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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy(PLOSL1)

MedGen UID:
387795
Concept ID:
C1857316
Disease or Syndrome
Synonyms: Brain-bone-fat disease; Dementia, prefrontal, with bone cysts; Dementia, progressive, with lipomembranous polycystic osteodysplasia; Nasu-Hakola disease; PLOSL1; POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY 1; Presenile dementia with bone cysts; TREM2-Related Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy; TYROBP-Related Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). [HPO:curators]
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Presenile dementia with bone cysts (702347001); PLOSL - polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (702347001); Nasu-Hakola disease (702347001); Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (702347001)
 
Gene (location): TYROBP (19q13.12)
OMIM®: 221770

Disease characteristics

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures (resulting from radiologically demonstrable polycystic osseous lesions), frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. The clinical course of PLOSL can be divided into four stages: (1) The latent stage is characterized by normal early development. (2) The osseous stage (3rd decade of life) is characterized by pain and tenderness, mostly in ankles and feet, usually following strain or injury. Fractures are typically diagnosed several years later, most commonly in the bones of the extremities. (3) In the early neurologic stage (4th decade of life), a change of personality begins to develop insidiously. Affected individuals show a frontal lobe syndrome (loss of judgment, euphoria, loss of social inhibitions, disturbance of concentration, and lack of insight, libido, and motor persistence) leading to serious social problems. (4) The late neurologic stage is characterized by progressive dementia and loss of mobility. Death usually occurs before age 50 years. [from GeneReviews]
Authors:
Juha Paloneva  |  Taina Autti  |  Panu Hakola, et. al.   view full author information

Additional descriptions

From OMIM
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy is characterized by presenile dementia along with large-scale destruction of cancellous bones. Initial symptoms, starting in the twenties, are pain and swelling resulting from cysts in the wrists and ankles. Extremity bone fractures could occur with minor trauma. At around 30 years of age, patients gradually develop neuropsychiatric symptoms, including epileptic seizures, agnosia, apraxia, speech disorder, memory disturbance, euphoria, and loss of social inhibitions. The disorder usuallly leads to death in the fifth decade of life (summary by Kondo et al., 2002). Genetic Heterogeneity of Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy Also see PLOSL2 (618193), cause by mutation in the TREM2 gene (605086) on chromosome 6p21.  http://www.omim.org/entry/221770
From GHR
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, commonly known as PLOSL, is a progressive disorder that affects the bones and brain. "Polycystic lipomembranous osteodysplasia" refers to cyst-like bone changes that can be seen on x-rays. "Sclerosing leukoencephalopathy" describes specific changes in the brain that are found in people with this disorder.The bone abnormalities associated with PLOSL usually become apparent in a person's twenties. In most affected individuals, pain and tenderness in the ankles and feet are the first symptoms of the disease. Several years later, broken bones (fractures) begin to occur frequently, particularly in bones of the ankles, feet, wrists, and hands. Bone pain and fractures are caused by thinning of the bones (osteoporosis) and cyst-like changes. These abnormalities weaken bones and make them more likely to break.The brain abnormalities characteristic of PLOSL typically appear in a person's thirties. Personality changes are among the first noticeable problems, followed by a loss of judgment, feelings of intense happiness (euphoria), a loss of inhibition, and poor concentration. These neurologic changes cause significant problems in an affected person's social and family life. As the disease progresses, it causes a severe decline in thinking and reasoning abilities (dementia). Affected people ultimately become unable to walk, speak, or care for themselves. People with this disease usually live only into their thirties or forties.  https://ghr.nlm.nih.gov/condition/polycystic-lipomembranous-osteodysplasia-with-sclerosing-leukoencephalopathy

