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Schimke immuno-osseous dysplasia(SIOD)

MedGen UID:
164078
Concept ID:
C0877024
Congenital Abnormality
Synonyms: Schimke immunoosseous dysplasia; Schimke syndrome; SIOD; Spondyloepiphyseal dysplasia nephrotic syndrome
SNOMED CT: Schimke immuno-osseous dysplasia (723995003); Schimke immunoosseous dysplasia (723995003); Schimke syndrome (723995003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): SMARCAL1 (2q35)
 
Monarch Initiative: MONDO:0009458
OMIM®: 242900
Orphanet: ORPHA1830

Disease characteristics

Excerpted from the GeneReview: Schimke Immunoosseous Dysplasia
Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small deformed capital femoral epiphyses, and shallow dysplastic acetabular fossae. Adult height is 136-157 cm for men and 98.5-143 cm for women. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease (ESRD). The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with death early in life to a juvenile or milder later-onset form with survival into adulthood if renal disease is appropriately treated. [from GeneReviews]
Authors:
Marie Morimoto  |  David B Lewis  |  Thomas Lücke, et. al.   view full author information

Additional description

From MedlinePlus Genetics
Schimke immuno-osseous dysplasia is a condition characterized by short stature, kidney disease, and a weakened immune system. In people with this condition, short stature is caused by flattened spinal bones (vertebrae), resulting in a shortened neck and trunk. Adult height is typically between 3 and 5 feet. Kidney (renal) disease often leads to life-threatening renal failure and end-stage renal disease (ESRD). Affected individuals also have a shortage of certain immune system cells called T cells. T cells identify foreign substances and defend the body against infection. A shortage of T cells causes a person to be more susceptible to illness.\n\nOther features frequently seen in people with this condition include an exaggerated curvature of the lower back (lordosis); darkened patches of skin (hyperpigmentation), typically on the chest and back; and a broad nasal bridge with a rounded tip of the nose.\n\nLess common signs and symptoms of Schimke immuno-osseous dysplasia include an accumulation of fatty deposits and scar-like tissue in the lining of the arteries (atherosclerosis), reduced blood flow to the brain (cerebral ischemia), migraine-like headaches, an underactive thyroid gland (hypothyroidism), decreased numbers of white blood cells (lymphopenia), underdeveloped hip bones (hypoplastic pelvis), abnormally small head size (microcephaly), a lack of sperm (azoospermia) in males, and irregular menstruation in females.\n\nIn severe cases, many signs of Schimke immuno-osseous dysplasia can be present at birth. People with mild cases of this disorder may not develop signs or symptoms until late childhood.  https://medlineplus.gov/genetics/condition/schimke-immuno-osseous-dysplasia

