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Infantile GM1 gangliosidosis(GM1G1)

MedGen UID:
75665
Concept ID:
C0268271
Disease or Syndrome
Synonyms: Gangliosidosis, generalized GM1, infantile form; Gangliosidosis, Generalized GM1, Type 1; GLB1 deficiency; GM1 gangliosidosis type 1; GM1-gangliosidosis, type I
SNOMED CT: Deficiency of beta-galactosidase isoenzymes A, B AND C (238026007); Infantile GM>1< gangliosidosis (238026007); GM>1< gangliosidosis, type 1 (238026007); Infantile gangliosidosis with bony involvement (238026007); Infantile GM1 gangliosidosis (238026007); Generalized gangliosidosis (238026007)
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): GLB1 (3p22.3)
 
Monarch Initiative: MONDO:0009260
OMIM®: 230500
Orphanet: ORPHA79255

Disease characteristics

Excerpted from the GeneReview: GLB1-Related Disorders
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. [from GeneReviews]
Authors:
Debra S Regier  |  Cynthia J Tifft  |  Caroline E Rothermel   view full author information

Additional descriptions

From OMIM
GM1-gangliosidosis is an autosomal recessive lysosomal storage disease characterized by accumulation of ganglioside substrates in lysosomes. Clinically, patients show variable degrees of neurodegeneration and skeletal abnormalities. There are 3 main clinical variants categorized by severity and variable residual beta-galactosidase activity. Type I, or infantile form (GM1G1), shows rapid psychomotor deterioration beginning within 6 months of birth, generalized central nervous system involvement, hepatosplenomegaly, facial dysmorphism, macular cherry-red spots, skeletal dysplasia, and early death. Type II, or late-infantile/juvenile form (GM1G2; 230600), has onset between 7 months and 3 years, shows generalized central nervous system involvement with psychomotor deterioration, seizures, localized skeletal involvement, and survival into childhood. Hepatosplenomegaly and cherry-red spots are usually not present. Type III, or adult/chronic form (GM1G3; 230650), shows onset from 3 to 30 years and is characterized by localized skeletal involvement and localized central nervous system involvement, such as dystonia or gait or speech disturbance. There is an inverse correlation between disease severity and residual enzyme activity (Suzuki et al., 2001). See also Morquio B disease (253010), an allelic disorder with skeletal anomalies and no neurologic involvement. The GM2-gangliosidoses include Tay-Sachs disease (272800) and Sandhoff disease (268800).  http://www.omim.org/entry/230500
From MedlinePlus Genetics
GM1 gangliosidosis type II occurs in one of two forms: the late infantile or the juvenile forms. Children with type II develop normally early in life, but they begin to show signs and symptoms of the condition around the age of 18 months (late infantile form) or 5 years (juvenile form). Individuals with GM1 gangliosidosis type II experience developmental regression but usually do not have cherry-red spots, coarse facial features, or enlarged organs. Type II usually progresses more slowly than type I, but it still  shortens life expectancy. People with the late infantile form typically survive into mid-childhood, while those with the juvenile form may live into early adulthood.

People with GM1 gangliosidosis type I can lose their vision due to clouding of the clear outer covering of the eye (the cornea) and the breakdown of the light-sensing tissue at the back of the eye (the retina). Affected individuals also develop a red area in the eye known as a cherry-red spot. In some cases, affected individuals have distinctive facial features that are described as "coarse," enlarged gums (gingival hypertrophy), and an enlarged and weakened heart muscle (cardiomyopathy). Individuals with type I usually do not survive past early childhood.

The signs and symptoms of the most severe form of GM1 gangliosidosis, called type I or the infantile form, usually develop by the age of 6 months. Infants with this form of the disorder typically appear normal until their development slows and the muscles used for movement weaken. Affected infants eventually lose the skills they had previously acquired (developmentally regress) and may develop an exaggerated startle reaction to loud noises. Over time, children with GM1 gangliosidosis type I develop an enlarged liver and spleen (hepatosplenomegaly) and skeletal abnormalities. Affected children often  have seizures and profound intellectual disability. 

GM1 gangliosidosis type III is the adult or chronic form of the condition, and this is the mildest form. The age at which symptoms first appear varies in people with GM1 gangliosidosis type III, although most affected individuals develop signs and symptoms in their teens. The characteristic features of this type include involuntary tensing of various muscles (dystonia) and abnormalities of the spinal bones (vertebrae). Life expectancy varies among people with GM1 gangliosidosis type III.

