Metachromatic Leukodystrophy (ARSA)

Metachromatic leukodystrophy (MLD) is an autosomal recessive disease caused by pathogenic variants in the gene ARSA. There are three major forms of MLD, all of which are progressive. Late infantile: This is the most severe form. Affected babies begin showing symptoms between 1-2 years old. They lose developmental milestones and become clumsy with slurred speech. Physical and mental abilities decline, and eventually affected children become bedridden. Life expectancy is in childhood or the teenage years. Juvenile: Affected children begin to display symptoms between 4-14 years old. Initial symptoms include trouble in school, behavioral problems, clumsiness, difficulty walking normally, slurred speech, and seizures. Life expectancy ranges from the teenage years to the 30s. Adult: Symptoms may begin at any point after puberty. The initial symptoms are variable. Some affected individuals present with personality changes and/or psychiatric diagnoses, while others first experience weakness and loss of coordination. Symptoms progress to include peripheral neuropathy (nerve pain), seizures, and eventually incontinence, abnormal movements, and inability to communicate. Life expectancy is 20 to 30 years after the first symptoms develop. It may be possible to predict which type of MLD a person will have based on the type of pathogenic variants inherited, although predictions cannot be made with 100% certainty. MLD can affect people of any ethnicity, but it is more common among Navajo Native Americans or Sephardic Jewish individuals from Yemen.

Disease Name
 GeneGuaranteed Exons 
 Inheritance Ethnicity
 Carrier Frequency
 Detection Rate
Residual Risk

Metachromatic LeukodystrophyARSA1-8 [8] (*19)ARAshkenazi Jewish< 1 in 500>95%0.000100190361687206
Metachromatic LeukodystrophyARSA1-8 [8] (*19)ARWorldwide1 in 10050%0.0050251256281407
Metachromatic LeukodystrophyARSA1-8 [8] (*19)ARSephardic Jewish – Yemenite1 in 46>95%0.00110987791342952
Metachromatic LeukodystrophyARSA1-8 [8] (*19)ARNavajo 1 in 25>95%0.00207900207900208