Clinical features

Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary loss of URINE, such as leaking of urine. It is a symptom of various underlying pathological processes. Major types of incontinence include URINARY URGE INCONTINENCE and URINARY STRESS INCONTINENCE.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary loss of URINE, such as leaking of urine. It is a symptom of various underlying pathological processes. Major types of incontinence include URINARY URGE INCONTINENCE and URINARY STRESS INCONTINENCE.
Abnormality of the foot
MedGen UID:
8888
Concept ID:
C0016506
Anatomical Abnormality
Alterations or deviations from normal shape or size which result in a disfigurement of the foot.
Abnormality of the hand
MedGen UID:
6715
Concept ID:
C0018564
Anatomical Abnormality
Alterations or deviations from normal shape or size which result in a disfigurement of the hand.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
A verbal or physical act of hostility.
Agnosia
MedGen UID:
174
Concept ID:
C0001816
Mental or Behavioral Dysfunction
A rare disorder characterized by the lack of ability to recognize individuals, objects, shapes, sounds, or smells. There is no loss of memory. It is caused by neurological damage in the brain, specifically in the occipital or parietal lobes.
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.
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 form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
A rapid, involuntary jerk of a muscle or group of muscles.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex characterized by upward movement of the great toe and an outward movement of the rest of the toes, when the sole of the foot is stroked. It is a normal reflex up to the age of two. Its presence beyond that age indicates neurological damage.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Neurological speech impairment
MedGen UID:
11531
Concept ID:
C0037822
Disease or Syndrome
A term referring to disorders characterized by the disruption of normal speech. It includes stuttering, lisps, dysarthria and voice disorders.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
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.
Lack of insight
MedGen UID:
65855
Concept ID:
C0233824
Mental or Behavioral Dysfunction
Personality changes
MedGen UID:
66817
Concept ID:
C0240735
Mental or Behavioral Dysfunction
A noticeable change in a person's behavior and thinking. Causes include depression, drug or alcohol abuse, brain injuries, brain tumors, and Alzheimer's disease.
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
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Disinhibition
MedGen UID:
140859
Concept ID:
C0424296
Mental or Behavioral Dysfunction
A lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Peripheral demyelination
MedGen UID:
451074
Concept ID:
C0878575
Pathologic Function
A loss of myelin from the internode regions along myelinated nerve fibers of the peripheral nervous system.
Basal ganglia calcification
MedGen UID:
234651
Concept ID:
C1389280
Pathologic Function
The presence of calcium deposition affecting one or more structures of the basal ganglia.
Axonal loss
MedGen UID:
316962
Concept ID:
C1832338
Finding
A reduction in the number of axons in the peripheral nervous system.
Primitive reflex
MedGen UID:
333065
Concept ID:
C1838319
Finding
The primitive reflexes are a group of behavioural motor responses which are found in normal early development, are subsequently inhibited, but may be released from inhibition by cerebral, usually frontal, damage. They are thus part of a broader group of reflexes which reflect release phenomena, such as exaggerated stretch reflexes and extensor plantars. They do however involve more complex motor responses than such simple stretch reflexes, and are often a normal feature in the neonate or infant.
Caudate atrophy
MedGen UID:
346745
Concept ID:
C1858116
Finding
Cerebral atrophy
MedGen UID:
892664
Concept ID:
C4020860
Disease or Syndrome
Abnormal upper motor neuron morphology
MedGen UID:
871241
Concept ID:
C4025723
Anatomical Abnormality
Any structural anomaly that affects the upper motor neuron.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Unicameral bone cyst
MedGen UID:
2696
Concept ID:
C0005937
Anatomical Abnormality
A benign fluid filled simple cyst of bone filled with serous fluid.
Pathologic fracture
MedGen UID:
42095
Concept ID:
C0016663
Pathologic Function
A pathologic fracture occurs when a bone breaks in an area that is weakened secondary to another disease process such as tumor, infection, and certain inherited bone disorders. A pathologic fracture can occur without a degree of trauma required to cause fracture in healthy bone.
Basal ganglia calcification
MedGen UID:
234651
Concept ID:
C1389280
Pathologic Function
The presence of calcium deposition affecting one or more structures of the basal ganglia.

Recent clinical studies

Etiology

Carmona S, Zahs K, Wu E, Dakin K, Bras J, Guerreiro R
Lancet Neurol 2018 Aug;17(8):721-730. Epub 2018 Jul 17 doi: 10.1016/S1474-4422(18)30232-1. PMID: 30033062
Kaivola K, Jansson L, Saarentaus E, Kiviharju A, Rantalainen V, Eriksson JG, Strandberg TE, Polvikoski T, Myllykangas L, Tienari PJ
Neurobiol Aging 2018 Apr;64:159.e1-159.e4. Epub 2017 Dec 18 doi: 10.1016/j.neurobiolaging.2017.12.008. PMID: 29336840
Darwent L, Carmona S, Lohmann E, Guven G, Kun-Rodrigues C, Bilgic B, Hanagasi H, Gurvit H, Erginel-Unaltuna N, Pak M, Hardy J, Singleton A, Brás J, Guerreiro R
Neurobiol Aging 2017 Oct;58:240.e1-240.e3. Epub 2017 Jun 28 doi: 10.1016/j.neurobiolaging.2017.06.019. PMID: 28716534Free PMC Article
Dardiotis E, Siokas V, Pantazi E, Dardioti M, Rikos D, Xiromerisiou G, Markou A, Papadimitriou D, Speletas M, Hadjigeorgiou GM
Neurobiol Aging 2017 May;53:194.e13-194.e22. Epub 2017 Jan 20 doi: 10.1016/j.neurobiolaging.2017.01.015. PMID: 28214109
Walter J
J Biol Chem 2016 Feb 26;291(9):4334-41. Epub 2015 Dec 22 doi: 10.1074/jbc.R115.704981. PMID: 26694609Free PMC Article

