More symptom information
Learn more about specific symptoms of this leukodystrophy in these pages.
Also known as: Arylsulfatase A deficiency
Metachromatic Leukodystrophy (MLD) is a rare lysosomal storage disorder caused by deficient activity of the enzyme arylsulfatase A. This leads to the build-up of sulfatides in cells, primarily affecting the nervous system’s white matter. MLD presents with progressive neurological symptoms, including developmental regression, loss of motor functions, seizures and loss of senses. It can manifest in early childhood or later in life. Treatment options vary based on the form and stage of the disease, and management focuses on addressing symptoms and supporting the patient’s well-being. Gene therapy is available in the UK and USA for treating MLD, please consult your specialist doctor for more information.
A new diagnosis can be overwhelming as it brings unique challenges and adjustments, but it is important to remember that you are not alone.
MLD is caused by mutations in either the ARSA or PSAP genes. These genes contribute to the break down of sulfatides, so mutations in them lead these sulfatides to build up. This build up is toxic to the nervous system, gradually destroying cells which produce myelin and preventing the ability of nerves to send signals from the brain.
ARSA creates an enzyme called Arylsulfatase A (PSAP creates proteins which help this enzyme to break down sulfatides). MLD can therefore also be called arylsulfatase A deficiency, although a small number of people with very low levels of this have no symptoms. These individuals are considered to have pseudoarylsulfatase A deficiency.
The PSAP gene provides instructions for making a protein called prosaposin. This protein is involved in a number of biological functions, including the development of the nervous system and the reproductive system. Prosaposin is the precursor of four smaller proteins called saposin A, B, C, and D, which are produced when prosaposin is broken up.
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 rarer than traditional MLD.
Autosomal recessive: In autosomal recessive conditions, two copies of the genetic mutation are needed to cause the condition. We all have two copies of every gene, one from our mother and one from our father. The parents of someone with an autosomal recessive condition both carry one copy of the gene with a genetic mutation. Therefore, someone with an autosomal recessive condition has two copies of the genetic mutation, one copy from each parent. Each child of parents that both carry the genetic mutation will have a 25% chance of having the condition, a 50% chance of carrying the genetic mutation (like the parent), and a 25% chance of not having the condition.
Genetic counselling is essential for affected families due to the inheritance pattern of the condition. This is available at hospitals and Regional Genetic Centres. Please contact your doctor if you have any questions.
Learn more about genetic testing and counselling here.
Those with MLD experience progressive loss of intellectual capacity and motor functions, such as the ability to walk. Peripheral neuropathy is common, as well as seizures, incontinence, blindness, hearing loss, inability to speak and paralysis. Eventual loss of responsiveness and awareness of surroundings follows.
The most common form of MLD is the late infantile form, affecting children from age 2. Those with this condition lose acquired motor skills and speech, experience hypotonia before muscle tone increases to the point of rigidity. Typically those with this form of MLD do not survive past childhood.
A rarer, juvenile form can occur between the age of 4 and adolescence. Behavioural problems are the first sign, with other described symptoms developing slowly. Those with this form can survive for 20 years from first symptoms.
The rarest form is the adult form, beginning in teenage years or later with behavioural problems including drug and alcohol abuse. Psychiatric symptoms such as hallucinations may follow before further symptoms. This also progresses slowly; life expectancy is 20-30 years from diagnosis.
Learn more about specific symptoms of this leukodystrophy in these pages.
Gene therapy is available in the UK for patients with Early Juvenile/Late infantile MLD through the NHS, the drug is known as Libmeldy. It is also available in the USA and known as Lenmeldy. Please consult your specialist doctor for more information.
There is condition management information that may be useful for you in managing your or your loved one’s leukodystrophy.
There may be a current clinical trial, natural history study or patient registry for your condition. Check our current research page and ask your specialist doctor for more information.
We understand that research is a significant priority and source of hope for the leukodystrophy community. There is more research in leukodystrophy now than ever before. Alex TLC actively promotes and supports research in a number of ways.
Every month we update our database of research summaries with the most recent research. This includes summaries of leukodystrophy articles, clinical trials and pharmaceutical press releases. Our summaries allow our community to read about relevant recent research developments in a format that is easily understood.
Learn about the ways in which we can help in the how we support you section. When you or a family member been diagnosed with a leukodystrophy it may be difficult to know where to go for more advice – this information could help.
Our services and equipment section is here to help leukodystrophy patients and their families manage their condition. All information is based on our knowledge of UK services, however, our team are happy to receive support requests from other countries – email us.
You may be introduced to many different medical professionals which you may find confusing. View our guide to the health and care professionals you may encounter, with short descriptions about what they do.
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