Metachromatic leukodystrophy

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Metachromatic leukodystrophy
Other namesMLD, Arylsulfatase A deficiency, ARSA deficiency
Sulfatide.png
Sulfatide
Specialty Endocrinology, neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Progressive neurologic decline
Complications Dementia, seizures, loss of motor skills
Usual onsetLate infantile (1-2 years), juvenile (3-20 years) or adulthood (around 40s)
DurationLate infantile (3-10 years), juvenile and adult (varies)
TypesLate infantile, juvenile, or adult
CausesLysosomal storage disease
Diagnostic method Enzyme based and genetics
TreatmentHSCT (pre-symptomatic), Gene therapy (late infantile), Palliative
Prognosis fatal
Frequency1 in 40,000 births

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. [1] [2] Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern. [2]

Contents

Signs and symptoms

Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.[ citation needed ]

Palliative care can help with many of the symptoms and usually improves quality of life and longevity.[ citation needed ]

Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the body's sulfatide.[ citation needed ]

Causes

Diagram showing the disrupted pathway Inborn errors of metabolism.svg
Diagram showing the disrupted pathway

MLD is directly caused by a deficiency of the enzyme arylsulfatase A [3] (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls. [4] However, assay of the ARSA enzyme activity alone is not sufficient for diagnosis; ARSA pseudodeficiency, which is characterized by enzyme activity that is 5~20% of normal controls does not cause MLD. [4] Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain (central nervous system – CNS) and the peripheral nerves (peripheral nervous system – PNS) which control, among other things the muscles related to mobility, cease to function properly.[ citation needed ]

Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. [5] When the arylsulfatase A enzyme level is normal but the sulfatides are still high – meaning that they are not being broken down because the enzyme is not activated – the resulting disease is saposin B deficiency, which presents similar to MLD. [4] Saposin B Deficiency is very rare, much more rare than traditional MLD. [4] The enzyme that is present is not "enabled" to a normal level of efficiency and can't break down the sulfatides which results in all of the same MLD symptoms and progression. [6]

A 2011 study contended sulfatide is not completely responsible for MLD because it is nontoxic. It has been suggested lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro. [7]

Genetics

Metachromatic leukodystrophy has an autosomal recessive pattern of inheritance. Autosomal recessive - en.svg
Metachromatic leukodystrophy has an autosomal recessive pattern of inheritance.

MLD has an autosomal recessive inheritance pattern. The inheritance probabilities per birth are as follows: [8]

In addition to these frequencies there is a 'pseudo'-deficiency that affects 7–15% of the population. [9] [10] People with the pseudo deficiency do not have any MLD problems unless they also have affected status. With the current diagnostic tests, Pseudo-deficiency reports as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist. This phenomenon wreaks havoc with traditional approaches to Newborn Screening so new screening methods are being developed.[ citation needed ]

Diagnosis

Clinical examination and MRI are often the first steps in an MLD diagnosis. MRI can be indicative of MLD but is not adequate as a confirming test. An ARSA-A enzyme level blood test with a confirming urinary sulfatide test is the best biochemical test for MLD. The confirming urinary sulfatide is important to distinguish between MLD and pseudo-MLD blood results. Genomic sequencing may also confirm MLD, however, there are likely more mutations than the over 200 already known to cause MLD that are not yet ascribed to MLD that cause MLD so in those cases a biochemical test is still warranted.[ citation needed ]

Newborn screening

MLD Foundation formally launched a newborn screening initiative in late 2017. The screen development started in the early 2010s at the University of Washington Gelb Biochemistry lab. A deidentified pilot study launched in April 2016 in Washington state. Positive results led to MLD being included in the ScreenPlus identified baby research project in New York state, which is currently scheduled to launch in Q1'2021.[ citation needed ]

Treatment

There is currently no approved treatment for MLD in symptomatic late infantile patients or for juvenile and adult-onset with advanced symptoms. These patients typically receive clinical treatment focused on pain and symptom management.[ citation needed ]Pre-symptomatic late infantile MLD patients, as well as those with juvenile or adult MLD that are either presymptomatic or displaying mild symptoms, can consider bone marrow transplantation (including stem cell transplantation), which may slow down the progression of the disease in the central nervous system.[ citation needed ] However, results in the peripheral nervous system have been less dramatic, and the long-term results of these therapies have been mixed.[ citation needed ]

In 2020 the European Medical Agency, approved the Cell Therapy Drug Libmeldy for treatment of infantile and juvenile forms of metachromatic leukodystrophy in Europe. Libmeldy is a type of advanced therapy medicine called a ‘gene therapy’. This type of medicine works by delivering genes into the body. The active substance in Libmeldy is stem cells, (CD34+ cells), derived from the patient's own bone marrow or blood, that have been modified to contain a copy of the gene to make ARSA and can divide to produce other sorts of blood cells. [11]

Atidarsagene autotemcel

A gene therapy called atidarsagene autotemcel was approved for medical use in the European Union in December 2020 and is sold under the trade name Libmeldy. [12] The indication is for use in children with the late infantile or early juvenile forms of MLD who have been identified as carriers of the defective gene but have not yet developed symptoms. [13] It is also indicated in children who have been diagnosed with the early juvenile form who have started developing symptoms but still have the ability to walk independently and before the onset of cognitive decline. [13]

In the United States, an Investigational New Drug application for atidarsagene autotemcel was accepted by the Food and Drug Administration in late 2020. [14]

Research directions

Several therapy options are currently being investigated using clinical trials primarily in late infantile patients. These therapies include gene therapy, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and potentially enzyme enhancement therapy (EET). In addition to the clinical trials, there are several other pre-clinical gene therapy research projects underway.[ citation needed ]

Epidemiology

The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide. [15] There is a much higher incidence in certain genetically isolated populations, such as 1 in 75 in Habbanites (a small group of Jews who immigrated to Israel from southern Arabia), 1 in 2,500 in the western portion of the Navajo Nation, and 1 in 8,000 among Arab groups in Israel. [15]

As an autosomal recessive disease, 1 in 40,000 equates to a 1 in 100 carrier frequency in the general population. [16]

In the US, there are an estimated 3,600 MLD births per year, with 1,900 alive; in Europe 3,100, and worldwide 49,000 alive. [16]

MLD is considered a rare disease in the US and other countries.[ citation needed ]

Research

Bone marrow and stem cell transplant therapies

Gene therapy

(current as of April 2021)

Two different approaches to gene therapy are currently being researched for MLD.

