Leukodystrophy

Last updated
Leukodystrophy
Adrenoleukodystrophy.jpg
T2 weighted axial scan of a human brain at the level of the 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 X-linked adrenoleukodystrophy.
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg

Leukodystrophies are a group of, usually, inherited disorders, characterized by degeneration of the white matter in the brain. [1] The word leukodystrophy comes from the Greek roots leuko, "white", dys, "abnormal" and troph, "growth". The leukodystrophies are caused by imperfect growth or development of the glial cells which produce the myelin sheath, the fatty insulating covering around nerve fibers. [2] Leukodystrophies may be classified as hypomyelinating or demyelinating 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 an autoimmune, infectious, or metabolic etiology. [4]

Contents

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 an MRI 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, although hematopoietic stem cell transplantations using bone marrow or cord 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 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.

Symptoms and signs

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. [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 progressive ataxia and rapid cognitive deterioration which has been described as mental retardation. [8] Epilepsy is commonplace for patients of all ages. [9] 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 . [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 a vegetative 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 and physician-assisted suicide. [12]

Causes

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 of myelin sheaths surrounding neuronal axons in the central nervous system as the result of a genetic mutation. [13] 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.[ citation needed ]

Genetic influence

Autorecessive Inheritance Pattern Autorecessive.svg
Autorecessive Inheritance Pattern

Inherited forms of leukodystrophy are 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. [14] 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. [15] 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 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]

Pathophysiology

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-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. [16]

Metachromatic leukodystrophy

Metachromatic leukodystrophy is the result of genetic defects in the enzymes associated with the cellular compartment called 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. [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 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 has some production of ASA, while an individual with two mutated non-null alleles develops the adult form. [18]

Krabbe disease

Globoid cell leukodystrophy PAS - Multinucleated macrophages ("globoid cells") and loss of myelinated fibers in a tissue sample of Krabbe's leukodystrophy Globoid cell leukodystrophy PAS.jpg
Globoid cell leukodystrophy PAS - Multinucleated macrophages ("globoid cells") and loss of myelinated fibers in a tissue sample of Krabbe's leukodystrophy

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). [19] GALC is a lysosomal enzyme responsible for the catabolism of galactolipids, especially the toxic lipid psychosine, that are widely distributed throughout the brain. A deficiency in GALC thus causes a buildup of these fatty acids, leading to an incursion by cells called "globoid macrophages" that destroy oligodendrocytes, thereby inhibiting any further myelin formation. [20] Given the presence of globoid macrophages clustered near white matter, Krabbe disease often is called globoid cell leukodystrophy.

Canavan disease

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 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; if it is not broken down by aspartoacylase, lipid levels in the brain increase, causing demyelination. [21]

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 myelin destabilization. [22] The inflammatory demyelination begins in the corpus 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

Alexander disease is unique from the leukodystrophies mentioned above, in that it is the result of spontaneous 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 of Glial fibrillary acidic protein (GFAP) as the result of a mutation in the GFAP gene, whose protein, rather than being found in association with lysosomes or peroxisomes, is an intermediate filament linked to the nuclear envelope. [23] Intermediate filaments are proteins responsible for the makeup of the cellular cytoskeleton; thus, this type of mutation causes abnormal structural development of a person's cells. Cytoskeletal and transporter molecule defects have been observed in the astrocytes of affected individuals. These astrocytes contain abnormally high levels of GFAP protein, affecting their development and function. [24]

Diagnosis

The degeneration of white matter, which reflects 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 fluid-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 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. [25] Multigene sequencing panels for undifferentiated leukodystrophy are offered for rapid molecular diagnosis after genetic counselling.[ citation needed ]

Types

Specific types of leukodystrophy include the following with their respective ICD-10 codes when available:[ citation needed ]


Treatment

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 and gene 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 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. [26] [ needs update ] 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. [26] [ needs update ]

