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Leukoencephalopathy, diffuse hereditary, with spheroids 1(HDLS1)

MedGen UID:
1794139
Concept ID:
C5561929
Disease or Syndrome
Synonyms: CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids; DEMENTIA, FAMILIAL, NEUMANN TYPE; Gliosis, familial progressive subcortical; HDLS1; SUBCORTICAL GLIOSIS OF NEUMANN
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): CSF1R (5q32)
 
Monarch Initiative: MONDO:0800027
OMIM®: 221820
Orphanet: ORPHA313808

Disease characteristics

Excerpted from the GeneReview: CSF1R-Related Disorder
The spectrum of CSF1R-related disorder ranges from early-onset disease (age <18 years) to late-onset disease (age ≥18 years). Early-onset disease is associated with hypotonia, delayed acquisition of developmental milestones, and non-neurologic manifestations (such as skeletal abnormalities); both early- and late-onset disease have similar neurodegenerative involvement. Most affected individuals eventually become bedridden with spasticity, rigidity, and loss of the ability to walk. They lose speech and voluntary movement and appear to be generally unaware of their surroundings. The last stage of disease progresses to a vegetative state with presence of primitive reflexes, such as visual and tactile grasp, mouth-opening reflex, and sucking reflex. Death most commonly results from pneumonia or other infections. About 500 individuals with CSF1R-related disorder have been reported to date. [from GeneReviews]
Authors:
Jaroslaw Dulski  |  Christina Sundal  |  Zbigniew K Wszolek   view full author information

Additional description

From OMIM
Hereditary diffuse leukoencephalopathy with spheroids-1 (HDLS1) 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). Genetic Heterogeneity of HDLS See also HDLS2 (619661), caused by mutation in the AARS1 gene (601065) on chromosome 16q22.  http://www.omim.org/entry/221820

Clinical features

From HPO
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
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.
Atypical behavior
MedGen UID:
14048
Concept ID:
C0004941
Sign or Symptom
Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.
Delusion
MedGen UID:
3715
Concept ID:
C0011253
Mental or Behavioral Dysfunction
A delusion is a fixed false belief held despite evidence to the contrary. The term delusion broadly encompasses all false judgments that possess the following external characteristics to a significant, albeit unspecified, extent
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
Gliosis is the focal proliferation of glial cells in the central nervous system.
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
Complete lack of speech or verbal communication in a person despite attempts to engage in conversation. Mutism as a phenomena assumes the individual has previous capacity for speech and in the pediatric population it assumes that the person is past the age of typical language development.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
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
A type of gait (walking) characterized by by dragging one's feet along or without lifting the feet fully from the ground.
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).
Auditory hallucination
MedGen UID:
115932
Concept ID:
C0233762
Sign or Symptom
Perception of sounds without auditory stimulus.
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.
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Global brain atrophy
MedGen UID:
66840
Concept ID:
C0241816
Pathologic Function
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
Parkinsonian disorder
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
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.
Corpus callosum atrophy
MedGen UID:
96560
Concept ID:
C0431370
Finding
The presence of atrophy (wasting) of the corpus callosum.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Postural instability
MedGen UID:
334529
Concept ID:
C1843921
Finding
A tendency to fall or the inability to keep oneself from falling; imbalance. The retropulsion test is widely regarded as the gold standard to evaluate postural instability, Use of the retropulsion test includes a rapid balance perturbation in the backward direction, and the number of balance correcting steps (or total absence thereof) is used to rate the degree of postural instability. Healthy subjects correct such perturbations with either one or two large steps, or without taking any steps, hinging rapidly at the hips while swinging the arms forward as a counterweight. In patients with balance impairment, balance correcting steps are often too small, forcing patients to take more than two steps. Taking three or more steps is generally considered to be abnormal, and taking more than five steps is regarded as being clearly abnormal. Markedly affected patients continue to step backward without ever regaining their balance and must be caught by the examiner (this would be called true retropulsion). Even more severely affected patients fail to correct entirely, and fall backward like a pushed toy soldier, without taking any corrective steps.
Neuronal loss in central nervous system
MedGen UID:
342515
Concept ID:
C1850496
Finding
Impaired executive functioning
MedGen UID:
1617231
Concept ID:
C4544271
Mental or Behavioral Dysfunction
A disturbance of executive functioning, which is broadly defined as the set of abilities that allow for the planning, executing, monitoring, and self-correcting of goal-directed behavior while inhibiting task-irrelevant behavior. At least some degree of executive skill is needed to complete most cognitive tasks, and deficits in executive abilities are central to many clinical conditions, including fronto-temporal dementia.
Somatic sensory dysfunction
MedGen UID:
1790456
Concept ID:
C5551413
Finding
An abnormality of the primary sensation that is mediated by peripheral nerves (pain, temperature, touch, vibration, joint position). The word hypoesthesia (or hypesthesia) refers to a reduction in cutaneous sensation to a specific type of testing.
Central nervous system axonal spheroid
MedGen UID:
1815105
Concept ID:
C5706199
Finding
Axonal spheroids are bubble-like biological features that form on most degenerating axons. During neurodegeneration, bubble-like swellings form along the length of the axon, a primary and early effect of dynamic axonal deformation. These varicosities, spheroids, or swellings have been described as beads on a string and branches bearing fruit, and they frequently appear on degenerating axons. The focal swellings on degenerating axons, axonal spheroids, are often filled with cellular debris such as organelles, pathological proteins, and disorganized cytoskeletal elements.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Konno T, Yoshida K, Mizuta I, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda SI, Onodera O, Wszolek ZK, Ikeuchi T
Eur J Neurol 2018 Jan;25(1):142-147. Epub 2017 Oct 19 doi: 10.1111/ene.13464. PMID: 28921817Free PMC Article

