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Hereditary diffuse leukoencephalopathy with spheroids(HDLS)

MedGen UID:
341741
Concept ID:
C1857300
Disease or Syndrome
Synonyms: Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia; CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids; DEMENTIA, FAMILIAL, NEUMANN TYPE; Gliosis, familial progressive subcortical; HDLS; LEUKOENCEPHALOPATHY WITH NEUROAXONAL SPHEROIDS, AUTOSOMAL DOMINANT; SUBCORTICAL GLIOSIS OF NEUMANN
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: HPO
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
 
Gene (location): CSF1R (5q32)
OMIM®: 221820
Orphanet: ORPHA313808

Disease characteristics

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which includes both hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), is characterized by executive dysfunction, memory decline, personality changes, motor impairments, and seizures. A frontal lobe syndrome (e.g., loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course. The mean age of onset is usually in the fourth decade. Affected individuals eventually become bedridden with spasticity and rigidity. The disease course ranges from two to 30 or more years (mean: 8 years).  [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Christina Sundal  |  Zbigniew Wszolek   view full author information

Additional descriptions

From OMIM
Hereditary diffuse leukoencephalopathy with spheroids is an autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes (summary by Rademakers et al., 2012).  http://www.omim.org/entry/221820
From GHR
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a neurological condition characterized by changes to certain areas of the brain. A hallmark of ALSP is leukoencephalopathy, which is the alteration of 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 them. The axons extend from nerve cells (neurons) and transmit nerve impulses throughout the body. Areas of damage to this brain tissue (white matter lesions) can be seen with magnetic resonance imaging (MRI). Another feature of ALSP is swellings called spheroids in the axons of the brain, which are a sign of axon damage. Also common in ALSP are abnormally pigmented glial cells. Glial cells are specialized brain cells that protect and maintain neurons. Damage to myelin and neurons is thought to contribute to many of the neurological signs and symptoms in people with ALSP. Symptoms of ALSP usually begin in a person's forties and worsen over time. Personality changes, including depression and a loss of social inhibitions, are among the earliest symptoms of ALSP. 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 ALSP have mild seizures, usually only when the condition begins. As ALSP progresses, it causes a severe decline in thinking and reasoning abilities (dementia). Over time, motor skills are affected, and people with ALSP 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. ALSP was previously thought to be two separate conditions, hereditary diffuse leukoencephalopathy with spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD), both of which cause very similar white matter damage and cognitive and movement problems. POLD was thought to be distinguished by the presence of pigmented glial cells and an absence of spheroids; however, people with HDLS can have pigmented cells, too, and people with POLD can have spheroids. HDLS and POLD are now considered to be part of the same disease spectrum, which researchers have recommended calling ALSP.  http://ghr.nlm.nih.gov/condition/adult-onset-leukoencephalopathy-with-axonal-spheroids-and-pigmented-glia

Clinical features

Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Shuffling gait
MedGen UID:
68545
Concept ID:
C0231688
Finding
Depression
MedGen UID:
137999
Concept ID:
C0344315
Finding
Postural instability
MedGen UID:
334529
Concept ID:
C1843921
Finding
Frontal lobe dementia
MedGen UID:
337641
Concept ID:
C1846712
Finding
CNS demyelination
MedGen UID:
336533
Concept ID:
C1849196
Finding
Neuronal loss in central nervous system
MedGen UID:
342515
Concept ID:
C1850496
Finding
Memory impairment
MedGen UID:
368424
Concept ID:
C1963167
Finding
Spasticity
MedGen UID:
504771
Concept ID:
CN001152
Finding
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Rigidity
MedGen UID:
505075
Concept ID:
CN001866
Finding
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Bradykinesia
MedGen UID:
505077
Concept ID:
CN001869
Finding
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Gliosis
MedGen UID:
505139
Concept ID:
CN001968
Finding
The presence of gliosis in the central nervous system.
Apraxia
MedGen UID:
505148
Concept ID:
CN001982
Finding
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
Mutism
MedGen UID:
505187
Concept ID:
CN002088
Finding
Leukoencephalopathy
MedGen UID:
505209
Concept ID:
CN002135
Finding
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Abnormality of the cerebral white matter
MedGen UID:
425101
Concept ID:
CN002271
Finding
An abnormality of the cerebral white matter.
Spasticity
MedGen UID:
504771
Concept ID:
CN001152
Finding
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHereditary diffuse leukoencephalopathy with spheroids
Follow this link to review classifications for Hereditary diffuse leukoencephalopathy with spheroids in Orphanet.

