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Metachromatic leukodystrophy(MLD)

MedGen UID:
6071
Concept ID:
C0023522
Disease or Syndrome
Synonyms: Arylsulfatase A Deficiency; Cerebral sclerosis diffuse metachromatic form; Cerebroside sulfatase deficiency; Metachromatic leukoencephalopathy; MLD; Sulfatide lipidosis
SNOMED CT: Metachromatic leukodystrophy (396338004); Sulfatide lipidosis (396338004); MLD (396338004); Metachromatic leucodystrophy (396338004); Metachromatic leukoencephaly (396338004); van Bogaert-Nijssen disease (396338004); Familial progressive cerebral sclerosis (396338004); MLD - Metachromatic leucodystrophy (396338004); Scholz-Bielschowsky-Henneberg diffuse cerebral sclerosis (44359008); Scholz cerebral sclerosis (44359008)
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): ARSA (22q13.33)
 
Monarch Initiative: MONDO:0018868
OMIM®: 250100
Orphanet: ORPHA512

Disease characteristics

Excerpted from the GeneReview: Arylsulfatase A Deficiency
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage is similar to earlier-onset forms. [from GeneReviews]
Authors:
Natalia Gomez-Ospina   view full author information

Additional descriptions

From OMIM
The metachromatic leukodystrophies comprise several allelic disorders. Kihara (1982) recognized 5 allelic forms of MLD: late infantile, juvenile, and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency; and 2 nonallelic forms: metachromatic leukodystrophy due to saposin B deficiency (249900) and multiple sulfatase deficiency or juvenile sulfatidosis (272200), a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy.  http://www.omim.org/entry/250100
From MedlinePlus Genetics
Metachromatic leukodystrophy is an inherited disorder characterized by the accumulation of fats called sulfatides in cells. This accumulation especially affects cells in the nervous system that produce myelin, the substance that insulates and protects nerves. Nerve cells covered by myelin make up a tissue called white matter. Sulfatide accumulation in myelin-producing cells causes progressive destruction of white matter (leukodystrophy) throughout the nervous system, including in the brain and spinal cord (the central nervous system) and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system).\n\nIn people with metachromatic leukodystrophy, white matter damage causes progressive deterioration of intellectual functions and motor skills, such as the ability to walk. Affected individuals also develop loss of sensation in the extremities (peripheral neuropathy), incontinence, seizures, paralysis, an inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive. While neurological problems are the primary feature of metachromatic leukodystrophy, effects of sulfatide accumulation on other organs and tissues have been reported, most often involving the gallbladder.\n\nThe most common form of metachromatic leukodystrophy, affecting about 50 to 60 percent of all individuals with this disorder, is called the late infantile form. This form of the disorder usually appears in the second year of life. Affected children lose any speech they have developed, become weak, and develop problems with walking (gait disturbance). As the disorder worsens, muscle tone generally first decreases, and then increases to the point of rigidity. Individuals with the late infantile form of metachromatic leukodystrophy typically do not survive past childhood.\n\nIn 20 to 30 percent of individuals with metachromatic leukodystrophy, onset occurs between the age of 4 and adolescence. In this juvenile form, the first signs of the disorder may be behavioral problems and increasing difficulty with schoolwork. Progression of the disorder is slower than in the late infantile form, and affected individuals may survive for about 20 years after diagnosis.\n\nThe adult form of metachromatic leukodystrophy affects approximately 15 to 20 percent of individuals with the disorder. In this form, the first symptoms appear during the teenage years or later. Often behavioral problems such as alcoholism, drug abuse, or difficulties at school or work are the first symptoms to appear. The affected individual may experience psychiatric symptoms such as delusions or hallucinations. People with the adult form of metachromatic leukodystrophy may survive for 20 to 30 years after diagnosis. During this time there may be some periods of relative stability and other periods of more rapid decline.\n\nMetachromatic leukodystrophy gets its name from the way cells with an accumulation of sulfatides appear when viewed under a microscope. The sulfatides form granules that are described as metachromatic, which means they pick up color differently than surrounding cellular material when stained for examination.  https://medlineplus.gov/genetics/condition/metachromatic-leukodystrophy