Diagnosis

Sahebari M, Abbasi B, Akhondpour Manteghi A, Abdollahi N
J Clin Rheumatol 2014 Apr;20(3):160-2. doi: 10.1097/RHU.0000000000000097. PMID: 24662559
Bock V, Botturi A, Gaviani P, Lamperti E, Maccagnano C, Piccio L, Silvani A, Salmaggi A
J Neurol Sci 2013 Mar 15;326(1-2):115-9. Epub 2013 Feb 9 doi: 10.1016/j.jns.2013.01.021. PMID: 23399524
Satoh J, Shimamura Y, Tabunoki H
Cell Mol Neurobiol 2012 Apr;32(3):337-43. Epub 2011 Nov 12 doi: 10.1007/s10571-011-9769-z. PMID: 22080356
Bianchin MM, Capella HM, Chaves DL, Steindel M, Grisard EC, Ganev GG, da Silva Júnior JP, Neto Evaldo S, Poffo MA, Walz R, Carlotti Júnior CG, Sakamoto AC
Cell Mol Neurobiol 2004 Feb;24(1):1-24. PMID: 15049507
Hakola HP, Puranen M
Acta Neurol Scand 1993 Nov;88(5):370-5. PMID: 8296538

Therapy

Hakola HP
Dement Geriatr Cogn Disord 1998 Jan-Feb;9(1):39-43. doi: 10.1159/000017020. PMID: 9469264
Pekkarinen P, Hovatta I, Hakola P, Järvi O, Kestilä M, Lenkkeri U, Adolfsson R, Holmgren G, Nylander PO, Tranebjaerg L, Terwilliger JD, Lönnqvist J, Peltonen L
Am J Hum Genet 1998 Feb;62(2):362-72. doi: 10.1086/301722. PMID: 9463329Free PMC Article

Prognosis

Darwent L, Carmona S, Lohmann E, Guven G, Kun-Rodrigues C, Bilgic B, Hanagasi H, Gurvit H, Erginel-Unaltuna N, Pak M, Hardy J, Singleton A, Brás J, Guerreiro R
Neurobiol Aging 2017 Oct;58:240.e1-240.e3. Epub 2017 Jun 28 doi: 10.1016/j.neurobiolaging.2017.06.019. PMID: 28716534Free PMC Article
Nwawka OK, Schneider R, Bansal M, Mintz DN, Lane J
Skeletal Radiol 2014 Oct;43(10):1449-55. Epub 2014 Apr 29 doi: 10.1007/s00256-014-1887-5. PMID: 24777445
Solje E, Hartikainen P, Valori M, Vanninen R, Tiihonen J, Hakola P, Tienari PJ, Remes AM
Neurobiol Aging 2014 Jul;35(7):1780.e13-7. Epub 2014 Feb 5 doi: 10.1016/j.neurobiolaging.2014.01.149. PMID: 24612676
Madry H, Prudlo J, Grgic A, Freyschmidt J
Clin Orthop Relat Res 2007 Jan;454:262-9. doi: 10.1097/01.blo.0000229364.57985.df. PMID: 16906106
Klünemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, De Bleecker JL, Rossor MN, Marienhagen J, Klein HE, Peltonen L, Paloneva J
Neurology 2005 May 10;64(9):1502-7. doi: 10.1212/01.WNL.0000160304.00003.CA. PMID: 15883308

Clinical prediction guides

Kaivola K, Jansson L, Saarentaus E, Kiviharju A, Rantalainen V, Eriksson JG, Strandberg TE, Polvikoski T, Myllykangas L, Tienari PJ
Neurobiol Aging 2018 Apr;64:159.e1-159.e4. Epub 2017 Dec 18 doi: 10.1016/j.neurobiolaging.2017.12.008. PMID: 29336840
Darwent L, Carmona S, Lohmann E, Guven G, Kun-Rodrigues C, Bilgic B, Hanagasi H, Gurvit H, Erginel-Unaltuna N, Pak M, Hardy J, Singleton A, Brás J, Guerreiro R
Neurobiol Aging 2017 Oct;58:240.e1-240.e3. Epub 2017 Jun 28 doi: 10.1016/j.neurobiolaging.2017.06.019. PMID: 28716534Free PMC Article
Oyanagi K, Kinoshita M, Suzuki-Kouyama E, Inoue T, Nakahara A, Tokiwai M, Arai N, Satoh JI, Aoki N, Jinnai K, Yazawa I, Arai K, Ishihara K, Kawamura M, Ishizawa K, Hasegawa K, Yagisita S, Amano N, Yoshida K, Terada S, Yoshida M, Akiyama H, Mitsuyama Y, Ikeda SI
Brain Pathol 2017 Nov;27(6):748-769. Epub 2017 Mar 2 doi: 10.1111/bpa.12443. PMID: 27608278
Hakola HP, Puranen M
Acta Neurol Scand 1993 Nov;88(5):370-5. PMID: 8296538
Iivanainen M, Hakola P, Erkinjuntti T, Sipponen JT, Ketonen L, Sulkava R, Sepponen RE
J Comput Assist Tomogr 1984 Oct;8(5):940-3. PMID: 6470263

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