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| {{short description|Group of disorders characterised by degeneration of white matter in the brain}} | | {{Short description|Group of disorders characterized by degeneration of white matter in the brain.}} |
| {{Infobox medical condition (new) | | {{Infobox medical condition (new) |
| | name = {{PAGENAME:}} | | | name = Leukodystrophy |
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| | | synonyms = White matter degeneration disorders |
| | synonyms = | | | image = Adrenoleukodystrophy.jpg |
| |image= Adrenoleukodystrophy.jpg | | | caption = [[Magnetic resonance imaging#T1 and T2|T2 weighted]] [[transverse plane|axial]] scan at the level of the [[caudate nucleus]] demonstrating marked loss of posterior [[white matter]], with reduced volume and increased signal intensity, consistent with [[X-linked adrenoleukodystrophy]]. |
| |caption= [[Magnetic resonance imaging#T1 and T2|T2 weighted]] [[transverse plane|axial]] scan at the level of the [[caudate nucleus|caudate]] heads demonstrates marked loss of posterior [[white matter]], with reduced volume and increased signal intensity. The anterior white matter is spared. Features are consistent with [[Sex linkage|X-linked]] [[adrenoleukodystrophy]]. | | | pronounce = |
| | pronounce = | | | field = [[Neurology]], [[Medical genetics]] |
| | field = | | | symptoms = [[Muscle rigidity]], [[ataxia]], [[vision loss]], [[hearing loss]], [[seizures]], [[cognitive decline]] |
| | symptoms = | | | complications = [[Progressive neurodegeneration]], [[paralysis]], [[dysphagia]], [[respiratory failure]], [[vegetative state]] |
| | complications = | | | onset = Typically in [[infancy]] or [[childhood]], but can also occur in [[adolescence]] or [[adulthood]] |
| | onset = | | | duration = Chronic and progressive |
| | duration = | | | types = [[Metachromatic leukodystrophy]], [[Krabbe disease]], [[Adrenoleukodystrophy]], [[Canavan disease]], [[Alexander disease]], [[Pelizaeus–Merzbacher disease]], [[Vanishing white matter disease]], [[Hypomyelination with atrophy of basal ganglia and cerebellum]] |
| | types = | | | causes = [[Genetic mutation]] affecting [[myelin]] production or maintenance |
| | causes = | | | risks = Family history, [[X-linked recessive]] or [[autosomal recessive]] inheritance |
| | risks = | | | diagnosis = [[Magnetic resonance imaging]], [[genetic testing]], [[nerve conduction study]], [[biochemical assays]] |
| | diagnosis = | | | differential = [[Multiple sclerosis]], [[Tay–Sachs disease]], [[Pelizaeus–Merzbacher disease]], [[vanishing white matter disease]] |
| | differential = | | | prevention = No known prevention; early genetic screening may help at-risk families |
| | prevention = | | | treatment = [[Hematopoietic stem cell transplantation]], [[gene therapy]], [[enzyme replacement therapy]], [[symptomatic management]] |
| | treatment = | | | medication = [[Steroids]], [[muscle relaxants]], [[antiepileptic drugs]] |
| | medication = | | | prognosis = Variable; life expectancy ranges from a few years in severe cases to decades in milder cases |
| | prognosis = | | | frequency = Estimated 1 in 7,600 births |
| | frequency = | | | deaths = Progressive neurodegeneration leads to fatality, often due to [[respiratory failure]] |
| | deaths = | |
| }} | | }} |
| '''Leukodystrophies''' are a group of usually inherited disorders characterized by [[neurodegeneration|degeneration]] of the [[white matter]] in the [[human brain|brain]].<ref name="SachdevKeshavan2010">{{cite book|last1=Sachdev|first1=Perminder S.|last2=Keshavan|first2=Matcheri S.|title=Secondary Schizophrenia|url=https://books.google.com/books?id=44_zy35zFnIC&pg=PA241|accessdate=15 August 2011|date=2010-03-15|publisher=Cambridge University Press|isbn=978-0-521-85697-3|pages=241–}}</ref> The word ''leukodystrophy'' comes from the [[Greek language|Greek]] roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". The leukodystrophies are caused by imperfect growth or development of the [[myelin|myelin sheath]], the fatty insulating covering around [[axon|nerve fibers]].<ref>{{citation-attribution|now=n|"[https://www.ninds.nih.gov/Disorders/All-Disorders/Leukodystrophy-Information-Page Leukodystrophy Information Page]". National Institute of Neurological Disorders and Stroke. 25 May 2017. Retrieved 18 March 2018.}}</ref> Leukodystrophies may be classified as hypomyelinating or [[demyelinating diseases]], depending on whether the damage is present before birth or occurs after. Other demyelinating diseases are usually not congenital and have a toxic or [[autoimmune]] cause.<ref>{{Citation|last=Vanderver|first=Adeline|title=Leukodystrophy Overview|date=1993|url=http://www.ncbi.nlm.nih.gov/books/NBK184570/|work=GeneReviews®|editor-last=Adam|editor-first=Margaret P.|publisher=University of Washington, Seattle|pmid=24501781|access-date=2020-01-23|last2=Tonduti|first2=Davide|last3=Schiffmann|first3=Raphael|last4=Schmidt|first4=Johanna|last5=van der Knaap|first5=Marjo S.|editor2-last=Ardinger|editor2-first=Holly H.|editor3-last=Pagon|editor3-first=Roberta A.|editor4-last=Wallace|editor4-first=Stephanie E.}}</ref>
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| When damage occurs to white matter, immune responses can lead to inflammation in the central nervous system (CNS), along with loss of myelin. The degeneration of white matter can be seen in an [[magnetic resonance imaging|MRI scan]] and used to diagnose leukodystrophy. Leukodystrophy is characterized by specific symptoms including decreased motor function, [[muscle rigidity]], and eventual degeneration of sight and hearing. While the disease is fatal, the age of onset is a key factor, as infants have a typical life expectancy of 2–8 years, while adults typically live more than a decade after onset. Treatment options are limited, although [[hematopoietic stem cell transplantation]]s using [[bone marrow]] or [[cord blood]] seem to help in certain types while further research is being done.
