| Leukodystrophy | |
|---|---|
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| T2 weightedaxial scan of a human brain at the level of thecaudate heads demonstrates marked loss of posteriorwhite matter, with reduced volume and increased signal intensity. The anterior white matter is spared. Features are consistent withX-linkedadrenoleukodystrophy. | |
| Specialty | Neurology  |
Leukodystrophies are a group of, usually, inherited disorders, characterized bydegeneration of thewhite matter in the brain.[1] The wordleukodystrophy comes from theGreek rootsleuko, "white",dys, "abnormal" andtroph, "growth". The leukodystrophies are caused by imperfect growth or development of theglial cells which produce themyelin sheath, the fatty insulating covering aroundnerve fibers.[2] Leukodystrophies may be classified as hypomyelinating ordemyelinating diseases, respectively, depending on whether the damage is present before birth or occurs after. While all leukodystrophies are the result of genetic mutations,[3] other demyelinating disorders have anautoimmune,infectious, ormetabolic etiology.[4]
When damage occurs to white matter, subsequent immune responses can lead to inflammation in the central nervous system (CNS), along with the loss of myelin. The degeneration of white matter can be seen in anMRI scan and is 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, althoughhematopoietic stem cell transplantations usingbone marrow orcord blood seem to help in certain leukodystrophy types, while further research is being done.
The combined incidence of the leukodystrophies is estimated at 1 in 7,600.[5] The majority of types involve the inheritance of anX-linked recessive, orX-linked dominant trait, while others, although involving a defective gene, are the result ofspontaneous mutation rather thangenetic inheritance.
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 andhypersensitivity to the environment are common, as well as some tell-tale physical signs includingmuscle rigidity and a backwards-bent head.[6] Botox therapy is often used to treat patients with spasticity.[7] 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 progressiveataxia and rapid cognitive deterioration which has been described asmental retardation.[8]Epilepsy is commonplace for patients of all ages.[9] More progressed patients show weakness indeglutition, leading to spastic coughing fits due to inhaled saliva. Classic symptomatic progression of juvenileX-linked adrenoleukodystrophy is shown in the 1992 film,Lorenzo's Oil.[10]
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 avegetative state and death.[6] 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.[11] The debilitating course of the disease has led to numerous philosophical and ethical arguments over experimental clinical trials, patients' rights andphysician-assisted suicide.[12]
While the more specific underlying causes of leukodystrophy are dependent upon the type, there are 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 ofmyelin sheaths surrounding neuronalaxons in thecentral nervous system as the result of agenetic mutation.[13] Myelin is a fatty white substance that acts as anelectrical 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 byoligodendrocytes (a type ofglial cell) in the central nervous system, an easy place to look for the cause is amutation or malfunctioning of these cells and in other glial cells.[citation needed]
Inherited forms of leukodystrophy are usually the result of anautosomal recessive inheritance pattern, although dominant inheritance patterns are not unheard of, as in the case of adult-onset leukodystrophy.[14] This means that the affectedallele is carried on anautosomal, or non-sex, chromosome and is masked by the dominant, unaffectedphenotype. In other words, for an individual to inherit the leukodystrophy phenotype, he or she must carry two of the recessive, mutant alleles.Krabbe disease andmetachromatic leukodystrophy (MLD) are two of such type. MLD is found on humanchromosome 22 at position q13.31.[15] Another type of inherited leukodystrophy isX-linked adrenoleukodystrophy (X-ALD). As its name implies, this type of leukodystrophy is the result of a mutation found on theX-chromosome. It is also carried in a recessive pattern. The X chromosome is asex chromosome, and since women have two "chances" of acquiring a normal X chromosome (one maternal x, one paternal x), and males only one chance (one maternal x), this disease is more likely to be seen in males than in females. The mutation resulting in adult-onset leukodystrophy is mapped at 5q23.[14]
Although there are nearly 40 different types of leukodystrophy, 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-Linkedadrenoleukodystrophy (ALD), (4)Canavan disease, and (5)Alexander disease. Each type of leukodystrophy has a uniquepathophysiology, 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 thecatabolism ofvery long chain fatty acids (VLCFAs) that are toxic to the myelin-producing cells of the central nervous system.[16]