Recent clinical studies

Etiology

Abe T, Kawarai T, Fujita K, Sako W, Terasawa Y, Matsuda T, Sakai W, Tsukamoto-Miyashiro A, Matsui N, Izumi Y, Kaji R, Harada M
Magn Reson Med Sci 2017 Oct 10;16(4):297-303. Epub 2016 Dec 26 doi: 10.2463/mrms.mp.2016-0016. PMID: 28025469Free PMC Article
Granberg T, Hashim F, Andersen O, Sundal C, Karrenbauer VD
Eur J Neurol 2016 Apr;23(4):817-22. Epub 2016 Jan 12 doi: 10.1111/ene.12948. PMID: 26756564
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. doi: 10.2169/internalmedicine.53.0863. PMID: 24390523
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. PMID: 24198292
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. PMID: 23572346Free PMC Article

Diagnosis

Guo L, Ikegawa S
J Hum Genet 2021 Dec;66(12):1139-1144. Epub 2021 Jun 16 doi: 10.1038/s10038-021-00942-w. PMID: 34135456
Stoiloudis P, Parissis D, Smyrni N, Stardeli T, Afrantou T, Konstantinopoulou E, Grigoriadis N, Ioannidis P
Neurol Sci 2021 Aug;42(8):3431-3433. Epub 2021 Apr 18 doi: 10.1007/s10072-021-05257-4. PMID: 33866445
Makary MS, Awan U, Kisanuki YY, Slone HW
Neuroradiol J 2019 Apr;32(2):139-142. Epub 2019 Jan 7 doi: 10.1177/1971400918822136. PMID: 30614382Free PMC Article
Stabile C, Taglia I, Battisti C, Bianchi S, Federico A
Neurol Sci 2016 Sep;37(9):1565-9. Epub 2016 Jun 23 doi: 10.1007/s10072-016-2634-6. PMID: 27338940
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):328-333. Epub 2014 Oct 13 doi: 10.1111/ene.12572. PMID: 25311247Free 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. PMID: 23787135Free PMC Article

Prognosis

Makary MS, Awan U, Kisanuki YY, Slone HW
Neuroradiol J 2019 Apr;32(2):139-142. Epub 2019 Jan 7 doi: 10.1177/1971400918822136. PMID: 30614382Free PMC Article
Adams SJ, Kirk A, Auer RN
J Clin Neurosci 2018 Feb;48:42-49. Epub 2017 Nov 6 doi: 10.1016/j.jocn.2017.10.060. PMID: 29122458
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):328-333. Epub 2014 Oct 13 doi: 10.1111/ene.12572. PMID: 25311247Free 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. 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. PMID: 23787135Free PMC Article

Clinical prediction guides

Mangeat G, Ouellette R, Wabartha M, De Leener B, Plattén M, Danylaité Karrenbauer V, Warntjes M, Stikov N, Mainero C, Cohen-Adad J, Granberg T
J Neuroimaging 2020 Sep;30(5):674-682. Epub 2020 May 26 doi: 10.1111/jon.12725. PMID: 32453488
Granberg T, Hashim F, Andersen O, Sundal C, Karrenbauer VD
Eur J Neurol 2016 Apr;23(4):817-22. Epub 2016 Jan 12 doi: 10.1111/ene.12948. PMID: 26756564
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
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. PMID: 24094860
Freeman SH, Hyman BT, Sims KB, Hedley-Whyte ET, Vossough A, Frosch MP, Schmahmann JD
Brain Pathol 2009 Jan;19(1):39-47. Epub 2008 Apr 15 doi: 10.1111/j.1750-3639.2008.00163.x. PMID: 18422757Free PMC Article

Recent systematic reviews

Mickeviciute GC, Valiuskyte M, Plattén M, Wszolek ZK, Andersen O, Danylaité Karrenbauer V, Ineichen BV, Granberg T
J Intern Med 2022 Mar;291(3):269-282. Epub 2021 Dec 22 doi: 10.1111/joim.13420. PMID: 34875121
Adams SJ, Kirk A, Auer RN
J Clin Neurosci 2018 Feb;48:42-49. Epub 2017 Nov 6 doi: 10.1016/j.jocn.2017.10.060. PMID: 29122458

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