| | '''Leukodystrophies''' are a group of genetic neurological disorders characterized by degeneration of the white matter in the [[brain]] due to abnormalities in the development, maintenance, or destruction of myelin. The term comes from the [[Greek language|Greek]] roots: ''leuko'' ("white"), ''dys'' ("abnormal"), and ''troph'' ("growth"). These disorders result from genetic mutations that impair the function of oligodendrocytes, the cells responsible for producing and maintaining [[myelin]], the fatty substance that insulates [[neuronal axon]]s and enables efficient nerve signal transmission. |
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| The combined incidence of the leukodystrophies is estimated at 1 in 7,600.<ref>{{cite journal|last1=Bonkowsky|first1=Joshua|title=The burden of inherited leukodystrophies in children|journal=Neurology|date=Aug 24, 2010|volume=75|issue=8|pages=718–725|doi=10.1212/WNL.0b013e3181eee46b|pmid=20660364|pmc=2931652}}</ref> The majority of types involve the inheritance of an [[X-linked recessive]], or [[X-linked dominant]] trait, while others, although involving a defective gene, are the result of [[spontaneous mutation]] rather than [[genetic inheritance]].
| | Leukodystrophies can be classified as: |
| | * Hypomyelinating leukodystrophies – Myelin formation is defective from birth. |
| | * Demyelinating leukodystrophies – Myelin forms normally but degenerates over time. |
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| ==Symptoms and signs==
| | These disorders differ from other [[demyelinating diseases]] such as [[multiple sclerosis]], which are usually autoimmune or toxic in nature rather than congenital. |
| Some specific symptoms vary from one type of leukodystrophy to the next, but the vast majority of symptoms are shared as the causes for the disease generally have the same effects. Symptoms are dependent on the age of onset, which is predominantly in infancy and early childhood, although the exact time of onset may be difficult to determine. [[Hyperirritability]] and [[hypersensitivity]] to the environment are common, as well as some tell-tale physical signs including [[muscle rigidity]] and a backwards-bent head.<ref name="Krabbe disease">{{cite journal|last1=Graziano|first1=AC|last2=Cardile|first2=V|title=History, genetic, and recent advances on Krabbe disease|journal=Gene|date=26 September 2014|volume=555|issue=1|pages=2–13|pmid=25260228|doi=10.1016/j.gene.2014.09.046}}</ref> Botox therapy is often used to treat patients with spasticity.<ref>{{cite journal | pmc = 161748 | page=240 | volume=28 | issue=3 | journal=Journal of Psychiatry and Neuroscience | title=Tardive dystonia and its treatment| year=2003 | last1=Rosebush | first1=P. I. }}</ref> Juvenile and adult onsets display similar symptoms including a decrease or loss in hearing and vision. While children do experience optic and auditory degeneration, the course of the disease is usually too rapid, causing death relatively quickly, whereas adults may live with these conditions for many years. In children, spastic activity often precedes progressive [[ataxia]] and rapid cognitive deterioration which has been described as [[mental retardation]].<ref name="Chinese article">{{cite journal|last1=Liu|first1=Y|last2=Zou|first2=L|last3=Meng|first3=Y|last4=Zhang|first4=Y|last5=Shi|first5=X|last6=Ju|first6=J|last7=Yang|first7=G|last8=Hu|first8=L|last9=Chen|first9=X|title=[A family with two children diagnosed with aspartylglucosaminuria-case report and literature review].|journal=Zhonghua Er Za Zhi|date=June 2014|volume=52|issue=6|pages=455–9|pmid=25190167}}</ref> [[Epilepsy]] is commonplace for patients of all ages.<ref name="Spanish population">{{cite journal|last1=Turon-Vinas|first1=E|last2=Pineda|first2=M|last3=Cusi|first3=V|last4=Lopez-Laso|first4=E|last5=Del Pozo|first5=RL|last6=Gutierez-Solana|first6=LG|last7=Moreno|first7=DC|last8=Sierra-Corcoles|first8=C|last9=Olabarrieta-Hoyos|first9=N|last10=Madruga-Garrido|first10=M|last11=Aguirre-Rodriguez|first11=J|last12=Gonzalez-Alvarez|first12=V|last13=O'Callaghan|first13=M|last14=Muchart|first14=J|last15=Armstrong-Moron|first15=J|title=Vanishing white matter disease in a Spanish population.|journal=J Cent Nerv Syst Dis.|date=13 July 2014|volume=6|pages=59–68|pmid=25089094|doi=10.4137/JCNSD.S13540|pmc=4116383}}</ref> More progressed patients show weakness in [[deglutition]], leading to spastic coughing fits due to inhaled saliva. Classic symptomatic progression of juvenile [[X-linked adrenoleukodystrophy]] is shown in the 1992 film, ''[[Lorenzo's Oil]]''.<ref name="Lorenzos Oil">{{cite web|url=https://www.forbes.com/sites/ritarubin/2016/03/13/lorenzos-oil-could-not-cure-lorenzo-but-newborn-screening-is-expected-to-save-others-from-his-fate/|title=Forbes.com: Lorenzo's Oil Could Not Cure Lorenzo, But Newborn Screening Is Expected To Save Others From His Fate|last=Rubin|first=Rita|date=March 13, 2016|website=Forbes.com|access-date=July 31, 2018}}.</ref>