GM1 gangliosidosis is an inherited disorder that destroys nerve cells (neurons) in the brain and spinal cord. This condition can be classified as one of three major types based on the age at which signs and symptoms first appear. However, the signs and symptoms of these three types can overlap, leading some researchers to believe that GM1 gangliosidosis occurs on a spectrum instead of as three distinct types.  https://medlineplus.gov/genetics/condition/gm1-gangliosidosis

Clinical features

From HPO
Abnormality of the urinary system
MedGen UID:
867444
Concept ID:
C4021821
Disease or Syndrome
An abnormality of the urinary system.
Primary dilated cardiomyopathy
MedGen UID:
2880
Concept ID:
C0007193
Disease or Syndrome
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.\n\nIt usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Abnormal heart valve morphology
MedGen UID:
892837
Concept ID:
C0241654
Finding
Any structural abnormality of a cardiac valve.
Cherry red spot of the macula
MedGen UID:
786046
Concept ID:
C2216370
Finding
Pallor of the perifoveal macula of the retina with appearance of a small circular reddish choroid shape as seen through the fovea centralis due to relative transparancy of the macula.
Severe short stature
MedGen UID:
3931
Concept ID:
C0013336
Disease or Syndrome
A severe degree of short stature, more than -4 SD from the mean corrected for age and sex.
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.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
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.
Cerebral degeneration
MedGen UID:
56343
Concept ID:
C0154671
Disease or Syndrome
A neurodegenerative disease that involves the telencephalon.
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.
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.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Hurler syndrome
MedGen UID:
39698
Concept ID:
C0086795
Disease or Syndrome
Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.
Joint stiffness
MedGen UID:
56403
Concept ID:
C0162298
Sign or Symptom
Joint stiffness is a perceived sensation of tightness in a joint or joints when attempting to move them after a period of inactivity. Joint stiffness typically subsides over time.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Thickened ribs
MedGen UID:
98096
Concept ID:
C0426820
Finding
Increased thickness (diameter) of ribs.
Beaking of vertebral bodies
MedGen UID:
341588
Concept ID:
C1856599
Finding
Anterior tongue-like protrusions of the vertebral bodies.
Hypoplastic vertebral bodies
MedGen UID:
354963
Concept ID:
C1863353
Congenital Abnormality
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Vacuolated lymphocytes
MedGen UID:
332307
Concept ID:
C1836855
Finding
The presence of clear, sharply defined vacuoles in the lymphocyte cytoplasm.
Decreased beta-galactosidase activity
MedGen UID:
383939
Concept ID:
C1856559
Finding
Abnormally decreased rate of beta-galactosidase activity. Beta-galactosidase activity can be measured in leukocyte, fibroblast, or plasma.
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Depressed nasal ridge
MedGen UID:
334631
Concept ID:
C1842876
Finding
Lack of prominence of the nose resulting from a posteriorly-placed nasal ridge.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Fabry disease
MedGen UID:
8083
Concept ID:
C0002986
Disease or Syndrome
Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (a-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% a-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, late-onset forms occur in males with greater than 1% a-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; renal failure, associated with ESRD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack.
Hypertrichosis
MedGen UID:
43787
Concept ID:
C0020555
Disease or Syndrome
Hypertrichosis is increased hair growth that is abnormal in quantity or location.
Hydrops fetalis
MedGen UID:
6947
Concept ID:
C0020305
Disease or Syndrome
The abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Infantile GM1 gangliosidosis in Orphanet.

Professional guidelines

PubMed

Herbst ZM, Hong X, Urdaneta L, Klein T, Waggoner C, Liao HC, Kubaski F, Giugliani R, Fuller M, Gelb MH
Mol Genet Metab 2023 Sep-Oct;140(1-2):107632. Epub 2023 Jun 24 doi: 10.1016/j.ymgme.2023.107632. PMID: 37407323Free PMC Article
Yuskiv N, Higaki K, Stockler-Ipsiroglu S
Int J Mol Sci 2020 Nov 30;21(23) doi: 10.3390/ijms21239121. PMID: 33266180Free PMC Article
Deodato F, Procopio E, Rampazzo A, Taurisano R, Donati MA, Dionisi-Vici C, Caciotti A, Morrone A, Scarpa M
Metab Brain Dis 2017 Oct;32(5):1529-1536. Epub 2017 Jun 3 doi: 10.1007/s11011-017-0044-y. PMID: 28577204

Recent clinical studies

Etiology

Lang FM, Korner P, Harnett M, Karunakara A, Tifft CJ
Mol Genet Metab 2020 Mar;129(3):228-235. Epub 2019 Dec 30 doi: 10.1016/j.ymgme.2019.12.012. PMID: 31937438Free PMC Article
Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR
Mol Genet Metab 2018 Feb;123(2):97-104. Epub 2017 Dec 20 doi: 10.1016/j.ymgme.2017.12.432. PMID: 29352662Free PMC Article

