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Genetics Home Reference: your guide to understanding genetic conditions
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Hereditary diffuse leukoencephalopathy with spheroids

(often shortened to HDLS)
Reviewed December 2012

What is HDLS?

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 underdiagnosed.

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.

Related Gene(s)

Changes in this gene are associated with hereditary diffuse leukoencephalopathy with spheroids.

  • CSF1R

How do people inherit HDLS?

This condition 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.

Where can I find information about diagnosis or management of HDLS?

These resources address the diagnosis or management of HDLS and may include treatment providers.

  • Gene Review: CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids (http://www.ncbi.nlm.nih.gov/books/NBK100239)
  • Genetic Testing Registry: Gliosis, familial progressive subcortical (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1857300)
  • MedlinePlus Encyclopedia: Dementia (http://www.nlm.nih.gov/medlineplus/ency/article/000739.htm)

You might also find information on the diagnosis or management of HDLS in Educational resources (http://www.ghr.nlm.nih.gov/condition/hereditary-diffuse-leukoencephalopathy-with-spheroids/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/hereditary-diffuse-leukoencephalopathy-with-spheroids/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about HDLS?

You may find the following resources about HDLS helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for HDLS?

  • adult-onset leukodystrophy with neuroaxonal spheroids
  • autosomal dominant leukoencephalopathy with neuroaxonal spheroids
  • hereditary diffuse leukoencephalopathy with axonal spheroids
  • neuroaxonal leukodystrophy

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about HDLS?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding HDLS?

autosomal ; autosomal dominant ; axons ; bradykinesia ; cell ; dementia ; depression ; differentiation ; familial ; gene ; glia ; hereditary ; imaging ; inherited ; involuntary ; involuntary trembling ; leukodystrophy ; leukoencephalopathy ; magnetic resonance imaging ; motor ; mutation ; neurological ; parkinsonism ; prevalence ; proliferation ; protein ; receptor ; sign ; tissue ; tremor ; white matter

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Ali ZS, Van Der Voorn JP, Powers JM. A comparative morphologic analysis of adult onset leukodystrophy with neuroaxonal spheroids and pigmented glia--a role for oxidative damage. J Neuropathol Exp Neurol. 2007 Jul;66(7):660-72. (http://www.ncbi.nlm.nih.gov/pubmed/17620991?dopt=Abstract)
  • Freeman SH, Hyman BT, Sims KB, Hedley-Whyte ET, Vossough A, Frosch MP, Schmahmann JD. Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations. Brain Pathol. 2009 Jan;19(1):39-47. doi: 10.1111/j.1750-3639.2008.00163.x. Epub 2008 Apr 15. (http://www.ncbi.nlm.nih.gov/pubmed/18422757?dopt=Abstract)
  • Gene Review: CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids (http://www.ncbi.nlm.nih.gov/books/NBK100239)
  • Kleinfeld K, Mobley B, Hedera P, Wegner A, Sriram S, Pawate S. Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol. 2013 Feb;260(2):558-71. doi: 10.1007/s00415-012-6680-6. Epub 2012 Sep 30. Review. (http://www.ncbi.nlm.nih.gov/pubmed/23052599?dopt=Abstract)
  • Mitsui J, Matsukawa T, Ishiura H, Higasa K, Yoshimura J, Saito TL, Ahsan B, Takahashi Y, Goto J, Iwata A, Niimi Y, Riku Y, Goto Y, Mano K, Yoshida M, Morishita S, Tsuji S. CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy. Am J Med Genet B Neuropsychiatr Genet. 2012 Dec;159B(8):951-7. doi: 10.1002/ajmg.b.32100. Epub 2012 Oct 4. (http://www.ncbi.nlm.nih.gov/pubmed/23038421?dopt=Abstract)
  • Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2011 Dec 25;44(2):200-5. doi: 10.1038/ng.1027. (http://www.ncbi.nlm.nih.gov/pubmed/22197934?dopt=Abstract)
  • Wider C, Van Gerpen JA, DeArmond S, Shuster EA, Dickson DW, Wszolek ZK. Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD): a single entity? Neurology. 2009 Jun 2;72(22):1953-9. doi: 10.1212/WNL.0b013e3181a826c0. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19487654?dopt=Abstract)

 

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 healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: December 2012
Published: October 20, 2014