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| Course and timetable are dependent on the age of onset with infants showing a lifespan of 2–8 years, juveniles 2–10 years and adults typically 10+ years. Adults typically see an extended period of stability followed by a decline to a [[vegetative state]] and death.<ref name="Krabbe disease" /> While treatments do exist, most are in the experimental phase and can only promise a halt in the progression of symptoms, although some gene therapies have shown some symptomatic improvement.<ref name=Biffi/> The debilitating course of the disease has led to numerous philosophical and ethical arguments over experimental clinical trials, patients’ rights and [[physician-assisted suicide]].<ref name=Ethics>{{cite journal|last1=Duchange|first1=N|last2=Darguy|first2=S|last3=d'Audiffret|first3=D|last4=Callies|first4=I|last5=Lapointe|first5=AS|last6=Loeve|first6=B|last7=Boespflug-Tanguy|first7=O|last8=Moutel|first8=G|title=Ethical management in the constitution of a European database for leukodystrophies rare diseases.|journal=Eur J Paediatr Neurol.|date=18 September 2014|volume=18|issue=5|pages=597–603|pmid=24786336|doi=10.1016/j.ejpn.2014.04.002|url=http://www.hal.inserm.fr/inserm-00995366/document}}</ref>
| | == Signs and Symptoms == |
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| ==Causes==
| | Symptoms of leukodystrophies vary by type and age of onset, but generally include: |
| While the more specific underlying causes of leukodystrophy are dependent upon the type, there are, however, common pathophysiological patterns that can be seen amongst all types. First and foremost, leukodystrophy is a neurodegenerative disease that is always the result of both impairment and maintenance of [[myelin]] sheaths surrounding neuronal [[axons]] in the [[central nervous system]] as the result of a [[genetic mutation]].<ref>{{cite journal|last1=Yang|first1=Edward|last2=Prabhu|first2=Sanjay P.|title=Imaging manifestations of the leukodystrophies, inherited disorders of white matter.|journal=Radiologic Clinics of North America|date=March 5, 2014|volume=52|issue=2|pages=279–319|doi=10.1016/j.rcl.2013.11.008|pmid=24582341}}</ref> Myelin is a fatty white substance that acts as an [[electrical insulator]] and coats axons in order to speed up impulses (i.e., [[action potentials]]) traveling down the axon. Thus, the natural result of a loss of this substance is decreased efficiency in impulse propagation. As myelin is produced by [[oligodendrocytes]] (a type of [[glial cell]]) in the central nervous system, an easy place to look for the cause is a [[mutation]] or malfunctioning of these cells and in other glial cells.
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| ===Genetic influence===
| | * Neuromuscular symptoms: |
| [[File:Autorecessive.svg|thumb|Autorecessive Inheritance Pattern]] | | * [[Muscle rigidity]] (spasticity) |
| Leukodystrophy is most often an inherited disease that is usually the result of an [[autosomal recessive]] inheritance pattern, although dominant inheritance patterns are not unheard of, as in the case of adult-onset leukodystrophy.<ref name="Autosomal Dominant Leukodystrophy">{{cite journal|last1=Lin|first1=Shu-Ting|last2=Ptacek|first2=Louis J.|last3=Fu|first3=Ying-Hui|title=Adult-Onset Autosomal Dominant Leukodystrophy: Linking Nuclear Envelope to Myelin|journal=The Journal of Neuroscience|date=January 26, 2011|volume=31|issue=4|pages=1163–1166|doi=10.1523/jneurosci.5994-10.2011|pmid=21273400|pmc=3078713}}</ref> This means that the affected [[allele]] is carried on an [[autosomal]], or non-sex, chromosome and is masked by the dominant, unaffected [[phenotype]]. In other words, for an individual to inherit the leukodystrophy phenotype, he or she must carry two of the recessive, mutant alleles. [[Krabbe disease]] and [[metachromatic leukodystrophy]] (MLD) are two of such type. MLD is found on human [[chromosome 22]] at position q13.31.<ref name="Metachromatic - Chromosome #">{{cite journal|last1=Coulter-Mackie|first1=MB|last2=Rip|first2=J|last3=Ludman|first3=MD|last4=Beis|first4=J|last5=Cole|first5=DEC|title=Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22|journal=Journal of Medical Genetics|date=October 1995|volume=32|issue=10|pmc=1051701|pmid=8558556|pages=787–91|doi=10.1136/jmg.32.10.787}}</ref> Another type of inherited leukodystrophy is [[X-linked adrenoleukodystrophy]] (X-ALD). As its name implies, this type of leukodystrophy is the result of a mutation found on the [[X-chromosome]]. It is also carried in a recessive pattern. The X chromosome is a [[sex chromosome]], and since women have two “chances” of acquiring a normal X chromosome (one maternal, one paternal), and males only one (one maternal), this disease is more likely to be seen in men than in women. The mutation resulting in adult-onset leukodystrophy is mapped at 5q23.<ref name="Autosomal Dominant Leukodystrophy" />
| | * Loss of motor control and coordination ([[ataxia]]) |
| | * Progressive [[muscle weakness]] |
| | * [[Swallowing difficulty]] ([[dysphagia]]) |
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| ==Pathophysiology==
| | * Cognitive and behavioral changes: |
| Although there are nearly forty different types of leukodystrophies, many are lacking in formal and comprehensive research. Most of the research so far has been done on five types: (1) [[metachromatic leukodystrophy]] (MLD), (2) [[Krabbe disease]], (3) X-Linked [[adrenoleukodystrophy]] (ALD), (4) [[Canavan disease]], and (5) [[Alexander disease]]. Each type of leukodystrophy has a unique [[pathophysiology]], but all five of these in some way affect a subset of glial cells, therefore disrupting myelin production and maintenance, and usually involve a mutation involving genes that code for enzymes necessary for the catabolism of [[very long chain fatty acids]] (VLCFAs) that are toxic to the myelin-producing cells of the central nervous system.<ref name=VFCLAs>{{cite journal|last1=Sassa|first1=Takayuki|last2=Kihara|first2=Akio|title=Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology|journal=Biomolecules & Therapeutics|date=March 22, 2014|volume=22|issue=2|pages=83–92|doi=10.4062/biomolther.2014.017|pmc=3975470|pmid=24753812}}</ref>
