Metachromatic Leukodystrophy (MLD)

Arylsulfatase A deficiency


Autosomal recessive

Inheritance from both parents will result in the disease

Age range at onset:

From age 2 (infantile) to adulthood

Specialists you may see:


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.


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 in-volved 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.[5] 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 rar-er than traditional MLD.