Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a rare genetic condition in which an abnormal accumulation of fat molecules (sulfatides) affects cells in the nervous system. In particular, metachromatic leukodystrophy affects the cells that produce myelin, the substance that insulates and protects nerve cells. Metachromatic leukodystrophy is one of about 50 diseases classified as lysosomal storage disorders (LSD). In these disorders, a genetic variation disrupts the normal activity of lysosomes in human cells.

Lysosomes contain specific proteins (enzymes) responsible for breaking down and recycling molecules such as fats and sugars. Individuals with a lysosomal storage disorder lack one of these necessary enzymes or do not have one of these enzymes in sufficient quantities to break down molecules for proper cell function. As a result, fats and sugars normally broken down by lysosomes can accumulate to toxic levels in the body’s cells and tissues, eventually leading to disease.

Children with metachromatic leukodystrophy can develop signs and symptoms as young as 2 or as late as adulthood. The majority of children with the condition first begin exhibiting symptoms between ages 2 and 4.

Symptoms and complications may include:

• Difficulty with balance
• Gait abnormalities
• Loss of gross or fine motor skills
• Loss of developmental skills such as talking
• Loss of sensation in the extremities (peripheral neuropathy)
• Visual impairment
• Hearing loss
• Seizures
• Gallbladder dysfunction

Metachromatic leukodystrophy is caused by genetic mutations in genes involved in the production of specific enzymes that cells need to function properly. This genetic condition is inherited in an autosomal recessive pattern, which means that children with the condition have received one defective copy of the ARSA or PSAP gene from each of their parents.

The majority of patients with metachromatic leukodystrophy have mutations in the ARSA gene, which is responsible for the production of an enzyme called arylsulfatase. Though much less common, some individuals with metachromatic leukodystrophy have mutations in the PSAP gene, which is responsible for the production of an enzyme called saposin B. Both arylsulfatase and saposin B are located in a cell’s lysosomes and are responsible for the conversion and recycling of specific fat molecules.

Genetic mutations in either the ARSA gene or the PSAP gene result in a deficiency of their corresponding enzyme, leading to an accumulation of fat molecules within cells which eventually causes them to malfunction.

There are currently no approved therapies that reverse the effects of metachromatic leukodystrophy. In 2024, the FDA approved LENMELDY™ (atidarsagene autotemcel), a one-time, customized gene therapy for children with early onset MLD (late infantile or early juvenile) who are pre-symptomatic or show only early symptoms. LENMELDY is made from a child’s own blood-forming stem cells, which are modified to carry a healthy copy of the ARSA gene, enabling the body to break down sulfatides and potentially prevent the disease from progressing.

In some patients, bone marrow transplant (BMT) or hematopoietic stem cell transplant (HSCT) have been effective at slowing or stopping the progression of disease. Additional therapies rely on interdisciplinary collaboration for the management of specific symptoms associated with the disease. For optimal outcomes, management plans are based on each individual child’s presentation and age, as well as a variety of other factors.

At the Boston Children’s Lysosomal Storage Disorder (BoLD) Program, our team of providers is committed to the care of complex patients. As part of Boston Children’s Hospital, we are prepared to meet the challenge of providing multifaceted care by partnering with you and your child to deliver direct care in our BoLD clinic. We work with the broad array of world-class specialists at Boston Children’s to optimize the care we provide your child with metachromatic leukodystrophy.