Clinical features

From HPO
Focal segmental glomerulosclerosis
MedGen UID:
4904
Concept ID:
C0017668
Disease or Syndrome
A renal disorder characterized by sclerotic lesions in the glomeruli. Causes include drugs, viruses, and malignancies (lymphomas), or it may be idiopathic. It presents with asymptomatic proteinuria or nephritic syndrome and it may lead to renal failure.
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
A collection of symptoms that include severe edema, proteinuria, and hypoalbuminemia; it is indicative of renal dysfunction.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
Diminished kidney function.
Hypoplasia of the capital femoral epiphysis
MedGen UID:
374176
Concept ID:
C1839254
Finding
Underdevelopment of the proximal epiphysis of the femur.
Shallow acetabular fossae
MedGen UID:
344384
Concept ID:
C1854910
Finding
Lateral displacement of the femoral head
MedGen UID:
340954
Concept ID:
C1855758
Finding
A developmental anomaly with lateral displacement of the femoral head.
Arteriosclerosis
MedGen UID:
2076
Concept ID:
C0003850
Disease or Syndrome
Sclerosis (hardening) of the arteries with increased thickness of the wall of arteries as well as increased stiffness and a loss of elasticity.
Transient ischemic attack
MedGen UID:
853
Concept ID:
C0007787
Disease or Syndrome
A brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Cerebral ischemia
MedGen UID:
182975
Concept ID:
C0917798
Pathologic Function
Diminished or absent blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurologic damage.
Intrauterine growth retardation
MedGen UID:
473406
Concept ID:
C1386048
Pathologic Function
Disproportionate short-trunk short stature
MedGen UID:
337580
Concept ID:
C1846435
Finding
A type of disproportionate short stature characterized by a short trunk but a average-sized limbs.
Protuberant abdomen
MedGen UID:
340750
Concept ID:
C1854928
Finding
A thrusting or bulging out of the abdomen.
Transient ischemic attack
MedGen UID:
853
Concept ID:
C0007787
Disease or Syndrome
A brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Elevated circulating thyroid-stimulating hormone concentration
MedGen UID:
108325
Concept ID:
C0586553
Finding
Increased concentration of thyroid-stimulating hormone (TSH) in the blood circulation.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
A broad category of disorders characterized by an impairment to the intelligence an individual possesses. These impairments can result from trauma, birth, or disease and are not restricted to any particular age group.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Abnormal T cell morphology
MedGen UID:
343416
Concept ID:
C1855752
Finding
An abnormality of T cells.
Abnormal immunoglobulin level
MedGen UID:
340953
Concept ID:
C1855755
Finding
An abnormal deviation from normal levels of immunoglobulins in blood.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Thoracic kyphosis
MedGen UID:
263148
Concept ID:
C1184919
Finding
Over curvature of the thoracic region, leading to a round back or if sever to a hump.
Lumbar hyperlordosis
MedGen UID:
263149
Concept ID:
C1184923
Finding
An abnormal accentuation of the inward curvature of the spine in the lumbar region.
Hypoplasia of the capital femoral epiphysis
MedGen UID:
374176
Concept ID:
C1839254
Finding
Underdevelopment of the proximal epiphysis of the femur.
Platyspondyly
MedGen UID:
335010
Concept ID:
C1844704
Finding
A flattened vertebral body shape with reduced distance between the vertebral endplates.
Disproportionate short-trunk short stature
MedGen UID:
337580
Concept ID:
C1846435
Finding
A type of disproportionate short stature characterized by a short trunk but a average-sized limbs.
Shallow acetabular fossae
MedGen UID:
344384
Concept ID:
C1854910
Finding
Ovoid vertebral bodies
MedGen UID:
344549
Concept ID:
C1855665
Finding
When viewed in lateral radiographs, vertebral bodies have a roughly rectangular configuration. This term applies if the vertebral body appears rounded or oval.
Lateral displacement of the femoral head
MedGen UID:
340954
Concept ID:
C1855758
Finding
A developmental anomaly with lateral displacement of the femoral head.
Spondyloepiphyseal dysplasia congenita
MedGen UID:
412530
Concept ID:
C2745959
Congenital Abnormality
Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by Anderson et al., 1990).
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Abnormal T cell morphology
MedGen UID:
343416
Concept ID:
C1855752
Finding
An abnormality of T cells.
Abnormal immunoglobulin level
MedGen UID:
340953
Concept ID:
C1855755
Finding
An abnormal deviation from normal levels of immunoglobulins in blood.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Abnormal immunoglobulin level
MedGen UID:
340953
Concept ID:
C1855755
Finding
An abnormal deviation from normal levels of immunoglobulins in blood.
High pitched voice
MedGen UID:
66836
Concept ID:
C0241703
Finding
An abnormal increase in the pitch (frequency) of the voice.
Microdontia
MedGen UID:
66008
Concept ID:
C0240340
Congenital Abnormality
Decreased size of the teeth, which can be defined as a mesiodistal tooth diameter (width) more than 2 SD below mean. Alternatively, an apparently decreased maximum width of tooth.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Coarse hair
MedGen UID:
124454
Concept ID:
C0277959
Finding
Hair shafts are rough in texture.
Fine hair
MedGen UID:
98401
Concept ID:
C0423867
Finding
Hair that is fine or thin to the touch.
Hypermelanotic macule
MedGen UID:
375013
Concept ID:
C1842774
Finding
A hyperpigmented circumscribed area of change in normal skin color without elevation or depression of any size.
Elevated circulating thyroid-stimulating hormone concentration
MedGen UID:
108325
Concept ID:
C0586553
Finding
Increased concentration of thyroid-stimulating hormone (TSH) in the blood circulation.
Astigmatism
MedGen UID:
2473
Concept ID:
C0004106
Disease or Syndrome
Astigmatism (from the Greek 'a' meaning absence and 'stigma' meaning point) is a condition in which the parallel rays of light entering the eye through the refractive media are not focused on a single point. Both corneal and noncorneal factors contribute to refractive astigmatism. Corneal astigmatism is mainly the result of an aspheric anterior surface of the cornea, which can be measured readily by means of a keratometer; in a small fraction of cases (approximately 1 in 10) the effect is neutralized by the back surface. The curvature of the back surface of the cornea is not considered in most studies, because it is more difficult to measure; moreover, in the case of severe corneal astigmatism, there is evidence that both surfaces have the same configuration. Noncorneal factors are errors in the curvature of the 2 surfaces of the crystalline lens, irregularity in the refractive index of the lens, and an eccentric lens position. Since the cornea is the dominant component of the eye's refracting system, a highly astigmatic cornea is likely to result in a similarly astigmatic ocular refraction (summary by Clementi et al., 1998).
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.
Opacification of the corneal stroma
MedGen UID:
602191
Concept ID:
C0423250
Finding
Reduced transparency of the stroma of cornea.
Abnormal immunoglobulin level
MedGen UID:
340953
Concept ID:
C1855755
Finding
An abnormal deviation from normal levels of immunoglobulins in blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSchimke immuno-osseous dysplasia
Follow this link to review classifications for Schimke immuno-osseous dysplasia in Orphanet.

