MLD, or metachromatic leukodystrophy, is a rare inherited disease in which the body cannot break down certain fats called sulfatides. These fats build up in the nervous system and progressively destroy myelin, the protective insulation around nerve fibers. Without myelin, nerves lose the ability to send signals properly, leading to a decline in movement, speech, vision, and thinking that worsens over time. MLD most commonly appears in early childhood, though it can also begin in adolescence or adulthood.
What Causes MLD
MLD is caused by mutations in the ARSA gene, which provides instructions for making an enzyme called arylsulfatase A. This enzyme’s job is to break down sulfatides, a type of fat found throughout the nervous system. When the enzyme is missing or doesn’t work properly, sulfatides accumulate inside cells. That buildup is toxic to the cells responsible for producing myelin, and it gradually kills them. As more myelin-producing cells die, the insulation around nerves erodes, and nerve signaling breaks down across the brain and body.
A small number of people with MLD have mutations in a different gene called PSAP, which makes a helper protein (saposin B) that works alongside arylsulfatase A. The end result is the same: sulfatides can’t be cleared, and they accumulate to damaging levels.
MLD follows an autosomal recessive inheritance pattern, meaning a child must inherit a defective copy of the gene from both parents. If both parents are carriers, each pregnancy carries a 25% chance the child will have MLD. Carriers themselves typically have no symptoms.
The Three Forms of MLD
MLD is classified into three forms based on when symptoms first appear. The form determines how quickly the disease progresses.
Late Infantile MLD
This is the most common form, with symptoms starting around age 2 or younger. Children who were previously developing normally begin to lose skills they had already gained. Walking becomes unsteady, then impossible. Speech deteriorates. Muscle tone drops, and swallowing becomes difficult. The decline is rapid, and children typically lose most motor and cognitive abilities within a few years of symptom onset.
Juvenile MLD
Juvenile MLD typically begins between ages 3 and 16. The progression is somewhat slower than the late infantile form, but children gradually lose the ability to walk, develop intellectual decline, and may experience seizures, behavioral difficulties, and dementia. School performance often drops noticeably before the physical symptoms become obvious.
Adult MLD
The least common form, adult MLD starts after age 16 and progresses more slowly. Early signs are often psychiatric or behavioral: personality changes, emotional instability, problems at work or school, and sometimes substance misuse. Because these symptoms don’t immediately suggest a neurological disease, adult MLD is frequently misdiagnosed as a psychiatric condition for years before the true cause is identified. Motor symptoms like difficulty walking and slurred speech eventually develop as the disease advances.
Symptoms Across All Forms
Regardless of when it starts, MLD damages the same systems. As myelin loss spreads, the range of symptoms broadens:
- Movement: difficulty walking, stiff or rigid muscles, paralysis, poor coordination
- Communication: slurred or lost speech, difficulty swallowing
- Cognition: memory loss, intellectual decline, dementia
- Senses: progressive vision loss leading to blindness, hearing loss, reduced ability to feel touch or pain
- Other: seizures, loss of bladder and bowel control, gallbladder problems
In the late infantile form, these symptoms pile up quickly. In adult-onset MLD, they may unfold over a decade or longer.
How MLD Is Diagnosed
Diagnosis typically begins when a child or adult shows unexplained neurological decline. Doctors measure arylsulfatase A enzyme activity through a blood test. Normal levels are at or above 0.100 nmol/mL/hr; people with MLD fall well below that threshold. A urine test can also reveal excessive sulfatide levels, which is another hallmark of the disease.
Genetic testing of the ARSA gene confirms the diagnosis. This is especially important because some people have low enzyme activity without actually having MLD, a condition known as pseudodeficiency that can complicate interpretation of enzyme tests alone.
Brain MRI plays a key role in assessing how far the disease has progressed. In MLD, MRI reveals characteristic patterns of white matter damage. Early on, abnormal bright signals appear in the deep white matter near the center of the brain, particularly in the frontal and parietal regions. As the disease advances, a distinctive “tigroid pattern” emerges, with radiating stripes of normal-looking tissue within the areas of damage. This pattern is quite specific to MLD and indicates advanced disease. Changes in deeper brain structures like the basal ganglia and thalamus also appear as severity increases.
Treatment Options
For decades, MLD had no effective treatment. That changed in March 2024, when the FDA approved Lenmeldy (atidarsagene autotemcel), the first gene therapy for MLD. It works by collecting a child’s own blood stem cells, genetically modifying them in a lab to carry functional copies of the ARSA gene, and infusing them back into the patient. Before the infusion, the child undergoes high-dose chemotherapy to clear space in the bone marrow for the modified cells to take hold.
The therapy is approved for a specific group: children with pre-symptomatic late infantile MLD, pre-symptomatic early juvenile MLD, or early symptomatic early juvenile MLD. Timing is critical. In clinical trials, children treated before symptoms appeared showed significantly better motor and cognitive development compared to untreated children with the same disease. Pre-symptomatic early juvenile patients maintained normal development during follow-up. Two early juvenile patients who were treated after symptoms had already progressed died from disease advancement, underscoring why early intervention matters so much.
Lenmeldy is a one-time treatment. For children who don’t qualify for gene therapy, or whose disease has progressed too far, traditional stem cell transplant from a donor remains an option, though outcomes are less predictable and depend heavily on how early it’s performed.
Beyond these targeted approaches, care for MLD is largely supportive: physical therapy to maintain mobility as long as possible, speech therapy, medications to manage seizures and muscle stiffness, and nutritional support when swallowing becomes impaired.
Newborn Screening
Because gene therapy works best before symptoms appear, early detection is essential. In December 2025, the U.S. Secretary of Health and Human Services accepted a recommendation to add MLD to the Recommended Uniform Screening Panel (RUSP), the federal list of conditions that states are encouraged to screen for in every newborn. Sulfatide levels in newborn blood spots can flag babies who may have MLD, prompting confirmatory testing.
Adding MLD to the RUSP doesn’t require states to begin screening immediately. Each state determines its own timeline based on budget and public health priorities. But the federal recommendation provides significant momentum for states to adopt it, which could identify affected children years before they would otherwise be diagnosed.