Metachromatic leukodystrophy

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.
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.
Palliative care can help with many of the symptoms and usually improves quality of life and longevity.
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.
Causes.
MLD is directly caused by a deficiency of the enzyme arylsulfatase A (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. 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.
Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. 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. Saposin B Deficiency is very rare, much more rare than traditional MLD. 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.
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.
Genetics.
MLD has an autosomal recessive inheritance pattern. The inheritance probabilities "per birth" are as follows:
In addition to these frequencies there is a 'pseudo'-deficiency that affects 7–15% of the population.<ref name="147-150, DOI: 10.1007/BF00286589"></ref> 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.
"For further information, see recessive gene and dominance relationship. Also, consult the MLD genetics page at MLD Foundation. [revise or delete]"
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.
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. An Expert Advisory Group (EAG) was launched in February 2020 to define the MLD NSB flow and prepare a RUSP Nomination. Seven Working Focus Groups (WFG) are supporting the EAG in their efforts. In parallel, the MLD Community is organizing to support the worldwide implementation of MLD newborn screening.
Treatment.
There is currently no therapy or cure for MLD in "symptomatic" late infantile patients displaying symptoms, or for juvenile and adult-onset with "advanced" symptoms. These 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. 
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).
A gene therapy, Libmeldy™, was approved for medical use in the EU in December 2020. Libmeldy is indicated 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. 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. 
An IND for OTL-200 (the gene therapy's non-EU name) was accepted by the FDA in Q4'2020. The IND is a precursor to an anticipated NDA for FDA review of the gene therapy in the USA later in 2021 or 2022. Before COVID slowed things down, the trial sponsor had indicated a target submission for US FDA review during 1st half 2021. Doctors of patients outside the EU may apply to access OTL-200 through the Pre-Approval Access portal at Orchard therapeutics. 
Gene therapy was submitted to the EMA for review in December 2019. On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Libmeldy for the treatment of children with the 'late infantile' (LI) or 'early juvenile' (EJ) forms of metachromatic leukodystrophy (MLD). OTL-200 is being studied in late juveniles.
Epidemiology.
The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide. 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.
As an autosomal recessive disease, 1 in 40,000 equates to a 1 in 100 carrier frequency in the general population.
There are an estimated 3,600 MLD births per year, with 1,900 alive in the US, 3,100 in Europe, and 49,000 alive worldwide with MLD.
MLD is considered a rare disease in the US and other countries.
Research.
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)"
Natural history studies.
"Research & Clinical Trial updates provided by MLD Foundation