Metachromatic Leukodystrophy (MLD)

What is MLD?

MLD is an autosomal, progressive, recessive, genetic neurodegenerative disorder that causes the white matter (myelin) to break down (demyelination). It is known as a lysosomal storage disease that greatly reduces life expectancy by the destruction of the myelin in the Central Nervous System (CNS) and the Peripheral Nervous System (PNS).It is the most common of the Leukodystrophies.

What causes MLD?

A mutated ARSA gene (Arylsulfatase A) located on Chromosome 22 (22q13.13) disallows the production of the enzyme Arylsulfatase-A (ARSA) which prevents the break down of the sulfatides which build up and store themselves in the cells. A variant form of MLD can also be caused by a defect in the Prosaposin (PSAP) gene which does not produce sufficient Saposin B to break the sulfatides which store themselves in the cells. The PSAP gene is located on Chromosome 10 (10q21- q22). The outcome with both causes is the same as they store the unwanted material in the Lysosomes and this causes their destruction.

This build up of sulfatides causes the destruction of the white protective coating (myelin) on the transmitting arm of the neuron (Axon) which allows the nerve cell to send messages to others in a very rapid manner. Once this function is diminished or lost our body cannot function as it is meant and we progressively shut down because the axons die.

The Lysosome has been termed a “scavenger” cell or a “recycling” cell as its main function is to process unwanted material and redistribute for use in other parts of the cell. When, due a mutation it cannot do its job the unwanted material accumulates or stores itself in the cell which causes its malfunction and destruction.

Forms of MLD:

Late Infantile MLD

This presents before the age of three (3). There may be an initial period of apparent normal growth and development before some symptoms begin to appear. It is not uncommon then for rapid deterioration to occur.  Walking problems and muscle issues can be the first signs of MLD. The child can go through some or all of the symptoms listed below as it varies from child to child and also sibling to sibling due to the variety of mutations. The child eventually becomes bedridden, unable to speak or feed independently and a feeding tube becomes necessary. Death generally occurs between the ages 5 to10 years or earlier. Infantile MLD represents about 40-60% of all MLD cases.

Some MLD Symptoms:

  • Walking difficulties
  • Hypotonia: low muscle tone
  • Muscle spasms and cramps
  • Strabismus : cross-eyed
  • Spasticity: increased reflexes
  • Nystagmus: involuntary eye movement
  • Loss of sight
  • Swallowing problems
  • Decreased speech
  • Seizures
  • Ataxia: loss of the ability to coordinate muscular movement
  • Paralysis
  • Eventual absence of voluntary functions

Juvenile MLD

Onset is normally between 3-16 years, and the symptoms generally first become apparent during the early years of schooling where behavioural disturbance or a drop in scholastic performance occurs. The child may have difficulty understanding directions and some may have incontinence problems, difficulties in walking and difficulties with speech. This form can present with psychiatric symptoms and unfortunate misdiagnoses of Depression, Cerebral Palsy, Battens Disease, ADD, ADHD, Schizophrenia or even Alzheimer’s have been made.

Disease progression is slower than late infantile. Juvenile MLD represents about 25-40% of all MLD cases.

Adult MLD

Onset is normally after 16 years of age and this form of the disease is the rarest. It is initially defined by a slow decline in intellectual capacity, emotional and behavioural instability and problem with memory recall.  It is also subject to misdiagnoses as in its Juvenile form. It particularly seems to affects the Peripheral Nervous System (PNS) as well of course the Central Nervous System (CNS).

Peripheral neuropathy is commonly experienced and denotes a disorder of the peripheral nervous system. The peripheral nervous system consists of all the motor and sensory nerves that connect the brain and spinal cord to the rest of the body (i.e., the nerves outside the central nervous system). The symptoms and physical findings associated with peripheral neuropathies may be extremely complex and vary greatly from case to case. Common findings associated with peripheral neuropathy may include muscle weakness; pain; numbness; redness; and/or burning or tingling sensations in the affected areas, especially the extremities of the arms and legs. Gall bladder polyps and cholecystitis can also occur. It has a very slow progression and can take many decades to run its course. Adult MLD accounts for about 15-25% of all MLD cases.

