Hereditary diffuse leukoencephalopathy with spheroids

Alternate names

HDLS; Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; Leukoencephalopathy, diffuse hereditary, with spheroids; Adult-onset leukodystrophy with neuroaxonal spheroids; Autosomal dominant leukoencephalopathy with neuroaxonal spheroids; Hereditary diffuse leukoencephalopathy with axonal spheroids; Neuroaxonal leukodystrophy; Pigmentary orthochromatic leukodystrophy; POLD

Definition

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.

Cause

• 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), which 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).

Gene mutations

• Mutations in the CSF1R gene lead to a altered CSF-1 receptor protein which is unable to stimulate cell signaling pathways.
• Exactly how these gene mutations cause the signs and symptoms of HDLS is unknown.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

• HDLS is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
• In most cases, an affected person inherits the mutation from one affected parent.
• Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Signs and symptoms

• HDLS is characterized by leukoencephalopathy, which is damage to a type of brain tissue called white matter (made up of nerve fibers (axons) covered by myelin).
• Also common in HDLS are swellings called spheroids in the axons of the brain, which are a sign of axon damage.
• This damage is thought to contribute to the symptoms see in this condition, including personality changes (including a loss of social inhibitions and depression which are among the earliest symptoms of HDLS), memory loss and loss of executive function (the ability to plan and implement actions and develop problem-solving strategies which impairs skills such as impulse control, self-monitoring, and focusing attention appropriately).
• Some people with HDLS have mild seizures early in the disease and may experience a severe decline in thinking and reasoning abilities (dementia) as the disease progresses.
• 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.
• Over time, almost all affected individuals become unable to walk, speak, and care for themselves.

Diagnosis

The diagnosis is suspected in individuals with characteristic clinical and brain MRI findings and is confirmed by identification of a heterozygous pathogenic variant in CSF1R.[1].

Treatment

Supportive management includes: attention to general care and nutritional requirements; antiepileptic drugs for seizures; and antibiotic treatment for general and recurrent infections.[2].

NIH genetic and rare disease info

• NIH info on Hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids is a rare disease.

Hereditary diffuse leukoencephalopathy with spheroids Resources
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