Metachromatic leukodystrophy (MLD) is a rare, inherited, progressive neurological disorder belonging to the group of lysosomal storage diseases. It affects the myelin sheath, the protective covering that insulates nerve fibers in both the central nervous system (brain and spinal cord) and the peripheral nerves. The damage to this white matter leads to a progressive decline in neurological function, impacting motor skills, cognition, and sensory perception, which worsens over time.
The Genetic Cause and Underlying Mechanism
The disorder is inherited in an autosomal recessive pattern, meaning an individual must inherit a mutated gene from both parents to develop the condition. MLD is primarily caused by a mutation in the ARSA gene, which provides instructions for making the enzyme Arylsulfatase A (ARSA). Rarely, mutations in the PSAP gene, which codes for a protein that activates ARSA, can cause a similar disorder.
Arylsulfatase A is a lysosomal enzyme responsible for breaking down specific fatty substances called sulfatides. Sulfatides are glycosphingolipids found predominantly in the myelin sheath. When the ARSA enzyme is deficient or non-functional, the body cannot degrade the sulfatides efficiently, causing them to accumulate inside the cells.
This toxic buildup occurs in the myelin-producing cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. The accumulation interferes with the cells’ ability to maintain the myelin sheath, leading to demyelination. This damage impairs the nerves’ ability to conduct electrical impulses normally, causing the progressive neurological decline seen in MLD. The term “metachromatic” refers to how these accumulated sulfatides stain differently under a microscope.
Clinical Presentation and Disease Types
MLD is classified into three forms based on the age when symptoms first appear; earlier onset generally correlates with greater severity and faster progression.
Late Infantile Form
This is the most common form, accounting for 50–60% of all cases, typically beginning between 12 and 30 months of age. Children may initially appear to develop normally before experiencing a rapid and severe regression. Symptoms often start with difficulty walking or gait abnormalities, quickly leading to loss of motor skills, weak muscle tone, impaired speech and swallowing, and progressive loss of vision.
Juvenile Form
This form accounts for 20–30% of cases, with onset between 3 and 16 years of age. Progression is generally slower than the infantile type. Initial symptoms often involve a decline in school performance, behavioral difficulties, and a lack of coordination. Other symptoms include peripheral neuropathy, intellectual decline, and personality changes.
Adult Form
The Adult form is the least common, representing 15–20% of cases, with symptoms typically beginning after age 16. This form often presents initially with psychiatric issues, such as psychosis, hallucinations, or mood changes, which can lead to misdiagnosis. Motor symptoms, such as difficulty walking and peripheral neuropathy, tend to develop later, and the disease course is more protracted, often lasting over ten years.
Diagnostic Procedures
Diagnosis begins with initial laboratory screening to measure the activity of the Arylsulfatase A (ARSA) enzyme, usually in white blood cells. A significantly deficient enzyme level suggests MLD, though a condition called pseudodeficiency can also cause low ARSA activity without causing the disease.
To differentiate MLD from pseudodeficiency, follow-up biochemical tests confirm the accumulation of sulfatides, often by measuring their level in the patient’s urine. Neuroimaging is also used, with Magnetic Resonance Imaging (MRI) of the brain identifying characteristic white matter abnormalities, sometimes appearing in a distinctive “tigroid pattern.”
The definitive diagnosis requires genetic testing, which analyzes the patient’s DNA for mutations in the ARSA gene. Identifying two mutated copies of the gene confirms the diagnosis. Nerve conduction studies, which measure the speed of electrical impulses, are also frequently used to detect peripheral nerve damage.
Current Treatment and Management Strategies
Therapeutic strategies focus on slowing disease progression and managing symptoms, as no treatment can fully reverse damage once symptoms are established. Supportive care is a primary component of management, involving a multidisciplinary team. This includes physical and occupational therapy to maintain muscle function and mobility, and speech therapy for swallowing and communication difficulties.
For pre-symptomatic or very early-stage patients, disease-modifying treatments offer the best chance of stabilizing neurological function. Hematopoietic Stem Cell Transplantation (HSCT) is a standard option, replacing the patient’s stem cells with a donor’s cells that produce functional ARSA. HSCT is generally considered for pre-symptomatic or mildly symptomatic patients with the late juvenile and adult forms, as it can stabilize neurocognitive function, though motor function loss may still progress.
A significant advancement is gene therapy, approved in certain regions for children with pre-symptomatic late infantile and early juvenile MLD. This approach uses the patient’s own stem cells, which are genetically modified outside the body to carry a healthy copy of the ARSA gene. This one-time treatment, delivered via autologous HSCT, aims to provide a faster and more effective metabolic correction when administered before neurological decline.