Metachromatic Leukodystrophy

Metachromatic Leukodystrophy (MLD)

For more information please download our Guide to MLD.

What is MLD?

MLD or Metachromatic Leukodystrophy is one of a group of rare genetically inherited diseases known as the lysosomal storage diseases. The condition gets its name from the microscopic appearance of cells with the sulfatide accumulation that occurs in this disorder. The sulfatides form granules which are metachromatic, which means they pick up colour differently than surrounding cellular material when stained for microscopic examination.

What causes this disease?

In the course of normal life there is a continuous recycling process; this process requires a series of biochemical tools called enzymes. Individuals with MLD lack a specific enzyme or protein in every one of their cells. This leads to problems with the breakdown of fats called sulfatides (or sulphatides).

In nearly all cases, MLD develops as a result of a deficiency in the enzyme arylsulfatase A (ASA) also known as sulfatidase or cerebroside 3-sulfatase. ASA is responsible for breaking down sulfatide and other fats that contain 3-sulfogalactosyl. The protein produced by ASA is present in the lysosome, a compartment of the cell that specialises in general “cleanup” of the cell.

You may hear MLD referred to as a lysosomal storage disorder, since ASA is a lysosomal enzyme. In rare cases, a deficiency of the non-enzymatic activator protein saposin B, which helps arylsulfatase A with the breakdown of these fats, can also cause metachromatic leukodystrophy. When arylsufatase A and saposin B are unable to work together to break down sulfatides, they build up in cells within the nervous system, including the brain.

Does MLD affect individuals differently?

The severity of metachromatic leukodystrophy varies widely between patients. Although a big oversimplification, affected individuals are generally described as having one of three main forms of the condition. These forms are identified based on the age of the patient when their first signs and symptoms start to appear. They are known as the late infantile, juvenile and adult forms.

If the disease first develops between 6 months and 4 years of age, the individual is said to have the late-infantile form of metachromatic leukodystrophy. The condition is described as juvenile if it develops between 4 and 16 years of age. Individuals who are older than 16 years when they develop metachromatic leukodystrophy are described as having the adult form of the disease. More recently, it has been suggested that the description of the late-infantile form should be revised to include only children who present before 2-3 years of age.

How common is MLD?

Metachromatic leukodystrophy is the commonest of all the leukodystrophies. However, it is still a rare disease that affects between about 1 in 54,000 and 1 in 166,650 live births. The adult-onset form of metachromatic leukodystrophy affects 25% of all patients. The remaining patients can be divided roughly equally between the late infantile and juvenile forms.

How is the disease inherited?

Metachromatic leukodystrophy is caused by a faulty or ‘mutated’ gene and it affects both males and females equally. There are known to be more than 60 different genetic faults that can cause metachromatic leukodystrophy. In some cases it is possible to identify the genetic fault that caused the disease.

Inheritance of metachromatic leukodystrophy is autosomal recessive. This means that two copies of the abnormal gene (one from each parent) are required for the disease to develop. Thus, a child who is born to parents who both carry the autosomal recessive mutation has a 25% (1:4) chance of inheriting the faulty gene from both parents and developing the disease. There is a 50% (1:2) chance of the child inheriting one abnormal gene and being a carrier of the disease. Carriers of the faulty gene that causes metachromatic leukodystrophy are not affected by the disease. There is also a 25% (1:4) chance that the child will not inherit the faulty gene from either parent.

There is a more detailed explanation of this complex subject in the booklet on inheritance available from the MPS Society.