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary passage of urine outside the body.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary passage of urine outside the body.
Cholecystitis
MedGen UID:
920
Concept ID:
C0008325
Disease or Syndrome
The presence of inflammatory changes in the gallbladder.
Gallbladder dysfunction
MedGen UID:
66680
Concept ID:
C0232769
Finding
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
Delusions
MedGen UID:
3715
Concept ID:
C0011253
Mental or Behavioral Dysfunction
A false belief that is held despite evidence to the contrary.
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.
Dystonia
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Hallucinations
MedGen UID:
6709
Concept ID:
C0018524
Mental or Behavioral Dysfunction
Perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space.
Tetraplegia
MedGen UID:
19617
Concept ID:
C0034372
Disease or Syndrome
Paralysis of all four limbs, and trunk of the body below the level of an associated injury to the spinal cord. The etiology of quadriplegia is similar to that of paraplegia except that the lesion is in the cervical spinal cord rather than in the thoracic or lumbar segments of the spinal cord.
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
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Mood swings
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
Unstable emotional experiences and frequent mood changes; emotions that are easily aroused, intense, and/or out of proportion to events and circumstances.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Inherited congenital spastic tetraplegia is a rare, genetic, neurological disease characterized by non-progressive, variable spastic quadriparesis in multiple members of a family, in the absence of additional factors complicating pregnancy or birth (e.g. perinatal asphyxia, congenital infection). Additional clinical features include congenital hypotonia, intellectual disability, and developmental delay. Dysphagia, dysarthria, exotropia, nystagmus, seizures and brain atrophy with ventriculomegaly may be also present.
Loss of speech
MedGen UID:
107445
Concept ID:
C0542223
Finding
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
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.
Increased CSF protein
MedGen UID:
329971
Concept ID:
C1806780
Finding
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Progressive peripheral neuropathy
MedGen UID:
347816
Concept ID:
C1859178
Finding
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.
Bulbar palsy
MedGen UID:
898626
Concept ID:
C4082299
Disease or Syndrome
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Inherited congenital spastic tetraplegia is a rare, genetic, neurological disease characterized by non-progressive, variable spastic quadriparesis in multiple members of a family, in the absence of additional factors complicating pregnancy or birth (e.g. perinatal asphyxia, congenital infection). Additional clinical features include congenital hypotonia, intellectual disability, and developmental delay. Dysphagia, dysarthria, exotropia, nystagmus, seizures and brain atrophy with ventriculomegaly may be also present.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
EMG: neuropathic changes
MedGen UID:
867363
Concept ID:
C4021727
Finding
The presence of characteristic findings of denervation on electromyography (fibrillations, positive sharp waves, and giant motor unit potentials).
Bulbar palsy
MedGen UID:
898626
Concept ID:
C4082299
Disease or Syndrome
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.

Recent clinical studies

Etiology

Koshu K, Ikeda T, Tamura D, Muramatsu K, Osaka H, Ono S, Adachi K, Nanba E, Nakajima T, Yamagata T
Brain Dev 2021 Jan;43(1):140-143. Epub 2020 Aug 24 doi: 10.1016/j.braindev.2020.08.002. PMID: 32855001
Wu S, Hou M, Zhang Y, Song J, Guo Y, Liu P, Liu Y, Yi L, Pan X, We W, Chen Z
J Mol Neurosci 2021 Feb;71(2):245-251. Epub 2020 Jul 2 doi: 10.1007/s12031-020-01643-3. PMID: 32617873
Strobel S, Hesse N, Santhanakumaran V, Groeschel S, Bruchelt G, Krägeloh-Mann I, Böhringer J
Cells 2020 Nov 28;9(12) doi: 10.3390/cells9122553. PMID: 33260765Free PMC Article
Wolf NI, Breur M, Plug B, Beerepoot S, Westerveld ASR, van Rappard DF, de Vries SI, Kole MHP, Vanderver A, van der Knaap MS, Lindemans CA, van Hasselt PM, Boelens JJ, Matzner U, Gieselmann V, Bugiani M
Ann Clin Transl Neurol 2020 Feb;7(2):169-180. Epub 2020 Jan 22 doi: 10.1002/acn3.50975. PMID: 31967741Free PMC Article
Bergner CG, van der Meer F, Winkler A, Wrzos C, Türkmen M, Valizada E, Fitzner D, Hametner S, Hartmann C, Pfeifenbring S, Stoltenburg-Didinger G, Brück W, Nessler S, Stadelmann C
Glia 2019 Jun;67(6):1196-1209. Epub 2019 Feb 11 doi: 10.1002/glia.23598. PMID: 30980503Free PMC Article