Recent clinical studies

Etiology

Kinoshita M, Kondo Y, Yoshida K, Fukushima K, Hoshi K, Ishizawa K, Araki N, Yazawa I, Washimi Y, Saitoh B, Kira J, Ikeda S
Intern Med 2014;53(1):21-7. PMID: 24390523
Konno T, Tada M, Tada M, Koyama A, Nozaki H, Harigaya Y, Nishimiya J, Matsunaga A, Yoshikura N, Ishihara K, Arakawa M, Isami A, Okazaki K, Yokoo H, Itoh K, Yoneda M, Kawamura M, Inuzuka T, Takahashi H, Nishizawa M, Onodera O, Kakita A, Ikeuchi T
Neurology 2014 Jan 14;82(2):139-48. Epub 2013 Dec 13 doi: 10.1212/WNL.0000000000000046. [Epub ahead of print] PMID: 24336230Free PMC Article
Karle KN, Biskup S, Schüle R, Schweitzer KJ, Krüger R, Bauer P, Bender B, Nägele T, Schöls L
Neurology 2013 Dec 3;81(23):2039-44. Epub 2013 Nov 6 doi: 10.1212/01.wnl.0000436945.01023.ac. [Epub ahead of print] PMID: 24198292
Guerreiro R, Kara E, Le Ber I, Bras J, Rohrer JD, Taipa R, Lashley T, Dupuits C, Gurunlian N, Mochel F, Warren JD, Hannequin D, Sedel F, Depienne C, Camuzat A, Golfier V, Du Boisguéheneuc F, Schottlaender L, Fox NC, Beck J, Mead S, Rossor MN, Hardy J, Revesz T, Brice A, Houlden H
JAMA Neurol 2013 Jul;70(7):875-82. doi: 10.1001/jamaneurol.2013.698. PMID: 23649896Free PMC Article
Graff-Radford J, Rubin MN, Jones DT, Aksamit AJ, Ahlskog JE, Knopman DS, Petersen RC, Boeve BF, Josephs KA
J Neurol 2013 Jul;260(7):1880-8. Epub 2013 Apr 10 doi: 10.1007/s00415-013-6898-y. [Epub ahead of print] PMID: 23572346Free PMC Article

Diagnosis

Sundal C, Baker M, Karrenbauer V, Gustavsen M, Bedri S, Glaser A, Myhr KM, Haugarvoll K, Zetterberg H, Harbo H, Kockum I, Hillert J, Wszolek Z, Rademakers R, Andersen O
Eur J Neurol 2015 Feb;22(2):328-33. Epub 2014 Oct 13 doi: 10.1111/ene.12572. [Epub ahead of print] PMID: 25311247Free PMC Article
Kitani-Morii F, Kasai T, Tomonaga K, Saito K, Mizuta I, Yoshioka A, Nakagawa M, Mizuno T
Intern Med 2014;53(12):1377-80. Epub 2014 Jun 15 PMID: 24930661
Terasawa Y, Osaki Y, Kawarai T, Sugimoto T, Orlacchio A, Abe T, Izumi Y, Kaji R
J Neurol Sci 2013 Dec 15;335(1-2):213-5. Epub 2013 Aug 30 doi: 10.1016/j.jns.2013.08.027. [Epub ahead of print] PMID: 24094860
Kondo Y, Kinoshita M, Fukushima K, Yoshida K, Ikeda S
Intern Med 2013;52(4):503-6. Epub 2013 Feb 15 PMID: 23411710
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
Nat Genet 2011 Dec 25;44(2):200-5. doi: 10.1038/ng.1027. [Epub ahead of print] PMID: 22197934Free PMC Article