| | * [[Cognitive decline]] |
| | * Loss of developmental milestones in children |
| | * [[Hyperirritability]] and hypersensitivity to stimuli |
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| ===Metachromatic leukodystrophy===
| | * Sensory deficits: |
| {{Main|Metachromatic leukodystrophy}}
| | * Vision loss ([[optic atrophy]]) |
| [[Metachromatic leukodystrophy]] is the result of genetic defects in the enzymes associated with the cellular compartment the [[lysosome]]. MLD is one of two leukodystophies that are also a [[lysosomal storage disorder]]. MLD is inherited in an [[autosomal recessive]] way and is the result of mutations in three different ARSA [[alleles]] that encode the enzyme [[arylsulfatase A]] (ASA or sometimes ARSA), also called [[sulfatide]] [[sulfatase]].<ref name="Metachromatic - ABSTRACT only">{{cite journal|last1=Barboura|first1=Ilhem|last2=Ferchichi|first2=Salima|last3=Dandana|first3=Azza|last4=Jaidane|first4=Zaineb|last5=Ben Khelifa|first5=Souhaira|last6=Chahed|first6=Hinda|last7=Ben Mansour|first7=Rachida|last8=Chebel|first8=Saber|last9=Maire|first9=Irene|last10=Miled|first10=Abdelhedi|title=Metachromatic leucodystrophy. Clinical, biological, and therapeutic aspects|journal=Annales de Biologie Clinique|date=2010|volume=68|issue=4|pages=385–91|pmid=20650733|doi=10.1684/abc.2010.0448}}</ref> ASA is responsible for the breakdown of sulfatides, [[sphingolipids]] present in neuronal membranes as well as in myelin. When there is a mutation in the gene that encodes ASA, the result is it decreases production, which subsequently leads to diminished degradation of sulfatides, thus causing them to accumulate.<ref name="Metachromatic - ABSTRACT only" /> This accumulation of sulfatides is poisonous to oligodendrocytes, the myelin-producing cells of the CNS, effectively leading to a disturbance in myelin structure followed by [[demyelination]]. The pattern of inheritance of the three different alleles affects what type of MLD a person develops. Two [[null alleles]] are responsible for the infantile version, and do not allow for any production of ASA. A [[heterozygous]] individual (one null allele, one non-null allele) develops the juvenile form and sees some production of ASA, while an individual with two non-null alleles (but still mutated) develops the adult form.<ref name="Metachromatic Leuko 2. - ABSTRACT ONLY">{{cite journal|last1=Gieselman|first1=V|last2=Krageloh-Mann|first2=I|title=Metachromatic Leukodystrophy - An Update|journal=Neuropediatrics|date=2010|volume=41|issue=1|pages=1–6|pmid=20571983|doi=10.1055/s-0030-1253412}}</ref> | | * Hearing impairment |
| | * [[Epileptic seizures]] |
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| ===Krabbe disease===
| | * Advanced stage complications: |
| [[File:Globoid cell leukodystrophy PAS.jpg|thumb|Globoid cell leukodystrophy PAS - Multinucleated macrophages ("globoid cells") and loss of myelinated fibers in a case of Krabbe's leukodystrophy]]
| | * Respiratory failure |
| {{Main|Krabbe disease}}
| | * Loss of voluntary movements |
| Like MLD, [[Krabbe disease]] is another type of leukodystrophy with autosomal recessive inheritance that is the result of a [[lysosomal storage disorder]]. It is due to a deletion in exon 16 of the [[GALC]] gene that causes a [[frameshift mutation]] leading to a premature [[stop codon]]. The GALC gene, found on [[chromosome 14]] at position 31 (14q31), codes for the [[enzyme]] beta-galactocerebrosidase (GALC).<ref name="Szymanska - Krabbe">{{cite journal|last1=Szymanska|first1=Krystyna|last2=Lugowska|first2=Agnieszka|last3=Laure-Kamionowska|first3=Milena|last4=Gieruszczak-Bialek|first4=Dorota|last5=Musielak|first5=Malgorzata|last6=Eichler|first6=Sabrina|last7=Giese|first7=Anne-Katrin|last8=Rolfs|first8=Arndt|title=Diagnostic difficulties in Krabbe disesase: a report of two cases and review of literature|journal=Folia Neuropathol|date=2012|volume=50|issue=4|pages=346–356|pmid=23319190|doi=10.5114/fn.2012.32364|doi-access=free}}</ref> GALC is a lysosomal enzyme responsible for the catabolism of [[galactolipids]], especially psychosine, that are heavily distributed throughout the brain. A deficiency in GALC thus causes a buildup of these [[fatty acids]] known as globoid [[macrophages]] that destroy oligodendrocytes, thereby inhibiting myelin formation.<ref name="Globoid cells and arylsufatase - ABSTRACT ONLY">{{cite book|last1=Kohlschutter|first1=Alfried|title=Lysosomal leukodystrophies - Krabbe disease and metachromatic leukodystrophy|journal=Handbook of Clinical Neurology|date=April 25, 2013|volume=113|issue=Pediatric Neurology Part III|pages=1611–1618|url=|doi=10.1016/B978-0-444-59565-2.00029-0|pmid=23622382|isbn=9780444595652}}</ref>
| | * Vegetative state in severe cases |
