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Schimke immuno-osseous dysplasia(SIOD)

MedGen UID:
164078
Concept ID:
C0877024
Congenital Abnormality
Synonyms: Schimke immunoosseous dysplasia; 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
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 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 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 ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. 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. 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 a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated. [from GeneReviews]
Authors:
Elizabeth Lippner  |  Thomas Lücke  |  Carlos Salgado, et. al.   view full author information

Additional descriptions

From OMIM
Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Additionally, approximately half of affected individuals have hypothyroidism, half have episodic cerebral ischemia, and one-tenth have bone-marrow failure. SIOD has a marked variation in severity, ranging from in utero onset of growth retardation and death within the first 5 years of life to a milder course with the onset of symptoms late in the first decade or early in the second decade of life (summary by Boerkoel et al., 2002).  http://www.omim.org/entry/242900
From MedlinePlus Genetics
Schimke immuno-osseous dysplasia is a condition characterized by short stature, kidney disease, and a weakened immune system. People with this condition have flattened spinal bones (vertebrae) that shorten their neck and trunk. The adult height for people with this condition is typically between 3 and 5 feet. Additional skeletal problems in people with Schimke immuno-osseous dysplasia include abnormalities of the hip joints and the end of the leg bones where they meet the hip joint. These skeletal problems can cause the hip joints to break down (degenerate) over time, leading to joint pain and a limited range of movement. This combination of skeletal problems and spinal abnormalities is called spondyloepiphyseal dysplasia as it affects the bones of the spine (spondylo-) and the ends of long bones (epiphyses) in the legs. It affects most people with Schimke immuno-osseous dysplasia.People with Schimke immuno-osseous dysplasia often have kidney (renal) disease that may lead to life-threatening renal failure and end-stage renal disease (ESRD). 

Individuals with Schimke immuno-osseous dysplasia also have a shortage of immune system cells called T cells. T cells identify foreign substances and defend the body against infection. This shortage of T cells causes people with Schimke immuno-osseous dysplasia to have recurrent infections.

Other features frequently seen in people with Schimke immuno-osseous dysplasia include an exaggerated curvature of the lower back (lordosis); darkened patches of skin (hyperpigmentation), typically on the chest and back; abnormalities of the teeth; and a broad nasal bridge with a rounded tip of the nose.

Less common signs and symptoms of Schimke immuno-osseous dysplasia include an accumulation of fatty deposits in the lining of the arteries (atherosclerosis), reduced blood flow to the brain (ischemic stroke), migraine-like headaches, an underactive thyroid gland (hypothyroidism), a decrease in the number of blood cells (anemia), a lack of sperm (azoospermia), and irregular menstruation.

In severe cases, individuals with Schimke immuno-osseous dysplasia do not survive past childhood. In mild cases, people with Schimke immuno-osseous dysplasia can survive into adulthood.  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
Segmental accumulation of scar tissue in individual (but not all) glomeruli.
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Bilateral cryptorchidism
MedGen UID:
96568
Concept ID:
C0431663
Congenital Abnormality
Absence of both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
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 disorder
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.
Stroke disorder
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Cerebral ischemia
MedGen UID:
182975
Concept ID:
C0917798
Pathologic Function
Restriction of arterial blood supply to the brain associated with insufficient oxygenation to support the metabolic requirements of the tissue.
Pulmonary arterial hypertension
MedGen UID:
425404
Concept ID:
C2973725
Disease or Syndrome
Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Protuberant abdomen
MedGen UID:
340750
Concept ID:
C1854928
Finding
A thrusting or bulging out of the abdomen.
Migraine
MedGen UID:
57451
Concept ID:
C0149931
Disease or Syndrome
Migraine is a chronic neurological disorder characterized by episodic attacks of headache and associated symptoms.
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.
Abnormally high-pitched voice
MedGen UID:
66836
Concept ID:
C0241703
Finding
A persistent (minutes to hours) abnormal increase in the pitch (frequency) of the voice for the context or social situation or significantly different from baseline of the individual.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
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
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
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.
Spondyloepiphyseal dysplasia
MedGen UID:
20916
Concept ID:
C0038015
Finding
A disorder of bone growth affecting the vertebrae and the ends of the long bones (epiphyses).
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.
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.
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing. Dyspnea is a subjective feeling only the patient can rate, e.g., on a Borg scale.
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 circulating immunoglobulin concentration
MedGen UID:
340953
Concept ID:
C1855755
Finding
An abnormal deviation from normal levels of immunoglobulins in blood.
Decreased circulating antibody concentration
MedGen UID:
892481
Concept ID:
C4048270
Finding
An abnormally decreased level of immunoglobulin in blood.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
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.
Triangular face
MedGen UID:
324383
Concept ID:
C1835884
Finding
Facial contour, as viewed from the front, triangular in shape, with breadth at the temples and tapering to a narrow chin.
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.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Coarse hair
MedGen UID:
124454
Concept ID:
C0277959
Finding
Hair shafts are rough in texture.
Macule
MedGen UID:
451035
Concept ID:
C0332573
Sign or Symptom
A flat, distinct, discolored area of skin less than 1 cm wide that does not involve any change in the thickness or texture of the skin.
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.

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.

Professional guidelines

PubMed

Boerkoel CF, O'Neill S, André JL, Benke PJ, Bogdanovíć R, Bulla M, Burguet A, Cockfield S, Cordeiro I, Ehrich JH, Fründ S, Geary DF, Ieshima A, Illies F, Joseph MW, Kaitila I, Lama G, Leheup B, Ludman MD, McLeod DR, Medeira A, Milford DV, Ormälä T, Rener-Primec Z, Santava A, Santos HG, Schmidt B, Smith GC, Spranger J, Zupancic N, Weksberg R
Eur J Pediatr 2000 Jan-Feb;159(1-2):1-7. doi: 10.1007/s004310050001. PMID: 10653321

Recent clinical studies

Therapy

Vladyka O, Zieg J, Pátek O, Bloomfield M, Paračková Z, Šedivá A, Klocperk A
J Clin Immunol 2024 Aug 17;44(8):180. doi: 10.1007/s10875-024-01787-6. PMID: 39153074Free PMC Article
Bertaina A, Grimm PC, Weinberg K, Parkman R, Kristovich KM, Barbarito G, Lippner E, Dhamdhere G, Ramachandran V, Spatz JM, Fathallah-Shaykh S, Atkinson TP, Al-Uzri A, Aubert G, van der Elst K, Green SG, Agarwal R, Slepicka PF, Shah AJ, Roncarolo MG, Gallo A, Concepcion W, Lewis DB
N Engl J Med 2022 Jun 16;386(24):2295-2302. doi: 10.1056/NEJMoa2117028. PMID: 35704481Free 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
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
Basiratnia M, Fallahzadeh MH
Saudi Med J 2007 Mar;28(3):457-60. PMID: 17334480

Prognosis

Woo HA, Kim SH, Ahn YH, Min SI, Ha J, Ha IS, Cheong HI, Kang HG
Pediatr Transplant 2023 Dec;27(8):e14605. Epub 2023 Sep 11 doi: 10.1111/petr.14605. PMID: 37691539
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
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
Basiratnia M, Fallahzadeh MH
Saudi Med J 2007 Mar;28(3):457-60. PMID: 17334480

Clinical prediction guides

Bansal R, Hussain S, Chanana UB, Bisht D, Goel I, Muthuswami R
IUBMB Life 2020 Oct;72(10):2080-2096. Epub 2020 Aug 5 doi: 10.1002/iub.2354. PMID: 32754981
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
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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