Metachromatic leukodystrophy is the result of genetic defects in the enzymes associated with the cellular compartment called thelysosome. MLD is one of two leukodystophies that are also alysosomal storage disorder. MLD is inherited in anautosomal recessive way and is the result of mutations in three different ARSAalleles that encode the enzymearylsulfatase A (ASA or sometimes ARSA), also calledsulfatidesulfatase.[17] 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, it decreases ASA production, which subsequently leads to diminished degradation of sulfatides, thus causing them to accumulate.[17] This accumulation of sulfatides is toxic to oligodendrocytes, the myelin-producing cells of the CNS, effectively leading to a disturbance in myelin structure followed bydemyelination. The pattern of inheritance of the three different alleles affects what type of MLD a person develops. Twonull alleles are responsible for the infantile version, and do not allow for any production of ASA. Aheterozygous individual (one null allele, one non-null allele) develops the juvenile form and has some production of ASA, while an individual with two mutated non-null alleles develops the adult form.[18]
Like MLD,Krabbe disease is another type of leukodystrophy with autosomal recessive inheritance that is the result of alysosomal storage disorder. It is due to a deletion in exon 16 of theGALC gene that causes aframeshift mutation leading to a prematurestop codon. The GALC gene, found onchromosome 14 at position 31 (14q31), codes for theenzyme beta-galactocerebrosidase (GALC).[19] GALC is a lysosomal enzyme responsible for the catabolism ofgalactolipids, especially the toxic lipidpsychosine, that are widely distributed throughout the brain. A deficiency in GALC thus causes a buildup of thesefatty acids, leading to an incursion by cells called "globoidmacrophages" that destroy oligodendrocytes, thereby inhibiting any further myelin formation.[20] Given the presence of globoid macrophages clustered nearwhite matter, Krabbe disease often is called globoid cell leukodystrophy.
Canavan disease is a less-studied type of leukodystrophy that, like MLD and Krabbe disease, is also inherited in an autosomal recessive pattern. It is due to a mutation inthe ASPA gene that encodesaspartoacylase, an enzyme needed to metabolizeN-acetyl-L-aspartate (NAA). The mutation causes a deficiency of aspartoacyclase. NAA is involved in the formation oflipids; if it is not broken down by aspartoacylase, lipid levels in the brain increase, causing demyelination.[21]
In X-linked adrenoleukodystrophy (X-ALD), a mutation occurs in theperoxisomalATP-binding cassette (ABC transporter). This leads to cerebral inflammatorydemyelination caused by myelin destabilization.[22] The inflammatory demyelination begins in thecorpus callosum and slowly progresses outwards into both hemispheres. In X-ALD patients, abnormally high levels of VLCFA accumulate in various body tissues and fluids. This increased concentration then incorporates into various complex lipids where VLCFAs are not normally found.[22] This has been found to be directly involved in the cerebral inflammation of X-ALD. It is speculated that the accumulated and embedded VLCFA in the complex lipids could lead to the destabilization of the myelin sheath and eventually to demyelination.[citation needed]
Alexander disease is unique from the leukodystrophies mentioned above, in that it is the result ofspontaneous mutation, meaning that it is not inherited. The mutation found in an affected individual is not found in either of his or her parents. Symptoms result from the accumulation ofGlial fibrillary acidic protein (GFAP) as the result of a mutation inthe GFAP gene, whose protein, rather than being found in association with lysosomes or peroxisomes, is anintermediate filament linked to thenuclear envelope.[23] Intermediate filaments are proteins responsible for the makeup of the cellularcytoskeleton; thus, this type of mutation causes abnormal structural development of a person's cells.Cytoskeletal andtransporter molecule defects have been observed in theastrocytes of affected individuals. These astrocytes contain abnormally high levels of GFAP protein, affecting their development and function.[24]
The degeneration ofwhite matter, which reflects the degeneration of myelin, can be seen in a basicMRI and used to diagnose leukodystrophies of all types. T-1 and T-2 weightedfluid-attenuated inversion recovery (FLAIR) images are the most often used approach.[25] Electrophysiological and other kinds of laboratory testing can also be done. In particular,nerve conduction velocity is looked at to distinguish between leukodystrophy and otherdemyelinating 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.[25] Multigene sequencing panels for undifferentiated leukodystrophy are offered for rapid molecular diagnosis after genetic counselling.[citation needed]
Specific types of leukodystrophy include the following with their respectiveICD-10 codes when available:[citation needed]
With many different types of leukodystrophy, with many causes, treatment therapies will vary for each type. Studies and clinical trials are seeking to find therapies for each of the different leukodystrophies.Stem cell transplants andgene therapy appear to be the most promising in treating all leukodystrophies, providing they take place as early as possible, prior to extensive neurological damage.
