Leukodystrophy is caused primarily by genetic mutations that affect the development or maintenance of the white matter in the brain and spinal cord. White matter consists largely of myelin, a fatty substance that insulates nerve fibers and allows electrical signals to travel quickly and efficiently between nerve cells. When the myelin is damaged or fails to form properly, communication between nerve cells slows down or stops, leading to the symptoms of leukodystrophy.
At the core, leukodystrophies are inherited disorders caused by mutations in genes responsible for producing proteins or enzymes essential for myelin formation, maintenance, or repair. These genetic defects disrupt the normal metabolism of lipids, proteins, or other molecules critical to the structure and function of myelin. Because myelin is vital for proper nervous system function, its deterioration results in progressive neurological problems.
Different types of leukodystrophies arise from mutations in different genes, each affecting myelin in distinct ways. For example, metachromatic leukodystrophy is caused by a deficiency of the enzyme arylsulfatase A, which leads to the accumulation of sulfatides—fatty substances that damage myelin. Without enough arylsulfatase A, sulfatides build up inside cells, causing the breakdown of the protective myelin sheath around nerves. This enzyme deficiency is inherited in an autosomal recessive pattern, meaning a child must inherit defective copies of the gene from both parents to develop the disease.
Other leukodystrophies may result from mutations affecting the production of structural proteins in myelin or enzymes involved in lipid metabolism. These mutations can cause abnormal myelin formation during brain development or lead to its gradual destruction after birth. Some leukodystrophies are linked to defects in the genes that regulate the growth and maintenance of oligodendrocytes, the cells responsible for producing myelin in the central nervous system.
The genetic mutations causing leukodystrophies are often inherited, but the specific inheritance pattern can vary. Many leukodystrophies follow an autosomal recessive pattern, where both parents carry one defective gene but do not show symptoms themselves. Others may be inherited in an X-linked pattern, primarily affecting males, or rarely through autosomal dominant inheritance, where only one defective gene copy can cause disease.
In addition to genetic causes, leukodystrophies can sometimes be influenced by mutations that affect mitochondrial function or other cellular processes critical for nerve cell health. These mutations can impair energy production or cellular repair mechanisms, indirectly leading to myelin damage.
Because leukodystrophies involve the central nervous system’s white matter, the symptoms often include difficulties with movement, coordination, vision, hearing, and cognitive functions. The severity and progression depend on the specific type of leukodystrophy and the underlying genetic mutation.
In summary, leukodystrophy is caused by inherited genetic mutations that disrupt the normal formation, maintenance, or repair of myelin in the brain and spinal cord. These mutations affect enzymes, structural proteins, or cellular processes essential for healthy white matter, leading to progressive neurological impairment.