Recent clinical studies

Etiology

Lipska-Ziętkiewicz BS, Gellermann J, Boyer O, Gribouval O, Ziętkiewicz S, Kari JA, Shalaby MA, Ozaltin F, Dusek J, Melk A, Bayazit AK, Massella L, Hyla-Klekot L, Habbig S, Godron A, Szczepańska M, Bieniaś B, Drożdż D, Odeh R, Jarmużek W, Zachwieja K, Trautmann A, Antignac C, Schaefer F; PodoNet Consortium.
PLoS One 2017;12(8):e0180926. Epub 2017 Aug 10 doi: 10.1371/journal.pone.0180926. PMID: 28796785Free PMC Article
Morimoto M, Choi K, Boerkoel CF, Cho KS
Nucleus 2016 Nov;7(6):560-571. doi: 10.1080/19491034.2016.1255835. PMID: 27813696Free PMC Article
Gendronneau M, Kérourédan O, Taque S, Sixou JL, Bonnaure-Mallet M
Eur Arch Paediatr Dent 2014 Jun;15(3):217-21. Epub 2013 Dec 11 doi: 10.1007/s40368-013-0099-3. PMID: 24327104Free PMC Article
Motoyama O, Inoue M, Hasegawa A, Sakai K, Kawamura T, Aikawa A, Iitaka K
Pediatr Int 2010 Jun;52(3):e128-30. doi: 10.1111/j.1442-200X.2010.03057.x. PMID: 20723108
Clewing JM, Antalfy BC, Lücke T, Najafian B, Marwedel KM, Hori A, Powel RM, Do AF, Najera L, SantaCruz K, Hicks MJ, Armstrong DL, Boerkoel CF
J Med Genet 2007 Feb;44(2):122-30. Epub 2006 Jul 13 doi: 10.1136/jmg.2006.044313. PMID: 16840568Free PMC Article

Diagnosis

Bertulli C, Marzollo A, Doria M, Di Cesare S, La Scola C, Mencarelli F, Pasini A, Affinita MC, Vidal E, Magini P, Dimartino P, Masetti R, Greco L, Palomba P, Conti F, Pession A
Int J Mol Sci 2020 Nov 15;21(22) doi: 10.3390/ijms21228604. PMID: 33203071Free PMC Article
Xiong S, Shuai L, Li X, Dang X, Wu X, He Q
BMC Nephrol 2020 May 11;21(1):170. doi: 10.1186/s12882-020-01809-6. PMID: 32393263Free PMC Article
Polat Aİ, Yiş U, Ayanoğlu M, Hız AS, Güleryüz H, Öztürk Atasoy T, Boerkoel CF
Turk J Pediatr 2015 Sep-Oct;57(5):509-13. PMID: 27411420
Westbroek EM, Mukerji N, Kalanithi P, Steinberg GK
J Neurosurg Pediatr 2015 Feb;15(2):189-91. Epub 2014 Nov 28 doi: 10.3171/2014.10.PEDS14141. PMID: 25431900
Mobeireek A, Saleemi S, Khalid M, Imtiaz F, Almutairy EA
Am J Med Genet A 2015 Feb;167A(2):434-7. Epub 2014 Nov 26 doi: 10.1002/ajmg.a.36858. PMID: 25428399