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 healthy copy of the disease-causing gene with lentiviral vectors 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 the proximal cause of arrested demyelination and the quantity of stem cells needed are unclear. [11] While there continues to be an accumulation of very 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 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. [11] Current gene therapy research for metachromatic leukodystrophy has been reviewed with an emphasis on ex vivo transplantation of genetically modified hematopoietic stem cells. [28] [ needs update ]

Epidemiology

X-linked Recessive Inheritance 2928 X-linked Recessive Inheritance-new.jpg
X-linked Recessive Inheritance

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 of Ashkenazi 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 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, while female carriers are often symptomatic, though not as severely affected as males. [30]

Research

The National 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]

Society

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 by metachromatic leukodystrophy (MLD). [35]

The 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. [36]

The Leukodystrophy Alliance works to promote awareness and quality of care for those with leukodystrophy. [37]

Jill Kelly and her husband, NFL quarterback Jim Kelly, founded Hunter's Hope Foundation to fund research after their son Hunter (1997–2005) was diagnosed with infantile Krabbe leukodystrophy. [38]

Matthew and Michael Clark of Hull, UK had the condition. Both died, in 2013 and 2016 respectively.[ citation needed ] Their story was the subject of the Channel 4 documentary The Curious Case of the Clark Brothers. [39] [40]

Augusto and Michaela Odone founded The 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 ]

See also

Related Research Articles

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

Myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses pass along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon segmentally: in general, each axon is encased in multiple long sheaths with short gaps between, called nodes of Ranvier. At the nodes of Ranvier, which are approximately one thousandth of a mm in length, the axon's membrane is bare of myelin.

<span class="mw-page-title-main">Adrenoleukodystrophy</span> Medical condition

Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by failure of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. The long chain fatty acid buildup causes damage to the myelin sheath of the neurons of the brain, resulting in seizures and hyperactivity. Other symptoms include problems in speaking, listening, and understanding verbal instructions.

<span class="mw-page-title-main">Pelizaeus–Merzbacher disease</span> X-linked leukodystrophy

Pelizaeus–Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes in the central nervous system. It is caused by mutations in proteolipid protein 1 (PLP1), a major myelin protein. It is characterized by a decrease in the amount of insulating myelin surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to as leukodystrophies.

<span class="mw-page-title-main">Leigh syndrome</span> Mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

<span class="mw-page-title-main">Krabbe disease</span> Medical condition

Krabbe disease (KD) is a rare and often fatal lysosomal storage disease that results in progressive damage to the nervous system. KD involves dysfunctional metabolism of sphingolipids and is inherited in an autosomal recessive pattern. The disease is named after the Danish neurologist Knud Krabbe (1885–1961).

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.

A lipid storage disorder is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or, they produce enzymes that do not work properly. Over time, the buildup of fats may cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow.

<span class="mw-page-title-main">Sphingolipidoses</span> Medical condition

Sphingolipidoses are a class of lipid storage disorders or degenerative storage disorders caused by deficiency of an enzyme that is required for the catabolism of lipids that contain ceramide, also relating to sphingolipid metabolism. The main members of this group are Niemann–Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay–Sachs disease and metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked recessive. Taken together, sphingolipidoses have an incidence of approximately 1 in 10,000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.

Sulfatide, also known as 3-O-sulfogalactosylceramide, SM4, or sulfated galactocerebroside, is a class of sulfolipids, specifically a class of sulfoglycolipids, which are glycolipids that contain a sulfate group. Sulfatide is synthesized primarily starting in the endoplasmic reticulum and ending in the Golgi apparatus where ceramide is converted to galactocerebroside and later sulfated to make sulfatide. Of all of the galactolipids that are found in the myelin sheath, one fifth of them are sulfatide. Sulfatide is primarily found on the extracellular leaflet of the myelin plasma membrane produced by the oligodendrocytes in the central nervous system and in the Schwann cells in the peripheral nervous system. However, sulfatide is also present on the extracellular leaflet of the plasma membrane of many cells in eukaryotic organisms.

<span class="mw-page-title-main">Arylsulfatase A</span> Mammalian protein found in Homo sapiens

Arylsulfatase A is an enzyme that breaks down sulfatides, namely cerebroside 3-sulfate into cerebroside and sulfate. In humans, arylsulfatase A is encoded by the ARSA gene.

<span class="mw-page-title-main">Aspartoacylase</span> Hydrolytic enzyme encoded on human chromosome 17

Aspartoacylase is a hydrolytic enzyme that in humans is encoded by the ASPA gene. ASPA catalyzes the deacylation of N-acetyl-l-aspartate (N-acetylaspartate) into aspartate and acetate. It is a zinc-dependent hydrolase that promotes the deprotonation of water to use as a nucleophile in a mechanism analogous to many other zinc-dependent hydrolases. It is most commonly found in the brain, where it controls the levels of N-acetyl-l-aspartate. Mutations that result in loss of aspartoacylase activity are associated with Canavan disease, a rare autosomal recessive neurodegenerative disease.

The Myelin Project was a 501(c)(3) nonprofit organization established in 1989 by Augusto Odone and his wife, Michaela and their friend Patti Chapman. Their son, Lorenzo, suffered from adrenoleukodystrophy (ALD), the most common of the leukodystrophies. The story of the Odones' struggle was dramatized in the 1992 Hollywood film Lorenzo's Oil, starring the well-known actors Nick Nolte, Susan Sarandon and Peter Ustinov. After 20 years, the Myelin Project was merged into another organization called ALD Connect in July 2019.

<span class="mw-page-title-main">ABCD1</span> Protein-coding gene in humans

ABCD1 is a protein that transfers fatty acids into peroxisomes.

<span class="mw-page-title-main">Leukoencephalopathy with vanishing white matter</span> Neurological disease

Leukoencephalopathy with vanishing white matter is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor eIF2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. The disease belongs to a family of conditions called the Leukodystrophies.

<span class="mw-page-title-main">GJB1</span> Protein-coding gene in humans

Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system. However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system.

<span class="mw-page-title-main">Hereditary diffuse leukoencephalopathy with spheroids</span> Medical condition

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare adult onset autosomal dominant disorder characterized by cerebral white matter degeneration with demyelination and axonal spheroids leading to progressive cognitive and motor dysfunction. Spheroids are axonal swellings with discontinuous or absence of myelin sheaths. It is believed that the disease arises from primary microglial dysfunction that leads to secondary disruption of axonal integrity, neuroaxonal damage, and focal axonal spheroids leading to demyelination. Spheroids in HDLS resemble to some extent those produced by shear stress in a closed head injury with damage to axons, causing them to swell due to blockage of axoplasmic transport. In addition to trauma, axonal spheroids can be found in aged brain, stroke, and in other degenerative diseases. In HDLS, it is uncertain whether demyelination occurs prior to the axonal spheroids or what triggers neurodegeneration after apparently normal brain and white matter development, although genetic deficits suggest that demyelination and axonal pathology may be secondary to microglial dysfunction. The clinical syndrome in patients with HDLS is not specific and it can be mistaken for Alzheimer's disease, frontotemporal dementia, atypical Parkinsonism, multiple sclerosis, or corticobasal degeneration.

Shiverer mice are mice which possess the shiverer (shi/shi) mutation in the MBP gene. Shiverer mice develop a characteristic "shaking" or "shivering" gait within a few weeks of birth. They are commonly used as animal models of leukodystrophy in neuroscience research.

<span class="mw-page-title-main">Spongy degeneration of the central nervous system</span> Neurodegenerative disorder

Spongy degeneration of the central nervous system, also known as Canavan's disease, Van Bogaert-Bertrand type or Aspartoacylase (AspA) deficiency, is a rare autosomal recessive neurodegenerative disorder. It belongs to a group of genetic disorders known as leukodystrophies, where the growth and maintenance of myelin sheath in the central nervous system (CNS) are impaired. There are three types of spongy degeneration: infantile, congenital and juvenile, with juvenile being the most severe type. Common symptoms in infants include lack of motor skills, weak muscle tone, and macrocephaly. It may also be accompanied by difficulties in feeding and swallowing, seizures and sleep disturbances. Affected children typically die before the age of 10, but life expectancy can vary.

Elivaldogene autotemcel, sold under the brand name Skysona, is a gene therapy used to treat cerebral adrenoleukodystrophy (CALD). It was developed by Bluebird bio and was given breakthrough therapy designation by the U.S. Food and Drug Administration in May 2018.

References

  1. ↑ Sachdev, Perminder S.; Keshavan, Matcheri S. (2010-03-15). Secondary Schizophrenia. Cambridge University Press. pp. 241–. ISBN   978-0-521-85697-3 . Retrieved 15 August 2011.
  2. ↑ PD-icon.svg One or more of the preceding sentences incorporates text from this source, which is in the public domain : " Leukodystrophy Information Page ". National Institute of Neurological Disorders and Stroke. 25 May 2017. Retrieved 18 March 2018.
  3. ↑ "Leukodystrophy". www.ninds.nih.gov. Retrieved 2024-04-13.
  4. ↑ Coggan, Jay S.; Bittner, Stefan; Stiefel, Klaus M.; Meuth, Sven G.; Prescott, Steven A. (September 2015). "Physiological Dynamics in Demyelinating Diseases: Unraveling Complex Relationships through Computer Modeling". International Journal of Molecular Sciences. 16 (9): 21215–21236. doi: 10.3390/ijms160921215 . ISSN   1422-0067. PMC   4613250 . PMID   26370960.
  5. ↑ Bonkowsky, Joshua (Aug 24, 2010). "The burden of inherited leukodystrophies in children". Neurology. 75 (8): 718–725. doi:10.1212/WNL.0b013e3181eee46b. PMC   2931652 . PMID   20660364.
  6. 1 2 Graziano, AC; Cardile, V (26 September 2014). "History, genetic, and recent advances on Krabbe disease". Gene. 555 (1): 2–13. doi:10.1016/j.gene.2014.09.046. PMID   25260228.
  7. ↑ Rosebush, P. I. (2003). "Tardive dystonia and its treatment". Journal of Psychiatry and Neuroscience. 28 (3): 240. PMC   161748 .
  8. ↑ Liu, Y; Zou, L; Meng, Y; Zhang, Y; Shi, X; Ju, J; Yang, G; Hu, L; Chen, X (June 2014). "[A family with two children diagnosed with aspartylglucosaminuria-case report and literature review]". Zhonghua Er Za Zhi. 52 (6): 455–9. PMID   25190167.
  9. ↑ Turon-Vinas, E; Pineda, M; Cusi, V; Lopez-Laso, E; Del Pozo, RL; Gutierez-Solana, LG; Moreno, DC; Sierra-Corcoles, C; Olabarrieta-Hoyos, N; Madruga-Garrido, M; Aguirre-Rodriguez, J; Gonzalez-Alvarez, V; O'Callaghan, M; Muchart, J; Armstrong-Moron, J (13 July 2014). "Vanishing white matter disease in a Spanish population". J Cent Nerv Syst Dis. 6: 59–68. doi:10.4137/JCNSD.S13540. PMC   4116383 . PMID   25089094.