Enzyme replacement therapy (ERT)

(current as of February 2021)

Substrate reduction therapy

Natural history studies

See also

Related Research Articles

<span class="mw-page-title-main">Gene therapy</span> Medical field

Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

<span class="mw-page-title-main">Tay–Sachs disease</span> Human medical condition

Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. Less commonly, the disease may occur later in childhood, adolescence, or adulthood. These forms tend to be less severe, but the juvenile form typically results in death by age 15.

<span class="mw-page-title-main">Osteopetrosis</span> Rare disease of the bones

Osteopetrosis, literally "stone bone", also known as marble bone disease or Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.

<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">Alexander disease</span> Rare genetic disorder of the white matter of the brain

Alexander disease is a very rare autosomal dominant leukodystrophy, which are neurological conditions caused by anomalies in the myelin which protects nerve fibers in the brain. The most common type is the infantile form that usually begins during the first two years of life. Symptoms include mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal increase in head size and seizures. The juvenile form of Alexander disease has an onset between the ages of 2 and 13 years. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control. Adult-onset forms of Alexander disease are less common. The symptoms sometimes mimic those of Parkinson’s disease or multiple sclerosis, or may present primarily as a psychiatric disorder.

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

Glycogen storage disease type II, also called Pompe disease, and formerly known as GSD-IIa. It is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. GSD-II and Danon disease are the only glycogen storage diseases with a defect in lysosomal metabolism, and Pompe disease was the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.

<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).

<span class="mw-page-title-main">Leukodystrophy</span> Group of disorders characterised by degeneration of white matter in the brain

Leukodystrophies are a group of, usually, inherited disorders, characterized by degeneration of the white matter in the brain. 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. Leukodystrophies may be classified as hypomyelinating or demyelinating diseases, respectively, 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.

Batten disease is a fatal disease of the nervous system that typically begins in childhood. Onset of symptoms is usually between 5 and 10 years of age. Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).

<span class="mw-page-title-main">Neuronal ceroid lipofuscinosis</span> Medical condition

Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.

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

Sandhoff disease is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Accumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death. The rare autosomal recessive neurodegenerative disorder is clinically almost indistinguishable from Tay–Sachs disease, another genetic disorder that disrupts beta-hexosaminidases A and S. There are three subsets of Sandhoff disease based on when first symptoms appear: classic infantile, juvenile and adult late onset.

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.

Farber disease is an extremely rare, progressive, autosomal recessive lysosomal storage disease caused by a deficiency of the acid ceramidase enzyme. Acid ceramidase is responsible for breaking down ceramide into sphingosine and fatty acid. When the enzyme is deficient, this leads to an accumulation of fatty material in the lysosomes of the cells, leading to the signs and symptoms of this disorder.

<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.

<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">Galactosialidosis</span> Rare disease

Galactosialidosis, also known as neuraminidase deficiency with beta-galactosidase deficiency, is a genetic lysosomal storage disease. It is caused by a mutation in the CTSA gene which leads to a deficiency of enzymes β-galactosidase and neuraminidase. This deficiency inhibits the lysosomes of cells from functioning properly, resulting in the accumulation of toxic matter within the cell. Hallmark symptoms include abnormal spinal structure, vision problems, coarse facial features, hearing impairment, and intellectual disability. Because galactosialidosis involves the lysosomes of all cells, it can affect various areas of the body, including the brain, eyes, bones, and muscles. Depending on the patient's age at the onset of symptoms, the disease consists of three subtypes: early infantile, late infantile, and juvenile/adult. This condition is considered rare, with most cases having been in the juvenile/adult group of patients.

Metazym is an experimental recombinant enzyme that was studied in patients with late infantile metachromatic leukodystrophy, but found to be ineffective under the conditions of that trial. A subsequent clinical trial is ongoing. The drug became a source of controversy when a family attempted to purchase the drug for their child before it was approved. Jonckheere, Kingma, Eyskens, Bordon, & Jansen (2023) highlight the shift towards the need for newborn screening for metachromatic leukodystrophy as it allows for improved early detection and timely treatment as well.

Autophagic vacuolar myopathy (AVM) consists of multiple rare genetic disorders with common histological and pathological features on muscle biopsy. The features highlighted are vacuolar membranes of the autophagic vacuoles having sarcolemmal characteristics and an excess of autophagic vacuoles. There are currently five types of AVM identified. The signs and symptoms become more severe over the course of the disease. It begins with an inability to pick up small objects and progresses to difficulty in walking. The age of onset varies from early childhood to late adulthood, affecting people of all ages.

CDKL5 deficiency disorder (CDD) is a rare genetic disorder caused by pathogenic variants in the gene CDKL5.

Atidarsagene autotemcel, sold under the brand name Libmeldy, is a gene therapy treatment for metachromatic leukodystrophy (MLD) developed by Orchard Therapeutics. It contains an autologous CD34⁺ cell enriched population that contains haematopoietic stem and progenitor cells transduced using a lentiviral vector encoding the human arylsulfatase A (ARSA) gene.

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