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| Because of the presence of globoid cells clustered near [[white matter]], Krabbe disease often goes by the name globoid cell leukodystrophy. Furthermore, new research has shown that Krabbe disease and globoid cell leukodystrophy may be distinct disease entities due to the secretion of [[inflammatory mediators]] by [[natural killer cells]] in some cases.<ref name="Natural Killer Cells">{{cite journal|last1=Maghazachi|first1=Azzam A.|title=On the Role of Natural Killer Cells in Neurodegenerative Diseases|journal=Toxins (Basel)|date=February 5, 2013|volume=5|issue=2|pages=363–375|pmc=3640540|pmid=23430541|doi=10.3390/toxins5020363}}</ref> This research has shown that Natural Killer cells have receptors (TDAG8) for certain [[glycosphingolipids]] that build up in an individual with leukodystrophy, again due to insufficient GALC levels, and when bound, target the Natural Killer cells for destruction thereby preventing their [[cytotoxic]] effects. These sphingolipids have been identified as galactosyl sphingosine and glycosyl sphingosine and are not present in unaffected individuals.<ref name="Natural Killer Cells" />
| | == Causes == |
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| ===Canavan disease===
| | Leukodystrophies are caused by genetic mutations affecting enzymes or proteins critical for myelin metabolism. The inheritance patterns include: |
| {{Main|Canavan disease}}
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| [[Canavan disease]] is a lesser-studied type of leukodystrophy that, like MLD and Krabbe disease, is also passed on in an autosomal recessive inheritance pattern. It is due to a mutation in the ASPA gene that encodes [[aspartoacylase]], an enzyme needed to metabolize [[N-acetyl-L-aspartate]] (NAA). The mutation causes a deficiency of aspartoacyclase. NAA is involved in the formation of [[lipids]], and if it is not broken down by aspartoacylase, excess levels of it build up causing demyelination.<ref name="Canavan Disease - ULF">{{cite web|last1=United Leukodystrophy Foundation|title=Canavan Disease|url=http://ulf.org/canavan-disease|website=United Leukodystrophy Foundation|publisher=United Leukodystrophy Foundation, Inc.|accessdate=March 30, 2015}}</ref>
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| ===X-linked adrenoleukodystrophy===
| | * Autosomal recessive (e.g., [[Krabbe disease]], [[metachromatic leukodystrophy]]) |
| {{Main|Adrenoleukodystrophy}}
| | * X-linked recessive (e.g., [[X-linked adrenoleukodystrophy]]) |
| In X-linked adrenoleukodystrophy (X-ALD), a mutation occurs in the [[peroxisomal]] [[ATP-binding cassette]] ([[ABC transporter]]). This leads to cerebral inflammatory [[demyelination]] caused by the myelin destabilization that occurs in these patients.<ref name=berger>{{cite journal|last1=Berger|first1=J|last2=Forss-Petter|first2=S|last3=Eichler|first3=F.S.|title=Pathophysiology of X-Linked Adrenoleukodystrophy|journal=Biochimie|date=March 2014|volume=98|pages=135–142|doi=10.1016/j.biochi.2013.11.023|pmid=24316281|pmc=3988840}}</ref> The inflammatory demyelination begins in the [[corpus callosum]] and it slowly progresses outwards towards both hemispheres. In X-ALD patients, abnormally high levels of [[very long chain fatty acid]] (VLCFA) accumulate in various body tissues and fluids. This increased concentration then incorporates into various complex lipids where they are not normally found.<ref name=berger /> This has been found to be directly involved in the cerebral [[inflammation]]. The accumulated and embedded VLCFA in the complex lipids could lead to the destabilization of myelin sheath and eventually to demyelination.
| | * Autosomal dominant (e.g., [[Adult-onset leukodystrophy]]) |
| | * De novo mutations (e.g., [[Alexander disease]]) |
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| ===Alexander disease===
| | These mutations lead to: |
| {{Main|Alexander disease}}
| | * Toxic accumulation of metabolites (e.g., very-long-chain fatty acids in [[adrenoleukodystrophy]]) |
| [[Alexander disease]] is unique from the leukodystrophies mentioned above in that it is the result of [[spontaneous mutation]], that is it is not inherited. This means that the mutation found in the affected individual is not found in either of his or her parents. It is due to the accumulation of [[Glial fibrillary acidic protein]] ([[Glial fibrillary acidic protein|GFAP]]) as the result of a mutation in the GFAP gene; which, rather than being found in association with lysosomes or peroxisomes, is an [[intermediate filament]] linked to the [[nuclear envelope]].<ref name="Alexander's Disease">{{cite journal|last1=Singh|first1=Navneet|last2=Bixby|first2=Catherine|last3=Etienne|first3=Denzil|last4=Tubbs|first4=R. Shane|last5=Loukas|first5=Marios|title=Alexander's disease: reassessment of a neonatal form|journal=Child's Nervous System|date=December 2012|volume=28|issue=12|pages=2029–2031|doi=10.1007/s00381-012-1868-8|pmid=22890470}}</ref> Intermediate filaments are proteins responsible for the makeup of the cellular [[cytoskeleton]], and thus this type of mutation is involved in malfunctioning structural development of the cells. In fact, cytoskeletal and transporter molecule defects have been observed in the [[astrocytes]] (type of glial cell) of affected individuals. These astrocytes have an unhealthily large amount of [[Glial fibrillary acidic protein|GFAP]] that affects astrocyte formation and function.<ref name=GFAP>{{cite journal|last1=Hol|first1=Elly M.|last2=Pekny|first2=Milos|title=Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system|journal=Current Opinion in Cell Biology|date=February 2015|volume=32|issue=Cell Architecture|pages=121–130|doi=10.1016/j.ceb.2015.02.004|pmid=25726916}}</ref>
