Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a neurological condition characterized by changes to certain areas of the brain. A hallmark of HDLS is leukoencephalopathy, which is damage to a type of brain tissue called white matter. White matter consists of nerve fibers (axons) covered by a substance called myelin that insulates and protects the nerves. Areas of damage to this brain tissue (white matter lesions) can be seen with magnetic resonance imaging (MRI). Also common in HDLS are swellings called spheroids in the axons of the brain, which are a sign of axon damage. Damage to myelin and axons is thought to contribute to many of the neurological signs and symptoms in people with HDLS.
Symptoms of HDLS usually begin in a person's forties and worsen over time. Personality changes, including a loss of social inhibitions and depression, are among the earliest symptoms of HDLS. Affected individuals may develop memory loss and loss of executive function, which is the ability to plan and implement actions and develop problem-solving strategies. Loss of this function impairs skills such as impulse control, self-monitoring, and focusing attention appropriately. Some people with HDLS have mild seizures, usually only when the condition begins. As HDLS progresses, it causes a severe decline in thinking and reasoning abilities (dementia).
Over time, motor skills are affected, and people with HDLS may have difficulty walking. Many develop a pattern of movement abnormalities known as parkinsonism, which includes unusually slow movement (bradykinesia), involuntary trembling (tremor), and muscle stiffness (rigidity). The pattern of cognitive and motor problems are variable, even among individuals in the same family, although almost all affected individuals ultimately become unable to walk, speak, and care for themselves.
HDLS and another condition called familial pigmentary orthochromatic leukodystrophy (POLD) cause very similar white matter damage and cognitive and movement problems. POLD was thought to be distinguished by the presence of abnormally pigmented cells in the brain and an absence of spheroids; however, people with HDLS can have pigmented cells, too, and people with POLD can have spheroids. Some scientists suggest that these two conditions are related and could be combined into one condition named adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
How common is HDLS?
HDLS is thought to be a rare disorder, although the prevalence is unknown. Because it can be mistaken for other disorders with similar symptoms, HDLS may be under-diagnosed.
What genes are related to HDLS?
HDLS is caused by mutations in the CSF1R gene. This gene provides instructions for making a protein called colony stimulating factor 1 receptor (CSF-1 receptor). This protein is found in the outer membrane of certain types of cells. The CSF-1 receptor triggers signaling pathways that control many important cellular processes, such as cell growth and division (proliferation) and maturation of the cell to take on defined functions (differentiation).
CSF1R gene mutations in HDLS lead to an altered CSF-1 receptor protein that is likely unable to stimulate cell signaling pathways. It is unclear, though, how the gene mutations lead to white matter damage or cognitive and movement problems in people with HDLS.
The resources on this site should not be used as a substitute for
professional medical care or advice. Users seeking information about
a personal genetic disease, syndrome, or condition should consult with a qualified
See How can I find a genetics professional in my area? in the Handbook.