.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA). The ASA cDNA as well as the gene has been cloned. The gene is about 3 kb long and consists of 8 exons. The two most frequent alleles causing MLD have been characterized and the distribution of these alleles among patients with different clinical forms of MLD has revealed a simple genotype-phenotype correlation. Some individuals have low ASA activities but are healthy. This condition has been called ASA pseudodeficiency. These individuals are homozygous for the ASA pseudodeficiency allele which only encodes 5-10% of the ASA activity compared to the normal allele. The mutations in the PD allele have been characterized. Based on the knowledge of these mutations diagnostic assays have been developed to differentiate ASA deficiencies associated with PD or MLD.