  10. ↑ Rubin, Rita (March 13, 2016). "Forbes.com: Lorenzo's Oil Could Not Cure Lorenzo, But Newborn Screening Is Expected To Save Others From His Fate". Forbes.com. Retrieved July 31, 2018..
  11. 1 2 3 4 5 Biffi, A.; Aubourg, P.; Cartier, N. (2011). "Gene therapy for leukodystrophies". Human Molecular Genetics. 20 (R1): R42–R53. doi: 10.1093/hmg/ddr142 . PMID   21459776.
  12. ↑ Duchange, N; Darguy, S; d'Audiffret, D; Callies, I; Lapointe, AS; Loeve, B; Boespflug-Tanguy, O; Moutel, G (18 September 2014). "Ethical management in the constitution of a European database for leukodystrophies rare diseases". Eur J Paediatr Neurol. 18 (5): 597–603. doi:10.1016/j.ejpn.2014.04.002. PMID   24786336. S2CID   31385905.
  13. ↑ Yang, Edward; Prabhu, Sanjay P. (March 5, 2014). "Imaging manifestations of the leukodystrophies, inherited disorders of white matter". Radiologic Clinics of North America. 52 (2): 279–319. doi:10.1016/j.rcl.2013.11.008. PMID   24582341.
  14. 1 2 Lin, Shu-Ting; Ptacek, Louis J.; Fu, Ying-Hui (January 26, 2011). "Adult-Onset Autosomal Dominant Leukodystrophy: Linking Nuclear Envelope to Myelin". The Journal of Neuroscience. 31 (4): 1163–1166. doi:10.1523/jneurosci.5994-10.2011. PMC   3078713 . PMID   21273400.
  15. ↑ Coulter-Mackie, MB; Rip, J; Ludman, MD; Beis, J; Cole, DEC (October 1995). "Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22". Journal of Medical Genetics. 32 (10): 787–91. doi:10.1136/jmg.32.10.787. PMC   1051701 . PMID   8558556.
  16. ↑ Sassa, Takayuki; Kihara, Akio (March 22, 2014). "Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology". Biomolecules & Therapeutics. 22 (2): 83–92. doi:10.4062/biomolther.2014.017. PMC   3975470 . PMID   24753812.
  17. 1 2 Barboura, Ilhem; Ferchichi, Salima; Dandana, Azza; Jaidane, Zaineb; Ben Khelifa, Souhaira; Chahed, Hinda; Ben Mansour, Rachida; Chebel, Saber; Maire, Irene; Miled, Abdelhedi (2010). "Metachromatic leucodystrophy. Clinical, biological, and therapeutic aspects". Annales de Biologie Clinique. 68 (4): 385–91. doi:10.1684/abc.2010.0448. PMID   20650733.
  18. ↑ Gieselman, V; Krageloh-Mann, I (2010). "Metachromatic Leukodystrophy - An Update". Neuropediatrics. 41 (1): 1–6. doi:10.1055/s-0030-1253412. PMID   20571983.
  19. ↑ Szymanska, Krystyna; Lugowska, Agnieszka; Laure-Kamionowska, Milena; Gieruszczak-Bialek, Dorota; Musielak, Malgorzata; Eichler, Sabrina; Giese, Anne-Katrin; Rolfs, Arndt (2012). "Diagnostic difficulties in Krabbe disesase: a report of two cases and review of literature". Folia Neuropathol. 50 (4): 346–356. doi: 10.5114/fn.2012.32364 . PMID   23319190.
  20. ↑ Kohlschutter, Alfried (April 25, 2013). "Lysosomal leukodystrophies". Pediatric Neurology Part III. Handbook of Clinical Neurology. Vol. 113. pp. 1611–1618. doi:10.1016/B978-0-444-59565-2.00029-0. ISBN   9780444595652. PMID   23622382.
  21. ↑ United Leukodystrophy Foundation. "Canavan Disease". United Leukodystrophy Foundation. United Leukodystrophy Foundation, Inc. Retrieved March 30, 2015.
  22. 1 2 Berger, J; Forss-Petter, S; Eichler, F.S. (March 2014). "Pathophysiology of X-Linked Adrenoleukodystrophy". Biochimie. 98 (100): 135–142. doi:10.1016/j.biochi.2013.11.023. PMC   3988840 . PMID   24316281.