Therapy

Sundal C, Fujioka S, Van Gerpen JA, Wider C, Nicholson AM, Baker M, Shuster EA, Aasly J, Spina S, Ghetti B, Roeber S, Garbern J, Tselis A, Swerdlow RH, Miller BB, Borjesson-Hanson A, Uitti RJ, Ross OA, Stoessl AJ, Rademakers R, Josephs KA, Dickson DW, Broderick D, Wszolek ZK
Parkinsonism Relat Disord 2013 Oct;19(10):869-77. Epub 2013 Jun 17 doi: 10.1016/j.parkreldis.2013.05.013. [Epub ahead of print] PMID: 23787135Free PMC Article

Prognosis

Sundal C, Baker M, Karrenbauer V, Gustavsen M, Bedri S, Glaser A, Myhr KM, Haugarvoll K, Zetterberg H, Harbo H, Kockum I, Hillert J, Wszolek Z, Rademakers R, Andersen O
Eur J Neurol 2015 Feb;22(2):328-33. Epub 2014 Oct 13 doi: 10.1111/ene.12572. [Epub ahead of print] PMID: 25311247Free PMC Article
Bender B, Klose U, Lindig T, Biskup S, Nägele T, Schöls L, Karle KN
J Neurol 2014 Dec;261(12):2351-9. Epub 2014 Sep 20 doi: 10.1007/s00415-014-7509-2. [Epub ahead of print] PMID: 25239393
Karle KN, Biskup S, Schüle R, Schweitzer KJ, Krüger R, Bauer P, Bender B, Nägele T, Schöls L
Neurology 2013 Dec 3;81(23):2039-44. Epub 2013 Nov 6 doi: 10.1212/01.wnl.0000436945.01023.ac. [Epub ahead of print] PMID: 24198292
Sundal C, Fujioka S, Van Gerpen JA, Wider C, Nicholson AM, Baker M, Shuster EA, Aasly J, Spina S, Ghetti B, Roeber S, Garbern J, Tselis A, Swerdlow RH, Miller BB, Borjesson-Hanson A, Uitti RJ, Ross OA, Stoessl AJ, Rademakers R, Josephs KA, Dickson DW, Broderick D, Wszolek ZK
Parkinsonism Relat Disord 2013 Oct;19(10):869-77. Epub 2013 Jun 17 doi: 10.1016/j.parkreldis.2013.05.013. [Epub ahead of print] PMID: 23787135Free PMC Article
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
Am J Med Genet B Neuropsychiatr Genet 2012 Dec;159B(8):951-7. Epub 2012 Oct 4 doi: 10.1002/ajmg.b.32100. [Epub ahead of print] PMID: 23038421

Clinical prediction guides

Riku Y, Ando T, Goto Y, Mano K, Iwasaki Y, Sobue G, Yoshida M
J Neuropathol Exp Neurol 2014 Dec;73(12):1183-90. doi: 10.1097/NEN.0000000000000139. PMID: 25383640
Bender B, Klose U, Lindig T, Biskup S, Nägele T, Schöls L, Karle KN
J Neurol 2014 Dec;261(12):2351-9. Epub 2014 Sep 20 doi: 10.1007/s00415-014-7509-2. [Epub ahead of print] PMID: 25239393
Kinoshita M, Kondo Y, Yoshida K, Fukushima K, Hoshi K, Ishizawa K, Araki N, Yazawa I, Washimi Y, Saitoh B, Kira J, Ikeda S
Intern Med 2014;53(1):21-7. PMID: 24390523
Konno T, Tada M, Tada M, Koyama A, Nozaki H, Harigaya Y, Nishimiya J, Matsunaga A, Yoshikura N, Ishihara K, Arakawa M, Isami A, Okazaki K, Yokoo H, Itoh K, Yoneda M, Kawamura M, Inuzuka T, Takahashi H, Nishizawa M, Onodera O, Kakita A, Ikeuchi T
Neurology 2014 Jan 14;82(2):139-48. Epub 2013 Dec 13 doi: 10.1212/WNL.0000000000000046. [Epub ahead of print] PMID: 24336230Free PMC Article
Terasawa Y, Osaki Y, Kawarai T, Sugimoto T, Orlacchio A, Abe T, Izumi Y, Kaji R
J Neurol Sci 2013 Dec 15;335(1-2):213-5. Epub 2013 Aug 30 doi: 10.1016/j.jns.2013.08.027. [Epub ahead of print] PMID: 24094860

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