| | * Defective lysosomal enzyme function (e.g., [[arylsulfatase A]] deficiency in [[metachromatic leukodystrophy]]) |
| | * Abnormal myelin formation (e.g., [[Pelizaeus–Merzbacher disease]]) |
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| ==Diagnosis== | | == Types of Leukodystrophies == |
| The degeneration of [[white matter]], which shows the degeneration of myelin, can be seen in a basic [[MRI]] and used to diagnose leukodystrophies of all types. T-1 and T-2 weighted [[FLAIR]] images are the most useful. FLAIR stands for [[fluid-attenuated inversion recovery]].<ref name="Diagnosis - MRI">{{cite journal|last1=Kohlschutter|first1=Alfried|last2=Eichler|first2=Florian|title=Childhood leukodystrophies: a clinical perspective|journal=Expert Review of Neurotherapeutics|date=October 2011|volume=11|issue=10|pages=1485–1496|doi=10.1586/ern.11.135|pmid=21955203|url=https://zenodo.org/record/3440302}}</ref> Electrophysiological and other kinds of laboratory testing can also be done. In particular, [[nerve conduction velocity]] is looked at to distinguish between leukodystrophy and other [[demyelinating diseases]], as well as to distinguish between individual leukodystrophies. For example, individuals with X-ALD have normal conduction velocities, while those with Krabbe disease or metachromatic leukodystrophy have abnormalities in their conduction velocities.<ref name="Diagnosis - MRI" /> Next generation multigene sequencing panels for undifferentiated leukodystrophy can now be offered for rapid molecular diagnosis after appropriate genetic counselling.
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| ===Types===
| | There are over 30 different types of leukodystrophies. The most well-studied forms include: |
| Specific types of leukodystrophies include the following with their respective [[ICD|ICD-10]] codes when available:
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| * (E71.3) [[Adrenomyeloneuropathy]]
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| * (E75.2) [[Alexander disease]]
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| * (E75.5) [[Cerebrotendineous xanthomatosis]]
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| * [[Hereditary CNS demyelinating disease]]
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| ** (E75.2) [[Krabbe disease]]
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| **(E75.2) [[Metachromatic leukodystrophy]]
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| ** (E75.2) [[Pelizaeus–Merzbacher disease]]
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| ** (E75.2) [[Canavan disease]]
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| ** (E75.2) [[Hypomyelinating leukodystrophy type 7]] (4H syndrome)
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| ** (G93.49) [[Leukoencephalopathy with vanishing white matter]]
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| **(E71.3) [[Adrenoleukodystrophy]]
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| * (G60.1) [[Refsum disease]]
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| ==Treatment==
| | * [[Metachromatic leukodystrophy]] (MLD) – Caused by deficiency of [[arylsulfatase A]], leading to sulfatide accumulation and progressive demyelination. |
| With many different types of leukodystrophies and causes, treatment therapies vary for each type. Many studies and clinical trials are in progress to find treatment and therapies for each of the different leukodystrophies. [[Stem cell]] transplants and [[gene therapy]] appear to be the most promising in treating all leukodystrophies providing it is done as early as possible.
| | * [[Krabbe disease]] – Due to GALC gene mutation, causing toxic buildup of psychosine and loss of oligodendrocytes. |
| For hypomyelinating leukodystrophies, therapeutic research into cell-based therapies appears promising. [[Oligodendrocyte]] precursor cells and [[neural stem cells]] have been transplanted successfully and have shown to be healthy a year later. [[Fractional anisotropy]] and radial diffusivity maps showed possible myelination in the region of the transplant.<ref name=Pouwels>{{cite journal|last1=Pouwels|first1=P. J. W.|last2=Vanderver|first2=A.|last3=Bernard|first3=G.|last4=Wolf|first4=N.|last5=Dreha-Kulczewski|first5=S. W.|last6=Deoni|first6=S. C. L.|last7=Bertini|first7=E.|last8=Kohlschutter|first8=A.|last9=Richardson|first9=W.|last10=ffrench-Constant|first10=C.|last11=Kohler|first11=W.|last12=Barkovich|first12=A.|title=Hypomyelinating Leukodystrophies: Translational Research Progress and Prospects|journal=Ann. Neurol.|date=2014|doi=10.1002/ana.24194|volume=76|issue=1|pages=5–19|pmid=24916848|url=https://www.pure.ed.ac.uk/ws/files/16949724/Hypomyelinating_leukodystrophies_Translational_research_progress_and_prospects.pdf}}</ref> [[Induced pluripotent stem cells]], oligodendrocyte precursor cells, gene correction, and transplantation to promote the maturation, survival, and myelination of [[oligodendrocytes]] seem to be the primary routes for possible treatments.<ref name="Pouwels"/>
| | * [[Adrenoleukodystrophy]] (ALD) – Affects peroxisomal metabolism of very long chain fatty acids, leading to brain inflammation and demyelination. |
| | * [[Canavan disease]] – Caused by mutation in the ASPA gene, leading to N-acetylaspartic acid accumulation and myelin disruption. |