  23. ↑ Singh, Navneet; Bixby, Catherine; Etienne, Denzil; Tubbs, R. Shane; Loukas, Marios (December 2012). "Alexander's disease: reassessment of a neonatal form". Child's Nervous System. 28 (12): 2029–2031. doi:10.1007/s00381-012-1868-8. PMID   22890470. S2CID   5851209.
  24. ↑ Hol, Elly M.; Pekny, Milos (February 2015). "Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system". Current Opinion in Cell Biology. 32 (Cell Architecture): 121–130. doi:10.1016/j.ceb.2015.02.004. PMID   25726916.
  25. 1 2 Kohlschutter, Alfried; Eichler, Florian (October 2011). "Childhood leukodystrophies: a clinical perspective". Expert Review of Neurotherapeutics. 11 (10): 1485–1496. doi:10.1586/ern.11.135. PMID   21955203. S2CID   27471268.[ permanent dead link ]
  26. 1 2 Pouwels, P. J. W.; Vanderver, A.; Bernard, G.; Wolf, N.; Dreha-Kulczewski, S. W.; Deoni, S. C. L.; Bertini, E.; Kohlschutter, A.; Richardson, W.; ffrench-Constant, C.; Kohler, W.; Barkovich, A. (2014). "Hypomyelinating Leukodystrophies: Translational Research Progress and Prospects" (PDF). Ann. Neurol. 76 (1): 5–19. doi: 10.1002/ana.24194 . PMID   24916848. S2CID   19026052.
  27. ↑ "First baby receives life-saving gene therapy on NHS". NHS England. NHS. 15 Feb 2023. Retrieved 18 February 2023.
  28. ↑ Rosenberg, J. B.; Kaminsky, S. M.; Aubourg, P.; Crystal, R. G.; Sondhi, D. (2016). "Gene therapy for metachromatic leukodystrophy". Journal of Neuroscience Research. 94 (11): 1169–79. doi:10.1002/jnr.23792. PMC   5027970 . PMID   27638601.
  29. ↑ Fiegenbaum, Annette; Moore, Robert; Clarke, Joe; Hewson, Stacy; Chityat, David; Ray, Peter N.; Stockley, Tracy L. (January 15, 2004). "Canavan disease: Carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay". American Journal of Medical Genetics. 124A (2): 142–7. doi:10.1002/ajmg.a.20334. PMID   14699612. S2CID   25981659.
  30. ↑ Lesca, G; Vanier, MT; Creisson, E; Bendelac, N; Hainque, B; Ollagnon-Roman, E; Aubourg, P (August 2005). "X-linked adrenoleukodystrophy in a female proband: clinical presentation, biological diagnosis and family consequences". Archives de Pédiatrie. 12 (8): 1237–40. doi:10.1016/j.arcped.2005.03.050. PMID   15878823.
  31. ↑ "Leukodystrophy Information Page". www.ninds.nih.gov.
  32. ↑ "The Global Leukodystrophy Initiative". The Global Leukodystrophy Initiative.
  33. ↑ "Accueil -". ela-asso.com.
  34. ↑ "Research". United Leukodystrophy Foundation.
  35. ↑ "Home | Metachromatic leukodystrophy". curemld.
  36. ↑ "MLD Foundation". mldfoundation.org.
  37. ↑ "leukodystrophyalliance.org - This website is for sale! - leukodystrophyalliance Resources and Information". leukodystrophyalliance.org.{{cite web}}: Cite uses generic title (help)
  38. ↑ "Please Help Leukodystrophy Children". www.classy.org.
  39. ↑ "The Curious Case of the Clark Brothers - Channel 4". Channel 4. 20 November 2012. Archived from the original on 20 November 2012. Retrieved 26 November 2012.
  40. ↑ "The curious case of the boys who live backwards" . The Independent . 24 November 2012. Archived from the original on 2022-06-14. Retrieved 2 April 2021.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.