MLD-101 ... A Layperson's Overview

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Genetic sequencing for MLD can be used to help determine if extended family members are carriers, and can sometimes help identify the specific form of MLD in an affected loved one. This page will help you know when and how to access sequencing … and how to help inform your extended family.

FREE Sequencing!

The Lysosomal Storage Diseases (LSDs) genetic testing program provides access to sponsored, no-charge genetic testing and counseling for people suspected of having an LSD.  This program is also offered at no charge to the extended family.

MLD is a rare inherited (genetic) metabolic lysosomal disorder usually caused by a mutation on the ARSA-A gene on chromosome 22q13.


MLD is short for metachromatic leukodystrophy. Translated from doctor talk MLD means: meta – change, chromatic – color, leuko – white matter, dystrophy – degeneration. MLD’s name comes from a color observed on degenerated white  matter (nerves) that should not be there. Staining of the nerves of deceased patients was how the disease was observed before the advent of the MRI. 

This degeneration of myelin, the covering around the nerves, occurs in the Central Nervous System (CNS – brain) and Peripheral Nervous System (PNS – the rest of the body).


Basically people who are affected by MLD lack an enzyme in their blood called Arylsulfatase-A, (ARSA). Without this enzyme, sulfatides are NOT broken down and instead build-up in the white matter of the CNS and PNS causing demyelination (destruction) of the myelin sheath. 

The myelin sheath is the protective covering  wrapped around nerves. Without an intact myelin sheath there is a breakdown in communication across the brain and with other parts of the body. This loss of communication accounts for the loss of acquired functions, tone, paralysis, blindness, seizures, and eventual death seen in MLD.

Forms of MLD

Historically, there were considered to be three main types of MLD with different ages of onset: late-infantile, juvenile, and adult. More recently researchers have come to differentiate juvenile MLD into early-juvenile and late-juvenile form. The early juvenile form has an onset age of  3 – 7 years, while the late-juvenile is usually 7-16 years. The late-infantile form of MLD is the most commonly observed form of MLD.

Saposin B Deficiency is a very rare form of MLD where the ARSA enzyme levels are OK, but the activator for those enzymes is missing or low caused by a mutation in the prosaposin gene on chromosome 10q22. The symptoms are identical to MLD, but disease altering therapies will be different.

Those with Multiple Sulfatase Deficiency (MSD) (sometimes refered to as Austin’s Disease) have an activation deficiency that affects many enzymes, including ARSA. The clinical symptoms often look like MLD, but the disease biology and therapies are different.

About 1 in every 12 people have at least one mutation for MLD Pseudodeficiency, a different genetic usually non-disease causing disorder where the ARSA  enzyme is low, but not low enough normally cause disease.

MLD is not contagious and can not be passed to others through any sort of physical contact – it is a genetic condition.

Therapies & Research

At this time there is no cure for MLD. The only widely available treatment today is stem cell transplant (SCT or HSCT), the successor to bone marrow transplant.  Transplant is most effective in slowing the disease in people who are not showing any symptoms of MLD (pre-symptomatic). New therapies are coming!  

MLD’s first Gene Therapy (GT) was approved by the European Commission and the EMA in Europe at the end of 2020. The FDA approved gene therapy forUS patients March of 2024.

Enzyme Replacement Therapy (ERT) is completing its clinical trial and will not likely come to market. Advances continue in stem cell transplants.  Another gene therapy is still in the basic science stage with early preparations for clinical trial underway. 


MLD is an autosomal recessive genetic defect. Translated this means both males and females carry the gene and both parents need to carry the defective gene in order to have an affected child. When both parents are carriers the chances of having an affected MLD baby is 25% …1 in 4.

There are nearly 300 different mutations that are known or suspected to cause MLD. A very small handful of common mutations make up the great majority of MLD cases. Our experience, however, is the most frequent form of MLD, infantile onset, is often not diagnosed properly prior to significant disease progression and later onsets of MLD are often misdiagnosed as ADHD, ADD, or psychiatric conditions and hence the frequency might be higher than reported.  MLD Newborn Screening will help to identify those with MLD before symptoms – when therapies have the best outcomes.

Incidence and Prevalence

It is estimated that 1 in 100 of the general population are carriers and the affected birth rate is 1:40,000 – thus MLD gets its designation of being a rare disease.

We estimate that approximately 2,000 new late infantile babies are born each year (including 60 in the US and 100 in Europe), a total of 3,400 babies of all forms born worldwide, and there are approximately 66,000 people alive worldwide at any given time across all forms of MLD. We have a video with more details tables you can view here. (Source: MLD Foundation 2023)



The first report of MLD was in 1933 and is commonly credited to Dr. Joseph Godwin Greenfield,(1884-1958) a professor of pathology and clinical medicine at what is now the National Hospital for Neurology & Neurosurgery in London – the same campus as what is now the Great Ormond Street Hospital for Children.

MLD was first called Greenfield’s disease. The first published medical reports of MLD appeared in the early 1960’s with the first experimental bone marrow transplants treatments in the early 1980’s.

Testing & Diagnosis of MLD

The diagnosis of MLD is fairly straightforward once you know what you are looking for. Unfortunately, it is often after many misdiagnosis, and often after the disease is very progressed when the MLD sufferer is put in contact with staff that knows of MLD and performs the proper testing. Common misdiagnosis for MLD include Cerebral Palsy, Batton’s Disease, and ADHD – especially with children. In adults since the presentation is often first psychological, not physical, the misdiagnosis can be a variety of psychological conditions.

MRI can indicate white matter disease (or leukodystrophy) and can suggest MLD, but a MRI alone is not a definitive diagnostic tool for MLD.

Genetic testing can indicate MLD, but as far as what form of MLD it can be a is a toss up … it’s estimated that 50-60% of the time sequencing is conclusive, and the rest of time there is uncertainty.  Clinical symptoms can help reduce this uncertainty.

Usually a blood test is done first to check for enzyme levels, followed by a urine test to confirm the presence of sulfatides.

Newborn screening in the US will catch nearly every MLD baby pre-symptomatically – when the babies are eligible to have gene therapy and the therapy is most effective. MLD Newborn screening pilot studies have demonstrated excellent results.  MLD Foundation is in the process of submitting a formal Nomination to get MLD added to the RUSP, the US federal Recommended Newborn Screening Panel … and we are working to get newborn screening for MLD in every US state and territory.

Types of MLD – Onset/Progression

Late Infantile is estimated to be 50-60% of the diagnosis’ and usually presents after normal development during a baby’s first 12-18 months followed delay or regression of motor milestones.

Juvenile Onset is usually between ages 4-14. Onset usually starts with either motor or cognitive symptoms.

Adult Onset is characterized by normal development through puberty, and then symptoms present at some later age – generally from the 20’s through the 40’s. The initial adult onset signs are often changes cognitive abilities and personality.

Can we Cure MLD? – Treatments & Therapies

Some are calling gene therapy for pre-symptomatic late infantiles and early juveniles “curative”. You can read more about this on our gene therapy page. As of early 2021 the therapy is available only in Milano, Italy under a Compassionate Access program. During 2021, 5 gene therapy specialty centers are being opened around Europe (where the therapy is approved), but patients from other countries still must travel to Italy to access the therapy.   

The more widely available treatment (therapy) at present for anyone is a stem cell transplant (also called HSCT, cord-blood, or bone marrow transplant). Today’s successful stem cell or bone marrow transplant (BMT) is not a cure for MLD – at best it slows further deterioration by replacing the bad cells with “good” cells that can produce the missing enzyme. 

Neither gene therapy nor stem cell transplant are generally recommended for symptomatic late-infantiles.3,400