Metachromatic leukodystrophy
Metachromatic leukodystrophy is the result of genetic defects in the enzymes associated with the cellular compartment the lysosome. MLD is one of two leukodystophies that are also a lysosomal storage disorder. MLD is inherited in an autosomal recessive way and is the result of mutations in three different ARSA alleles that encode the enzyme arylsulfatase A (ASA or sometimes ARSA), also called sulfatide sulfatase. ASA is responsible for the breakdown of sulfatides, sphingolipids present in neuronal membranes as well as in myelin. When there is a mutation in the gene that encodes ASA, the result is it decreases production, which subsequently leads to diminished degradation of sulfatides, thus causing them to accumulate. This accumulation of sulfatides is poisonous to oligodendrocytes, the myelin-producing cells of the CNS, effectively leading to a disturbance in myelin structure followed by demyelination. The pattern of inheritance of the three different alleles affects what type of MLD a person develops. Two null alleles are responsible for the infantile version, and do not allow for any production of ASA. A heterozygous individual (one null allele, one non-null allele) develops the juvenile form and sees some production of ASA, while an individual with two non-null alleles (but still mutated) develops the adult form. Krabbe disease
Like MLD, Krabbe disease is another type of leukodystrophy with autosomal recessive inheritance that is the result of a lysosomal storage disorder. It is due to a deletion in exon 16 of the GALC gene that causes a frameshift mutation leading to a premature stop codon.
Epidemiology
Currently, no research has shown a higher prevalence of most leukodystrophy types in any one place around the world. There is, however, a higher prevalence of the Canavan disease in the Jewish population. 1 in 40 individuals of Ashkenazi Jewish descent are carriers of Canavan disease. This estimates to roughly 2.5%. Additionally, due to an autosomal recessive inheritance patterns, there is no significant difference found between affected males and affected females for most types of leukodystrophy including, but not limited to, metachromatic leukodystrophy, Krabbe disease, Canavan disease, and Alexander disease. The one exception to this is any type of leukodystrophy carried on a sex chromosome, such as X-linked adrenoleukodystrophy, which is carried on the X-chromosome. Because of the inheritance pattern of X-linked diseases, males are more often affected by this type of leukodystrophy, although female carriers are often symptomatic, though not as severely so as males. Research
The National Institute of Neurological Disorders and Stroke (NINDS, under the U.S. National Institutes of Health) supports research on genetic disorders, including the leukodystrophies. NINDS also supports researchers who are working with the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) which promotes advances in the diagnosis and treatment of leukodystrophies.The European Leukodystrophy Association also supports research into leukodystrophy. As of 2020, more than 387 research projects have been funded. Each year, ELA invites the international scientific community to submit research projects in the field of genetic leukodystrophies, the cerebral white matter in premature infants, and of myelin repair.