For hypomyelinating leukodystrophies, therapeutic research into cell-based therapies appears promising.Oligodendrocyte precursor cells andneural 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.[26][needs update]Induced pluripotent stem cells, oligodendrocyte precursor cells, gene correction, and transplantation to promote the maturation, survival, and myelination ofoligodendrocytes seem to be the primary routes for possible treatments.[26][needs update]
For three types of leukodystrophies (X-linked adrenoleukodystrophy (X-ALD),metachromatic leukodystrophy (MLD) andKrabbe Disease (globoid cell leukodystrophy - GLD), gene therapy using autologoushematopoietic stem cells to transfer the healthy copy of the disease-causing gene withlentiviralvectors has been shown to succeed and has been used in clinical trials for X-ALD and MLD.[11][27] The progression of X-ALD has been shown to be disrupted with hematopoietic stem cell gene therapy, although theproximal cause of arresteddemyelination and the quantity of stem cells needed are unclear.[11] While there continues to be an accumulation ofvery long chain fatty acids in the brain, this seems not to be the immediate causal factor behind the disease, as gene therapy does not correct the accumulation.[11][needs update]
For those leukodystrophies that result from a deficiency of lysozyme enzymes, such asKrabbe disease, enzyme replacement therapy seems hopeful. However, enzyme delivery proves difficult, because theblood–brain barrier severely limits what can pass into the central nervous system.[11] Current gene therapy research for metachromatic leukodystrophy has been reviewed with an emphasis onex vivo transplantation of genetically modified hematopoietic stem cells.[28][needs update]
Currently, no research has shown a higher prevalence of most leukodystrophy types in any one place around the world. There is, however, a higher prevalence of Canavan disease in the Jewish population. One in 40 individuals ofAshkenazi Jewish descent are carriers of Canavan disease.[29] This extrapolates to roughly 2.5%. Additionally, due to their autosomal recessive inheritance patterns, there is no significant difference found between males and 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 asex 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, while female carriers are often symptomatic, though not as severely affected as males.[30]
TheNational Institute of Neurological Disorders and Stroke (NINDS, under the U.S.National Institutes of Health) supports research on genetic disorders, including the leukodystrophies.[31] NINDS also supports researchers who are working with the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) which promotes advances in the diagnosis and treatment of leukodystrophies.[32]
The European Leukodystrophy Association also supports research into leukodystrophy. As of 2020, more than 387 research projects have been funded. Each year, ELA invites the international scientific community to submit research projects in the field of genetic leukodystrophies, the cerebral white matter in premature infants, and of myelin repair.[33]
The United Leukodystrophy Foundation (ULF), incorporated in 1982, is a non-profit, voluntary health organization dedicated to funding cutting-edge research and to providing patients and their families with disease information and medical referrals.[34]
Cure MLD is a global network of patient advocates and nonprofits dedicated to helping families impacted bymetachromatic leukodystrophy (MLD).[35]
TheMLD 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.[36]
TheLeukodystrophy Alliance works to promote awareness and quality of care for those with leukodystrophy.[37]
Jill Kelly and her husband,NFLquarterbackJim Kelly, foundedHunter's Hope Foundation to fund research after their son Hunter (1997–2005) was diagnosed with infantile Krabbe leukodystrophy.[38]
Matthew and Michael Clark ofHull, UK had the condition. Both died, in 2013 and 2016 respectively.[citation needed] Their story was the subject of the Channel 4 documentaryThe Curious Case of the Clark Brothers.[39][40]
Augusto and Michaela Odone foundedThe Myelin Project after their son,Lorenzo was diagnosed with Adrenoleukodystrophy (ALD). The 1992 film,Lorenzo's Oil is a true story about a boy with Adrenoleukodystrophy (ALD).[citation needed]
One or more of the preceding sentences incorporates text from this source, which is in thepublic domain: "Leukodystrophy Information Page". National Institute of Neurological Disorders and Stroke. 25 May 2017. Retrieved 18 March 2018.