| | * [[Alexander disease]] – Associated with mutations in the GFAP gene, leading to astrocyte dysfunction and myelin loss. |
| | * [[Vanishing white matter disease]] (VWM) – Affects eukaryotic initiation factor 2B (eIF2B), causing chronic white matter degradation. |
| | * [[Pelizaeus–Merzbacher disease]] – X-linked disorder affecting proteolipid protein 1 (PLP1), leading to defective myelin formation. |
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| For three types of leukodystrophies ([[X-linked adrenoleukodystrophy]] (X-ALD), [[metachromatic leukodystrophy]] (MLD) and [[Krabbe Disease]] (globoid cell leukodystrophy - GLD), gene therapy using autologous [[hematopoietic stem cells]] to transfer the disease gene with [[lentiviral]] [[Viral vector|vector]]s have shown to be successful and are currently being used in clinical trials for X-ALD and MLD.<ref name=Biffi>{{Cite journal |doi = 10.1093/hmg/ddr142|pmid = 21459776|title = Gene therapy for leukodystrophies|journal = Human Molecular Genetics|volume = 20|issue = R1|pages = R42–R53|year = 2011|last1 = Biffi|first1 = A.|last2 = Aubourg|first2 = P.|last3 = Cartier|first3 = N.}}</ref> The progression of X-ALD has shown to be disrupted with hematopoietic stem cell gene therapy but the exact reason why [[demyelination]] stops and the amount of stem cells needed is unclear.<ref name=Biffi /> While there is an accumulation of [[very long chain fatty acids]] in the brain, it does not seem to be the reason behind the disease as gene therapy does not correct it.<ref name=Biffi />
| | == Diagnosis == |
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| Adeno-associated [[vector (molecular biology)|vector]]s have also been used in intracerebral injections to treat MLD. In some patients with MLD, their IQ increased, nerve conduction improved, their MRIs appeared stable, and had normal enzyme levels.<ref name=Biffi /> Although the greater majority of patients seem to improve after the transplant, some do not respond well to treatment, which may cause devastating outcomes. For those leukodystrophies that result from a deficiency of lysozyme enzymes, such as [[Krabbe disease]], enzyme replacement therapy seems hopeful. However, enzyme delivery proves difficult, because the [[blood-brain barrier]] severely limits what can pass into the central nervous system.<ref name=Biffi /> Due to this obstacle, most research and clinical trials are turning to allogeneic hematopoietic stem cell transplantation.
| | Diagnosis is made using: |
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| ==Epidemiology==
| | * [[Magnetic resonance imaging]] (MRI) – Detects white matter abnormalities. |
| [[File:2928 X-linked Recessive Inheritance-new.jpg|thumb|X-linked Recessive Inheritance]] | | * Genetic testing – Identifies specific mutations. |
| Currently, no research has shown a higher prevalence of most leukodsytrophy types in any one place around the world. There is, however, a higher prevalence of the [[Canavan disease]] in the Jewish population. 1 in 40 individuals of [[Ashkenazi]] Jewish descent are carriers of Canavan disease.<ref name="Ashkenazi Jews/Canavan - ABSTRACT ONLY">{{cite journal|last1=Fiegenbaum|first1=Annette|last2=Moore|first2=Robert|last3=Clarke|first3=Joe|last4=Hewson|first4=Stacy|last5=Chityat|first5=David|last6=Ray|first6=Peter N.|last7=Stockley|first7=Tracy L.|title=Canavan disease: Carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay|journal=American Journal of Medical Genetics|date=January 15, 2004|volume=124A|issue=2|pages=142–7|doi=10.1002/ajmg.a.20334|pmid=14699612}}</ref> This estimates to roughly 2.5%. Additionally, due to an autosomal recessive inheritance patterns, there is no significant difference found between affected males and affected females for most types of leukodystrophy including, but not limited to, metachromatic leukodystrophy, Krabbe disease, Canavan disease, and Alexander disease. The one exception to this is any type of leukodystrophy carried on a [[sex chromosome]], such as X-linked adrenoleukodystrophy, which is carried on the X-chromosome. Because of the inheritance pattern of X-linked diseases, males are more often affected by this type of leukodystrophy, although female carriers are often symptomatic, though not as severely so as males.<ref name="Genetics - Epidemiology - ABSTRACT">{{cite journal|last1=Lesca|first1=G|last2=Vanier|first2=MT|last3=Creisson|first3=E|last4=Bendelac|first4=N|last5=Hainque|first5=B|last6=Ollagnon-Roman|first6=E|last7=Aubourg|first7=P|title=X-linked adrenoleukodystrophy in a female proband: clinical presentation, biological diagnosis and family consequences|journal=Archives de Pédiatrie|date=August 2005|volume=12|issue=8|pages=1237–40|pmid=15878823|doi=10.1016/j.arcped.2005.03.050}}</ref> To date, there have been no found cases of a leukodystrophy carried on the Y chromosome.
| | * Nerve conduction studies – Differentiate leukodystrophy from other demyelinating conditions. |
| | * Biochemical assays – Measure levels of enzymes or toxic metabolites. |
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| ==Current research== | | == Treatment == |
| MLD Foundation provides updates on [https://mldfoundation.org/research-current.html MLD research], including (as of 2019) two active clinical trials evaluating gene therapy and enzyme replacement therapy, and various lines of basic research. They are also active in [http://newbornscreening.us newborn screening].