Therapy

Bertulli C, Marzollo A, Doria M, Di Cesare S, La Scola C, Mencarelli F, Pasini A, Affinita MC, Vidal E, Magini P, Dimartino P, Masetti R, Greco L, Palomba P, Conti F, Pession A
Int J Mol Sci 2020 Nov 15;21(22) doi: 10.3390/ijms21228604. PMID: 33203071Free PMC Article
Grenda R, Jarmużek W, Latoszyńska J, Prokurat S, Rubik J
Pediatr Transplant 2016 Dec;20(8):1148-1151. Epub 2016 Sep 26 doi: 10.1111/petr.12828. PMID: 27671102
Yavuz S, Bayazıt AK, Anarat A, Gonlusen G, Alsancak P
Pediatr Int 2015 Apr;57(2):310-3. doi: 10.1111/ped.12455. PMID: 25868949
Gendronneau M, Kérourédan O, Taque S, Sixou JL, Bonnaure-Mallet M
Eur Arch Paediatr Dent 2014 Jun;15(3):217-21. Epub 2013 Dec 11 doi: 10.1007/s40368-013-0099-3. PMID: 24327104Free PMC Article
Baradaran-Heravi A, Lange J, Asakura Y, Cochat P, Massella L, Boerkoel CF
Am J Med Genet A 2013 Oct;161A(10):2609-13. Epub 2013 Aug 15 doi: 10.1002/ajmg.a.36111. PMID: 23950031Free PMC Article

Prognosis

Lipska-Ziętkiewicz BS, Gellermann J, Boyer O, Gribouval O, Ziętkiewicz S, Kari JA, Shalaby MA, Ozaltin F, Dusek J, Melk A, Bayazit AK, Massella L, Hyla-Klekot L, Habbig S, Godron A, Szczepańska M, Bieniaś B, Drożdż D, Odeh R, Jarmużek W, Zachwieja K, Trautmann A, Antignac C, Schaefer F; PodoNet Consortium.
PLoS One 2017;12(8):e0180926. Epub 2017 Aug 10 doi: 10.1371/journal.pone.0180926. PMID: 28796785Free PMC Article
Yavuz S, Bayazıt AK, Anarat A, Gonlusen G, Alsancak P
Pediatr Int 2015 Apr;57(2):310-3. doi: 10.1111/ped.12455. PMID: 25868949
Westbroek EM, Mukerji N, Kalanithi P, Steinberg GK
J Neurosurg Pediatr 2015 Feb;15(2):189-91. Epub 2014 Nov 28 doi: 10.3171/2014.10.PEDS14141. PMID: 25431900
Santangelo L, Gigante M, Netti GS, Diella S, Puteo F, Carbone V, Grandaliano G, Giordano M, Gesualdo L
BMC Nephrol 2014 Mar 3;15:41. doi: 10.1186/1471-2369-15-41. PMID: 24589093Free PMC Article
Baradaran-Heravi A, Lange J, Asakura Y, Cochat P, Massella L, Boerkoel CF
Am J Med Genet A 2013 Oct;161A(10):2609-13. Epub 2013 Aug 15 doi: 10.1002/ajmg.a.36111. PMID: 23950031Free PMC Article

Clinical prediction guides

Prato G, De Grandis E, Mancardi MM, Cordani R, Giacomini T, Pisciotta L, Uccella S, Severino M, Tortora D, Pavanello M, Bertamino M, Verrina E, Caridi G, Di Rocco M, Nobili L
Brain Dev 2020 May;42(5):408-413. Epub 2020 Feb 27 doi: 10.1016/j.braindev.2020.01.008. PMID: 32115305
Lipska-Ziętkiewicz BS, Gellermann J, Boyer O, Gribouval O, Ziętkiewicz S, Kari JA, Shalaby MA, Ozaltin F, Dusek J, Melk A, Bayazit AK, Massella L, Hyla-Klekot L, Habbig S, Godron A, Szczepańska M, Bieniaś B, Drożdż D, Odeh R, Jarmużek W, Zachwieja K, Trautmann A, Antignac C, Schaefer F; PodoNet Consortium.
PLoS One 2017;12(8):e0180926. Epub 2017 Aug 10 doi: 10.1371/journal.pone.0180926. PMID: 28796785Free PMC Article
Baradaran-Heravi A, Lange J, Asakura Y, Cochat P, Massella L, Boerkoel CF
Am J Med Genet A 2013 Oct;161A(10):2609-13. Epub 2013 Aug 15 doi: 10.1002/ajmg.a.36111. PMID: 23950031Free PMC Article
Sobek AK, Evers C, Dekomien G
Mol Cell Probes 2013 Feb;27(1):32-7. Epub 2012 Aug 27 doi: 10.1016/j.mcp.2012.08.007. PMID: 23010210
Deguchi K, Clewing JM, Elizondo LI, Hirano R, Huang C, Choi K, Sloan EA, Lücke T, Marwedel KM, Powell RD Jr, Santa Cruz K, Willaime-Morawek S, Inoue K, Lou S, Northrop JL, Kanemura Y, van der Kooy D, Okano H, Armstrong DL, Boerkoel CF
J Neuropathol Exp Neurol 2008 Jun;67(6):565-77. doi: 10.1097/NEN.0b013e3181772777. PMID: 18520775

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