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 that 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. (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls. 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. However, sulfatides ultimately result in functional impairment of oligodendrocytes and Schwann cells, leading to widespread demyelination, resulting in the neurological impairments hallmark of MLD. 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) cease to function properly, resulting in mobility impairments and intellectual decline. 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.

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

Genetics

thumb|Metachromatic leukodystrophy has an autosomal recessive pattern of inheritance.

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

  • If both parents are carriers:
  • 25% (1 in 4) of children will have the disease
  • 50% (2 in 4) of children will be carriers, but unaffected
  • 25% (1 in 4) children will be free of MLD – unaffected child that is not a carrier
  • If one parent is affected and one is free of MLD:
  • 0% (0) children will have the disorder – only one parent is affected, other parent always gives normal gene
  • 100% (4 in 4) children will be carriers (but unaffected)
  • If one parent is a carrier and the other is free of MLD:
  • 50% (2 in 4) children will be carriers (but unaffected)
  • 50% (2 in 4) children will be free of MLD – unaffected child that is not a carrier

In addition to these frequencies, there is a 'pseudo'-deficiency that affects 7–15% of the population. 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.

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. 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.

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, by Professor Michael H. Gelb. A deidentified pilot study was 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.

Treatment

There is currently no approved treatment for MLD in symptomatic late infantile patients or for juvenile and adult-onset with advanced symptoms. There is a treatment for pre-symptomatic patients and certain others with the condition.

Symptomatic patients typically receive clinical treatment focused on pain and symptom management.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. However, results in the peripheral nervous system have been less dramatic, and the long-term results of these therapies have been mixed.

In 2020 the European Medical Agency approved the cell therapy drug atidarsagene autotemcel (Libmeldy) for the treatment of infantile and juvenile forms of metachromatic leukodystrophy in Europe.

Presymptomatic patients can be cured with one treatment of atidarsagene autotemcel, which is a type of advanced medicine called a ‘gene therapy’. This type of medicine works by delivering genes into the body. The active substance in atidarsagene autotemcel is CD34+ stem cells. They are retrieved from the patient's own bone marrow or blood. They are then modified to contain a copy of the gene to make functional ARSA. After confirming that the cells contain an active copy of the gene, they are injected into the patient's bone marrow. CD34+ cells can divide to produce other sorts of blood cells.

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.

Epidemiology

The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide.

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

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.

  • Gene therapy for late infantile and early juvenile patients was approved by the European Commission in December 2020, after receiving a favorable European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) review in October 2020. The product is being marketed in the EU as Libmeldy. It is a gene therapy medicinal product, for which CD34+ haematopoietic stem and progenitor cells are collected either from the patient's own bone marrow or mobilised peripheral blood. These cells are transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene to insert a functional gene to produce the ARSA enzyme. Additional information can be found on the MLD Foundation's Gene Therapy page and at the Clinical Trials.gov site.
  • In November 2020, Orchard Therapeutics acknowledged IND discussions with the FDA as the part of their effort to seek FDA approval in the USA.
  • A trial for late juveniles was launched in February 2020.
  • Orchard Therapeutics acquired the gene therapy IP from GSK in April 2018.
  • Recruiting for the Phase I/II Clinical Trial formally started on March 24, 2010, after approval from the Italian Authorities. Recruiting the initial cohort of 8 patients was completed in mid-March 2013. The trial was to test the efficacy and safety of autologous (using the patient's cells) hematopoietic stem cell transplantation (HSCT) after genetic modification to deliver a super-therapeutic (over-expressing) ARSA enzyme to the nervous system by the route of the blood cells. Using the patient's stem cells with genetic correction should reduce or eliminate the complications of graft vs. host disease and provide a long-term solution to proper ARSA expression in MLD patients. Bench and animal tests showed positive results. The researchers published 2-year outcomes for the first three patients in July 2013. Results were described as promising.
  • The trial was at a single center at the San Raffaele Institute in Milan, Italy. All costs were to be paid by the researchers. This was a 3-year study. In March 2013, the last of the 8 primary trial patients started therapy. The trial had several compassionate access patients and ultimately was expanded to 20 patients.
  • In late 2013 GSK exercised its option for the San Rafaelle gene therapy technology and is working with the Milan Investigators to prepare for the next phase of study.
  • Intracerebral Gene therapy – A Phase I/II Clinical Trial started recruiting in Paris in late March, 2013 for an Intracerebral Gene Therapy clinical trial where special "vectors" carrying genetically modified material are directly injected into a dozen sites in the brain. The hope is that the corrected cells and the enzyme they produce will then diffuse into surrounding areas of the brain. Extensive work in the lab and some encouraging ALD studies provided the basis for this trial. This trial was subsequently terminated before completion.

Enzyme replacement therapy (ERT)

(current as of February 2021)

  • Takeda acquired the MLD ERT from Shire in early 2018 and continues to develop and studying their intrathecal SHP 611 (formerly HGT-1110) ERT [Enzyme Replacement Therapy].
  • Clinical Trial
  • A third global trial studying the late infantile form of MLD for 42 patients aged 6 – 72 months launched in April 2019 and was fully recruited in January 2021. This is the first time ERT study sites are open in the US.
  • Clinical trial information & inclusion criteria can be found on the MLD Foundation's ERT page and at the Clinical Trials.gov site.

Substrate reduction therapy

  • Biomarin South (formerly Zacharon before being acquired by Biomarin in January 2013) from San Diego had initiated a drug discovery program for MLD. This program is based on using assays that measure sulfatide accumulation in cultured fibroblasts as a means to discover and develop small-molecule drugs for MLD. (This approach differs from other approaches that have measured enzyme activity to discover effective drugs.) As of July 2011, Zacharon has begun adapting the assays it developed for other lysosomal storage diseases so that they can be employed to discover and develop drugs for MLD. (current March 2013)
  • The Cooper Health System (New Jersey) sponsored a clinical trial underway to determine the safety and efficacy of a Vitamin K antagonist (Warfarin) in treating Metachromatic Leukodystrophy (MLD) in 2009. No results are known to have been published. (current March 2013)

Natural history studies

  • A natural history study (NHS) launched in Washington, DC in January 2014 to study 30 patients with additional study centers opened in the US, Europe, South America, Southeast Asia, and South America. Due to challenges in recruiting this study has been cancelled.
  • A natural history study has been underway in Pittsburgh, PA since November 2012.

Metazym drug studies

References

  • Some portions of this article are courtesy of the public domain text available at the National Institute of Neurological Disorders and Stroke: