Metachromatic leukodystrophy (MLD) is a rare, inherited neurological disorder that progressively damages the nervous system, leading to a decline in motor and cognitive functions. MLD is classified as a lysosomal storage disease, involving the accumulation of certain substances within cells. It affects an estimated 1 in 40,000 to 160,000 individuals worldwide.
Understanding Metachromatic Leukodystrophy
MLD arises from a genetic mutation, most commonly in the ARSA gene, which produces the enzyme arylsulfatase A. This enzyme is located within lysosomes, cellular structures that break down waste materials. A deficiency in arylsulfatase A prevents the proper degradation of fatty substances known as sulfatides.
The accumulation of these sulfatides damages the myelin sheath. Myelin is a protective covering that insulates nerve cells, allowing efficient electrical signal transmission. When sulfatides build up, they become toxic and cause the gradual destruction of myelin, known as demyelination. This impairs nerve signal transmission, causing neurological symptoms. While the ARSA gene is the primary cause, mutations in the PSAP gene, which affects a protein that assists arylsulfatase A, can also lead to MLD.
How MLD Progresses
MLD progresses differently based on age of onset, categorized into three forms: late infantile, juvenile, and adult. The late infantile form is the most common, typically appears between 12 and 20 months. Children with this form may initially develop normally but then experience difficulty walking, muscle weakness, and speech impairment; symptoms progress rapidly. As the disease advances, they may lose the ability to walk and talk, develop spasticity, and experience seizures; most children do not survive past age five.
The juvenile form of MLD usually presents between 3 and 10 years. Initial signs often include a decline in school performance, behavioral problems, and gait disturbances. Similar to the late infantile form, juvenile MLD symptoms progress slower, potentially over decades.
Adult MLD is the rarest form, with onset after age 16, sometimes as late as the fourth or fifth decade. This form often begins with psychiatric changes, such as personality shifts or psychosis, and can also involve neurological symptoms like weakness, loss of coordination, and seizures. The adult disease course is variable, with periods of stability and decline, extending over two to three decades.
Identifying MLD
Diagnosing MLD involves clinical evaluation and specific laboratory tests. Healthcare providers assess symptoms and medical history. Biochemical tests measure arylsulfatase A enzyme activity in blood or urine samples to identify a deficiency. These tests indicate MLD.
Genetic testing confirms the diagnosis by identifying specific mutations in the ARSA gene. Imaging studies, such as Magnetic Resonance Imaging (MRI) of the brain, also aid diagnosis. An MRI can reveal characteristic changes in the brain’s white matter, indicating demyelination. Early diagnosis is important, as varied symptoms can lead to misdiagnosis.
Managing MLD
There is no cure for MLD, but treatments manage symptoms and, in some cases, slow progression. Hematopoietic stem cell transplantation (HSCT) is a treatment option for presymptomatic or early-stage cases, particularly in juvenile and adult MLD, and occasionally in late-infantile forms. This procedure transplants healthy donor stem cells to provide the functional arylsulfatase A enzyme. HSCT offers clinical and survival benefits but is invasive and does not reverse existing damage.
Emerging therapies are also being investigated. Gene therapy aims to introduce a healthy ARSA gene into cells, potentially leading to higher enzyme production. One such gene therapy received marketing authorization in Europe in 2020. Enzyme replacement therapy (ERT) seeks to provide the missing enzyme directly.
Supportive care improves quality of life for affected individuals. This includes physical therapy for motor difficulties, occupational therapy for daily activities, and speech therapy for communication and swallowing. Nutritional support is provided if swallowing becomes difficult, and pain management alleviates discomfort. Medications control symptoms like seizures.