Diagnosis

Amr K, Fateen E, Mansour L, Tosson AM, Zaki MS, Salam GMA, Mohamed AN, El-Bassyouni HT
J Mol Neurosci 2021 May;71(5):1112-1130. Epub 2020 Nov 13 doi: 10.1007/s12031-020-01734-1. PMID: 33185815
Mingbunjerdsuk D, Wong M, Bozarth X, Sun A
J Child Neurol 2021 Feb;36(2):148-151. Epub 2020 Sep 29 doi: 10.1177/0883073820960308. PMID: 32991243
Koshu K, Ikeda T, Tamura D, Muramatsu K, Osaka H, Ono S, Adachi K, Nanba E, Nakajima T, Yamagata T
Brain Dev 2021 Jan;43(1):140-143. Epub 2020 Aug 24 doi: 10.1016/j.braindev.2020.08.002. PMID: 32855001
Wu S, Hou M, Zhang Y, Song J, Guo Y, Liu P, Liu Y, Yi L, Pan X, We W, Chen Z
J Mol Neurosci 2021 Feb;71(2):245-251. Epub 2020 Jul 2 doi: 10.1007/s12031-020-01643-3. PMID: 32617873
Strobel S, Hesse N, Santhanakumaran V, Groeschel S, Bruchelt G, Krägeloh-Mann I, Böhringer J
Cells 2020 Nov 28;9(12) doi: 10.3390/cells9122553. PMID: 33260765Free PMC Article

Therapy

Babcock MC, Mikulka CR, Wang B, Chandriani S, Chandra S, Xu Y, Webster K, Feng Y, Nelvagal HR, Giaramita A, Yip BK, Lo M, Jiang X, Chao Q, Woloszynek JC, Shen Y, Bhagwat S, Sands MS, Crawford BE
Sci Rep 2021 Jul 14;11(1):14486. doi: 10.1038/s41598-021-93601-1. PMID: 34262084Free PMC Article
Í Dali C, Sevin C, Krägeloh-Mann I, Giugliani R, Sakai N, Wu J, Wasilewski M
Mol Genet Metab 2020 Sep - Oct;131(1-2):235-244. Epub 2020 Jul 16 doi: 10.1016/j.ymgme.2020.07.002. PMID: 32792226
Elgün S, Waibel J, Kehrer C, van Rappard D, Böhringer J, Beck-Wödl S, Just J, Schöls L, Wolf N, Krägeloh-Mann I, Groeschel S
Orphanet J Rare Dis 2019 Jun 11;14(1):136. doi: 10.1186/s13023-019-1113-6. PMID: 31186049Free PMC Article
Simonis H, Yaghootfam C, Sylvester M, Gieselmann V, Matzner U
Hum Mol Genet 2019 Jun 1;28(11):1810-1821. doi: 10.1093/hmg/ddz020. PMID: 30657900
Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, Canale S, Lopez ID, Morena F, Calabria A, Fiori R, Silvani P, Rancoita PM, Gabaldo M, Benedicenti F, Antonioli G, Assanelli A, Cicalese MP, Del Carro U, Sora MG, Martino S, Quattrini A, Montini E, Di Serio C, Ciceri F, Roncarolo MG, Aiuti A, Naldini L, Biffi A
Lancet 2016 Jul 30;388(10043):476-87. Epub 2016 Jun 8 doi: 10.1016/S0140-6736(16)30374-9. PMID: 27289174