Diagnosis

Noh ES, Park HM, Kim MS, Park HD, Cho SY, Jin DK
Medicine (Baltimore) 2022 Jan 7;101(1):e28435. doi: 10.1097/MD.0000000000028435. PMID: 35029890Free PMC Article
Mohamed FE, Al Sorkhy M, Ghattas MA, Al-Gazali L, Al-Dirbashi O, Al-Jasmi F, Ali BR
Hum Genet 2020 May;139(5):657-673. Epub 2020 Mar 26 doi: 10.1007/s00439-020-02153-3. PMID: 32219518
Lang FM, Korner P, Harnett M, Karunakara A, Tifft CJ
Mol Genet Metab 2020 Mar;129(3):228-235. Epub 2019 Dec 30 doi: 10.1016/j.ymgme.2019.12.012. PMID: 31937438Free PMC Article
Lee JS, Choi JM, Lee M, Kim SY, Lee S, Lim BC, Cheon JE, Kim IO, Kim KJ, Choi M, Seong MW, Chae JH
Brain Dev 2018 May;40(5):383-390. Epub 2018 Feb 10 doi: 10.1016/j.braindev.2018.01.009. PMID: 29439846
Erol I, Alehan F, Pourbagher MA, Canan O, Vefa Yildirim S
Eur J Paediatr Neurol 2006 Sep-Nov;10(5-6):245-8. Epub 2006 Oct 17 doi: 10.1016/j.ejpn.2006.08.005. PMID: 17052929

Therapy

Lang FM, Korner P, Harnett M, Karunakara A, Tifft CJ
Mol Genet Metab 2020 Mar;129(3):228-235. Epub 2019 Dec 30 doi: 10.1016/j.ymgme.2019.12.012. PMID: 31937438Free PMC Article
Iwasaki H, Watanabe H, Iida M, Ogawa S, Tabe M, Higaki K, Nanba E, Suzuki Y
Brain Dev 2006 Sep;28(8):482-6. Epub 2006 Apr 17 doi: 10.1016/j.braindev.2006.02.002. PMID: 16617000

Prognosis

Lang FM, Korner P, Harnett M, Karunakara A, Tifft CJ
Mol Genet Metab 2020 Mar;129(3):228-235. Epub 2019 Dec 30 doi: 10.1016/j.ymgme.2019.12.012. PMID: 31937438Free PMC Article
Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR
Mol Genet Metab 2018 Feb;123(2):97-104. Epub 2017 Dec 20 doi: 10.1016/j.ymgme.2017.12.432. PMID: 29352662Free PMC Article
Caciotti A, Garman SC, Rivera-Colón Y, Procopio E, Catarzi S, Ferri L, Guido C, Martelli P, Parini R, Antuzzi D, Battini R, Sibilio M, Simonati A, Fontana E, Salviati A, Akinci G, Cereda C, Dionisi-Vici C, Deodato F, d'Amico A, d'Azzo A, Bertini E, Filocamo M, Scarpa M, di Rocco M, Tifft CJ, Ciani F, Gasperini S, Pasquini E, Guerrini R, Donati MA, Morrone A
Biochim Biophys Acta 2011 Jul;1812(7):782-90. Epub 2011 Apr 7 doi: 10.1016/j.bbadis.2011.03.018. PMID: 21497194Free PMC Article

Clinical prediction guides

Lang FM, Korner P, Harnett M, Karunakara A, Tifft CJ
Mol Genet Metab 2020 Mar;129(3):228-235. Epub 2019 Dec 30 doi: 10.1016/j.ymgme.2019.12.012. PMID: 31937438Free PMC Article
Vedak P, Sells R, De Souza A, Hoang MP, Kroshinsky D
Pediatr Dermatol 2015 Nov-Dec;32(6):e294-5. Epub 2015 Sep 4 doi: 10.1111/pde.12666. PMID: 26337817
Caciotti A, Garman SC, Rivera-Colón Y, Procopio E, Catarzi S, Ferri L, Guido C, Martelli P, Parini R, Antuzzi D, Battini R, Sibilio M, Simonati A, Fontana E, Salviati A, Akinci G, Cereda C, Dionisi-Vici C, Deodato F, d'Amico A, d'Azzo A, Bertini E, Filocamo M, Scarpa M, di Rocco M, Tifft CJ, Ciani F, Gasperini S, Pasquini E, Guerrini R, Donati MA, Morrone A
Biochim Biophys Acta 2011 Jul;1812(7):782-90. Epub 2011 Apr 7 doi: 10.1016/j.bbadis.2011.03.018. PMID: 21497194Free PMC Article
van der Voorn JP, Kamphorst W, van der Knaap MS, Powers JM
Acta Neuropathol 2004 Jun;107(6):539-45. Epub 2004 Mar 20 doi: 10.1007/s00401-004-0848-9. PMID: 15042387
Kobayashi T, Shinnoh N, Kuroiwa Y
Biochim Biophys Acta 1986 Jan 3;875(1):115-21. PMID: 3079639

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