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Hereditary diffuse leukoencephalopathy with spheroids(HDLS)

MedGen UID:
341741
Concept ID:
C1857300
Disease or Syndrome
Synonyms: CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids; DEMENTIA, FAMILIAL, NEUMANN TYPE; Gliosis, familial progressive subcortical; HDLS; LEUKOENCEPHALOPATHY WITH NEUROAXONAL SPHEROIDS, AUTOSOMAL DOMINANT; LEUKOENCEPHALOPATHY, ADULT-ONSET, WITH AXONAL SPHEROIDS AND PIGMENTED GLIA; SUBCORTICAL GLIOSIS OF NEUMANN
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
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).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): CSF1R (5q32)
OMIM®: 221820

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]
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.  https://ghr.nlm.nih.gov/condition/adult-onset-leukoencephalopathy-with-axonal-spheroids-and-pigmented-glia

Clinical features

Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A group of cognitive disorders characterized by the inability to perform previously learned skills that cannot be attributed to deficits of motor or sensory function. The two major subtypes of this condition are ideomotor (see APRAXIA, IDEOMOTOR) and ideational apraxia, which refers to loss of the ability to mentally formulate the processes involved with performing an action. For example, dressing apraxia may result from an inability to mentally formulate the act of placing clothes on the body. Apraxias are generally associated with lesions of the dominant PARIETAL LOBE and supramarginal gyrus. (From Adams et al., Principles of Neurology, 6th ed, pp56-7)
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Depression is a serious medical illness that involves the brain. It's more than just a feeling of being "down in the dumps" or "blue" for a few days. If you are one of the more than 20 million people in the United States who have depression, the feelings do not go away. They persist and interfere with your everyday life. Symptoms can include : -Sadness. -Loss of interest or pleasure in activities you used to enjoy. -Change in weight. -Difficulty sleeping or oversleeping. -Energy loss. -Feelings of worthlessness. -Thoughts of death or suicide. Depression is a disorder of the brain. There are a variety of causes, including genetic, environmental, psychological, and biochemical factors. Depression usually starts between the ages of 15 and 30, and is much more common in women. Women can also get postpartum depression after the birth of a baby. Some people get seasonal affective disorder in the winter. Depression is one part of bipolar disorder. There are effective treatments for depression, including antidepressants and talk therapy. Most people do best by using both. . NIH: National Institute of Mental Health.
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
The presence of gliosis in the central nervous system.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
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.
Muscle Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Mutism
MedGen UID:
6476
Concept ID:
C0026884
Disease or Syndrome
The inability to generate oral-verbal expression, despite normal comprehension of speech. This may be associated with BRAIN DISEASES or MENTAL DISORDERS. Organic mutism may be associated with damage to the FRONTAL LOBE; BRAIN STEM; THALAMUS; and CEREBELLUM. Selective mutism is a psychological condition that usually affects children characterized by continuous refusal to speak in social situations by a child who is able and willing to speak to selected persons. Kussmal aphasia refers to mutism in psychosis. (From Fortschr Neurol Psychiatr 1994; 62(9):337-44)
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Shuffling gait
MedGen UID:
68545
Concept ID:
C0231688
Finding
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
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).
Memory impairment
MedGen UID:
68579
Concept ID:
C0233794
Mental or Behavioral Dysfunction
An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
Any of various diseases affecting the white matter of the central nervous system.
Frontal lobe dementia
MedGen UID:
572577
Concept ID:
C0338455
Disease or Syndrome
CNS demyelination
MedGen UID:
137898
Concept ID:
C0338474
Disease or Syndrome
A loss of myelin from nerve fibers in the central nervous system.
Abnormality of the cerebral white matter
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
Non-specific white matter changes in the BRAIN, often seen after age 65. Changes include loss of AXONS; MYELIN pallor, GLIOSIS, loss of ependymal cells, and enlarged perivascular spaces. Leukoaraiosis is a risk factor for DEMENTIA and CEREBROVASCULAR DISORDERS.
Postural instability
MedGen UID:
334529
Concept ID:
C1843921
Finding
Neuronal loss in central nervous system
MedGen UID:
342515
Concept ID:
C1850496
Finding
Muscle Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.

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

Robinson JL, Suh E, Wood EM, Lee EB, Coslett HB, Raible K, Lee VM, Trojanowski JQ, Van Deerlin VM
Acta Neuropathol Commun 2015 Jul 4;3:42. doi: 10.1186/s40478-015-0219-x. [Epub ahead of print] PMID: 26141825Free PMC Article
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

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

Meyer-Ohlendorf M, Braczynski A, Al-Qaisi O, Gessler F, Biskup S, Weise L, Steinbach JP, Wagner M, Mittelbronn M, Bähr O
BMC Neurol 2015 Jul 4;15:103. doi: 10.1186/s12883-015-0368-3. [Epub ahead of print] PMID: 26141177Free PMC Article
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

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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