Pseudo Arylsulfatase-A Deficiency: (PD)

Pseudo Arylsulfatase-A Deficiency does not cause MLD.  ARSA pseudodeficiency is a condition that results in individuals having only 5% to 15% of ARSA enzyme function. However, this deficiency does not appear to pose a health risk and individuals do not develop MLD. ARSA pseudodeficiency is present in about 1% to 2% of Europeans and therefore the diagnosis of MLD must be confirmed with other tests, including urinary sulfatide measurement. There are people who have MLD and PD so it vital that extensive testing be carried out as outlined below. 

How do we diagnose MLD?

In order for a medical professional to correctly diagnose MLD, a number of tests must be undertaken.

  • A magnetic resonance image (MRI) of the brain to look for white matter abnormalities.
  • Urine and blood (an MRI is not definitive in diagnosing MLD) – this measures urine sulfatide levels and the blood arylsulfatase A (ARSA) enzyme levels. Low enzyme levels are not definititive because of  a condition called ARSA Pseudodeficiency as discussed in the previous paragraph.  
  • An Evoked Potential Test – measures the brains activity in response to nerve stimulation
  • A Nerve Conduction Test – measures the travel speed of signals sent along the nerve
  • DNA Testing – this can test for the known mutations and is very helpful if there is a family history.
  • Prenatal diagnosis for MLD is available – by Chorionic Villi (CV) biopsies or Amniotic fluid cultures. It is essential to confirm before testing the foetus that a parent does not have the Pseudo Arylsulfatase-A Deficiency as it will not prove a diagnosis of MLD if they do.


Metachromatic leukodystrophy (MLD) is rare and has a worldwide incidence of 1 in 40,000 to 160,000 births. However, the incidence is reported to be significantly higher in isolated populations including Habbanite Jews (1 in 75), certain Arab groups in Israel (1 in 8,000), and populations from the western portion of the Navajo Nation (1 in 2,500).

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. MLD affects both genders in equal numbers and is more in common in babies and young children.


As mentioned a mutated ARSA gene (Arylsulfatase A) located on Chromosome 22 (22q13.13) or mutated PSAP gene which is located on Chromosome 10 (10q21-q22) causes MLD .It is an Autosomal recessive condition being that it is found on a non sex chromosome (an autosome) and both parents must have the mutation. The parents of a child with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. This means that there is a 1 in 4 chance (25%) chance that a child will be unaffected, there is a 2 in  4 chance (50%) that the child be a carrier and a 1 in 4 chance (50%) that child will be affected.

It is most important that all those families involved with MLD contact a genetic counsellor for a full explanation of its inheritance, consequences and of all the available options for having future children.

Treatments for MLD:

Treatment is mainly symptomatic and supportive. Bone Marrow Transplant (BMT) and hematopoietic stem cell transplants (HSCT) have been successful in slowing or stopping MLD in patients who are pre-symptomatic or have been diagnosed and display a very minimum of mild symptoms.

These transplants are Allogeneic not Autologous and involve chemotherapy some times with radiation and Graft versus Host (GVHD) complications. Autologous means the person is there own donor. It can be a long and stressful procedure and therefore needs careful consideration. It is thoroughly recommended that you contact an MLD transplant expert to discuss these options.

Gene therapy, enzyme replacement therapy and other alternatives are currently being explored by research scientists

Are there other names for MLD?

  • ARSA
  • Arylsulfatase A Deficiency
  • Cerebroside Sulfatase Deficiency
  • Diffuse Cerebral Sclerosis
  • Greenfield Disease
  • Late-Onset Metachromatic Leukodystrophy
  • Metachromatic Form of Diffuse Cerebral
  • Metachromatic Leukoencephalopathy
  • MLD
  • Sulfatide Lipidosis
  • Sulfatidosis

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