The primary cause of this rare genetic disorder is a deficiency of the enzyme arylsulfatase A (ARSA), which is essential for breaking down sulfatides in cells12. This deficiency leads to the accumulation of sulfatides, particularly in the brain and nervous system, resulting in progressive damage to the myelin sheath. The condition is inherited in an autosomal recessive pattern, meaning both parents must carry a copy of the mutated gene for their child to be affected3. Each pregnancy between carrier parents has a 25% chance of producing an affected child, a 50% chance of a carrier child, and a 25% chance of a child who neither has the condition nor is a carrier4.

Symptoms of MLD vary significantly based on the age of onset:

• Late Infantile (1-2 years): Loss of motor skills, difficulty walking, impaired speech, trouble swallowing, muscle weakness, and seizures12.
• Juvenile (4-16 years): Cognitive decline, behavioral problems, difficulty with schoolwork, loss of motor skills, and seizures12.
• Adult (after 16 years): Psychiatric symptoms, including personality changes and emotional instability, seizures, dementia, and gradual loss of motor functions32.

The progression rate differs among these forms, with the late infantile form being the most aggressive, while the adult form typically advances more slowly45.

Diagnosis of MLD typically involves a combination of clinical evaluation, imaging studies, and laboratory tests. MRI scans often reveal characteristic white matter abnormalities12. Blood tests measure arylsulfatase A enzyme levels, while urine tests detect elevated sulfatide concentrations3. Genetic testing identifies mutations in the ARSA gene, confirming the diagnosis4. In some cases, a nerve biopsy may be performed to examine myelin damage5. Prenatal testing is available for at-risk pregnancies through chorionic villus sampling or amniocentesis6.

Currently, there is no cure for MLD, and treatment primarily focuses on managing symptoms and improving quality of life. Supportive therapies include physical, occupational, and speech therapy, as well as medications for seizures and other symptoms12. For pre-symptomatic or minimally symptomatic children, stem cell transplants may be recommended to slow disease progression3. In 2024, the FDA approved Lenmeldy, the first gene therapy for children with certain forms of MLD, offering a potential breakthrough in treatment4. Prognosis varies depending on the age of onset and symptom severity, with life expectancy ranging from a few years to several decades after diagnosis52.

Current research in MLD treatment focuses on gene therapy and enzyme replacement approaches. A groundbreaking study published in Molecular Therapy demonstrated the potential of intravenous gene therapy using an adeno-associated virus vector (AAVPHP.eB) carrying the ARSA enzyme gene1. This method showed promise in correcting sulfatide storage anomalies in a mouse model of MLD, potentially offering a non-invasive treatment option. Additionally, clinical trials are exploring intrathecal enzyme replacement therapy for children with late-infantile MLD3. The recently FDA-approved gene therapy, Atidarsagene autotemcel (Lenmeldy), represents a significant advancement for presymptomatic late infantile, presymptomatic early juvenile, or early symptomatic early juvenile MLD patients5. Ongoing research also investigates stem cell therapies and substrate reduction therapy, aiming to reduce sulfatide accumulation rather than increasing enzyme production3.