Prognosis

Mingbunjerdsuk D, Wong M, Bozarth X, Sun A
J Child Neurol 2021 Feb;36(2):148-151. Epub 2020 Sep 29 doi: 10.1177/0883073820960308. PMID: 32991243
Beerepoot S, van Dooren SJM, Salomons GS, Boelens JJ, Jacobs EH, van der Knaap MS, van Kuilenburg ABP, Wolf NI
Neurogenetics 2020 Oct;21(4):289-299. Epub 2020 Jul 7 doi: 10.1007/s10048-020-00621-6. PMID: 32632536Free PMC Article
Narayanan DL, Matta D, Gupta N, Kabra M, Ranganath P, Aggarwal S, Phadke SR, Datar C, Gowrishankar K, Kamate M, Jain JMN, Dalal A
J Hum Genet 2019 Apr;64(4):323-331. Epub 2019 Jan 23 doi: 10.1038/s10038-019-0560-1. PMID: 30674982
Meneghini V, Frati G, Sala D, De Cicco S, Luciani M, Cavazzin C, Paulis M, Mentzen W, Morena F, Giannelli S, Sanvito F, Villa A, Bulfone A, Broccoli V, Martino S, Gritti A
Stem Cells Transl Med 2017 Feb;6(2):352-368. Epub 2016 Sep 16 doi: 10.5966/sctm.2015-0414. PMID: 28191778Free PMC Article
Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, Canale S, Lopez ID, Morena F, Calabria A, Fiori R, Silvani P, Rancoita PM, Gabaldo M, Benedicenti F, Antonioli G, Assanelli A, Cicalese MP, Del Carro U, Sora MG, Martino S, Quattrini A, Montini E, Di Serio C, Ciceri F, Roncarolo MG, Aiuti A, Naldini L, Biffi A
Lancet 2016 Jul 30;388(10043):476-87. Epub 2016 Jun 8 doi: 10.1016/S0140-6736(16)30374-9. PMID: 27289174

Clinical prediction guides

Koshu K, Ikeda T, Tamura D, Muramatsu K, Osaka H, Ono S, Adachi K, Nanba E, Nakajima T, Yamagata T
Brain Dev 2021 Jan;43(1):140-143. Epub 2020 Aug 24 doi: 10.1016/j.braindev.2020.08.002. PMID: 32855001
Í Dali C, Sevin C, Krägeloh-Mann I, Giugliani R, Sakai N, Wu J, Wasilewski M
Mol Genet Metab 2020 Sep - Oct;131(1-2):235-244. Epub 2020 Jul 16 doi: 10.1016/j.ymgme.2020.07.002. PMID: 32792226
Beerepoot S, van Dooren SJM, Salomons GS, Boelens JJ, Jacobs EH, van der Knaap MS, van Kuilenburg ABP, Wolf NI
Neurogenetics 2020 Oct;21(4):289-299. Epub 2020 Jul 7 doi: 10.1007/s10048-020-00621-6. PMID: 32632536Free PMC Article
Bergner CG, van der Meer F, Winkler A, Wrzos C, Türkmen M, Valizada E, Fitzner D, Hametner S, Hartmann C, Pfeifenbring S, Stoltenburg-Didinger G, Brück W, Nessler S, Stadelmann C
Glia 2019 Jun;67(6):1196-1209. Epub 2019 Feb 11 doi: 10.1002/glia.23598. PMID: 30980503Free PMC Article
Meneghini V, Frati G, Sala D, De Cicco S, Luciani M, Cavazzin C, Paulis M, Mentzen W, Morena F, Giannelli S, Sanvito F, Villa A, Bulfone A, Broccoli V, Martino S, Gritti A
Stem Cells Transl Med 2017 Feb;6(2):352-368. Epub 2016 Sep 16 doi: 10.5966/sctm.2015-0414. PMID: 28191778Free PMC Article

Recent systematic reviews

Schlotawa L, Preiskorn J, Ahrens-Nicklas R, Schiller S, Adang LA, Gärtner J, Friede T
J Inherit Metab Dis 2020 Nov;43(6):1288-1297. Epub 2020 Jul 22 doi: 10.1002/jimd.12282. PMID: 32621519
Kolevzon A, Delaby E, Berry-Kravis E, Buxbaum JD, Betancur C
Mol Autism 2019;10:50. Epub 2019 Dec 24 doi: 10.1186/s13229-019-0291-3. PMID: 31879555Free 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
Musolino PL, Lund TC, Pan J, Escolar ML, Paker AM, Duncan CN, Eichler FS
Neuropediatrics 2014 Jun;45(3):169-74. Epub 2014 Jan 23 doi: 10.1055/s-0033-1364179. PMID: 24459069Free PMC Article
Mahmood A, Berry J, Wenger DA, Escolar M, Sobeih M, Raymond G, Eichler FS
J Child Neurol 2010 May;25(5):572-80. Epub 2009 Dec 28 doi: 10.1177/0883073809341669. PMID: 20038527Free PMC Article

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