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| The [https://theGLIA.org Global Leukodystrophy Initiative] was formed in 2013 to bring together clinicians, researchers and advocacy groups to focus and improve both clinical care and research.
| | Currently, there is no cure for leukodystrophies, but treatment focuses on slowing progression and managing symptoms. |
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| In addition, many research groups are studying the cellular processes of myelination, which may provide insights into leukodystrophy. Researchers in [[New York state|New York]] have successfully cured leukodystrophy in mice, using skin cells to repair damaged [[myelin]] sheaths. Researchers hypothesize that this treatment may possibly be used in curing human [[multiple sclerosis]].<ref>{{cite web|url=http://www.dailytech.com/Human+Skin+Cells+Used+to+Create+Stem+Cells+Treat+Brain+Disease+in+Mice/article29864.htm|title=Human Skin Cells Used to Create Stem Cells, Treat Brain Disease in Mice|publisher=DailyTech|date=8 February 2013|accessdate=9 February 2013|archive-url=https://web.archive.org/web/20180107184714/http://www.dailytech.com/Human+Skin+Cells+Used+to+Create+Stem+Cells+Treat+Brain+Disease+in+Mice/article29864.htm|archive-date=7 January 2018|url-status=dead}}</ref>
| | Potential Therapies: |
| | 1. Hematopoietic stem cell transplantation (HSCT): |
| | * Used for X-ALD and MLD. |
| | * Slows disease progression, especially if performed before symptom onset. |
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| ==Society==
| | 2. Gene therapy: |
| [https://curemld.com Cure MLD] is a global network of patient advocates and nonprofits dedicated to helping families impacted by metachromatic leukodystrophy (MLD). Cure MLD is here to connect families with resources, information, support, and others dealing with MLD. Cure MLD provides travel grants, care packages, emotional support, educational materials, and opportunities to interact with families and patients. Support for the site comes from Chloe's Fight, Love for Loie and The Hammond Family, The Sullivan Family and Friends, Gavin Flying for a Cure, The Calliope Joy Foundation/Cal's Cupcakes, Fundacion Lautaro te Necesita (Argentina), Leukodystrophy Resource and Research Organization (Australia), Bethany's Hope (Canada), and MLD families around the globe. "We are united in our mission to '''Cure MLD'''"
| | * Lentiviral gene therapy is being tested for X-ALD and MLD. |
| | * Experimental stage for other leukodystrophies. |
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| [https://MLDfoundation.org MLD Foundation] was co-founded by Dean and Teryn Suhr in 2001 after the diagnosis in 1995 of two of their daughters with MLD. MLD Foundation serves families and works with researchers, clinicians, regulators, payors, and policy-makers around the world on MLD, leukodystrophy, lysosomal, and rare disease issues. The foundation's mission is "''We C.A.R.E.™'' ... '''C'''ompassion for families, increasing '''A'''wareness, influencing & funding '''R'''esearch, and promoting '''E'''ducation for metachromatic leukodystrophy, a very rare terminal genetic neuro-metabolic disease where over half the cases affect infants."
| | 3. Enzyme replacement therapy (ERT): |
| | * Potential treatment for Krabbe disease and MLD. |
| | * Difficulty: Blood-brain barrier limits enzyme delivery. |
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| The [http://LeukodystrophyAlliance.org World Leukodystrophy Alliance] is increasing awareness and working to improve quality of care for the leukodystrophies.
| | 4. Symptomatic management: |
| | * Physical therapy for spasticity. |
| | * Anti-seizure medications for epilepsy. |
| | * Nutritional support for swallowing difficulties. |
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| Jill Kelly and her husband, [[NFL]] [[quarterback]] [[Jim Kelly]], founded [http://www.huntershope.org Hunter's Hope] after their son Hunter (1997-2005) was diagnosed with infantile Krabbe leukodystrophy.<ref name="hunters">Staff report (October 25, 2012). [http://www.buffalonews.com/apps/pbcs.dll/article?AID=/20121025/CITYANDREGION/121029534/1010 Game show winners donate portion to Hunter’s Hope.] ''[[Buffalo News]]''</ref> Matthew and Michael Clark of [[Kingston upon Hull|Hull]], UK were sufferers, unfortunately both succumbing to the illness and dying in 2013 & 2016 respectively. Their story was the subject of the Channel 4 documentary ''The Curious Case of the Clark Brothers''.<ref name="Channel4">{{cite web |url=http://www.channel4.com/programmes/the-curious-case-of-the-clark-brothers |title= The Curious Case of the Clark Brothers |accessdate= 2012-11-26}}</ref>
| | == Prognosis == |
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| [[Augusto, Michaela, and Lorenzo Odone|Augusto and Michaela Odone]] founded [[The Myelin Project]] after their son, [[Augusto, Michaela, and Lorenzo Odone|Lorenzo]] was diagnosed with Adrenoleukodystrophy (ALD).
| | * Infantile-onset forms (e.g., Krabbe disease, MLD) → Severe progression and short life expectancy (2–10 years). |
| | * Juvenile and adult-onset forms → Slower progression; patients may survive decades with supportive care. |
| | * Stem cell and gene therapy have shown promising results in early-diagnosed cases. |
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| The 1992 film, ''[[Lorenzo's Oil]]'' is a true story about a boy suffering from Adrenoleukodystrophy (ALD).
| | == See Also == |
| | * [[Leukoencephalopathy]] |
| | * [[Neurodegeneration]] |
| | * [[Myelin sheath]] |
| | * [[Neurological disorders]] |
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| ==See also== | | == External Links == |
| *[[Leukoencephalopathy]] | | * [https://mldfoundation.org/ MLD Foundation – Metachromatic Leukodystrophy Resources] |
| | | * [https://theGLIA.org Global Leukodystrophy Initiative] |
| ==References==
| | * [https://www.leukodystrophyalliance.org/ World Leukodystrophy Alliance] |
| {{Reflist}}
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| == External links ==
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| {{Medical resources
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| | DiseasesDB = 32504
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| | ICD10 = {{ICD10|E|75|2|e|75}}
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| | ICD9 = {{ICD9|330.0}}
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| {{CNS diseases of the nervous system}} | | {{CNS diseases of the nervous system}} |
| | | {{rarediseases}} |
| [[Category:Central nervous system disorders]] | | [[Category:Central nervous system disorders]] |
| [[Category:Rare diseases]] | | [[Category:Rare diseases]] |
| | [[Category:Leukodystrophy]] |
| | [[Category:Myelin disorders]] |
