Metachromatic leukodystrophy

Overview

Metachromatic leukodystrophy is a rare hereditary (genetic) disorder that causes fatty substances (lipids) to build up in cells, particularly in the brain, spinal cord and peripheral nerves. This buildup is caused by a deficiency of an enzyme that helps break down lipids called sulfatides. The brain and nervous system progressively lose function because the substance that covers and protects the nerve cells (myelin) is damaged.

There are three forms of metachromatic leukodystrophy, which involve different age ranges: late infantile form, juvenile form and adult form. Signs and symptoms can vary. The infantile form is the most common and progresses more rapidly than the other forms.

There is no cure for metachromatic leukodystrophy yet. Depending on the form and age of onset, early identification and treatment may help manage some signs and symptoms and delay progression of the disorder.

Symptoms

Damage to the protective myelin covering the nerves results in progressive worsening of brain and nervous system functions, including:

• Loss of the ability to detect sensations, such as touch, pain, heat and sound
• Loss of intellectual, thinking and memory skills
• Loss of motor skills, such as walking, moving, speaking and swallowing
• Stiff, rigid muscles, poor muscle function and paralysis
• Loss of bladder and bowel function
• Gallbladder problems
• Blindness
• Hearing loss
• Seizures
• Emotional and behavioral problems, including unstable emotions and substance misuse

Each form of metachromatic leukodystrophy occurs at a different age and can have different initial signs and symptoms and rates of progression:

• Late infantile form. This is the most common form of metachromatic leukodystrophy, starting around 2 years of age or younger. Progressive loss of speech and muscle function occurs rapidly. Children with this form often do not survive beyond childhood.
• Juvenile form. This is the second most common form and starts in children between 3 and 16 years of age. Early signs are behavior and cognitive problems and increasing difficulty in school. Loss of the ability to walk may occur. Although the juvenile form doesn't progress as fast as the late infantile form, survival is generally less than 20 years after symptoms begin.
• Adult form. This form is less common and typically starts after age 16. Signs progress slowly and may begin with behavior and psychiatric problems, drug and alcohol misuse, and issues with school and work. Psychotic symptoms such as delusions and hallucinations may occur. The course of this form varies, with periods of stable symptoms and periods of rapid decline in functioning. Adults may survive for several decades after initial symptoms.

When to see a doctor

Talk to your doctor if you observe any signs listed above or if you have concerns about your own signs or symptoms.

Causes

Metachromatic leukodystrophy is an inherited disorder caused by an abnormal (mutated) gene. The condition is inherited in an autosomal recessive pattern. The abnormal recessive gene is located on one of the nonsex chromosomes (autosomes). To inherit an autosomal recessive disorder, both parents must be carriers, but they do not typically show signs of the condition. The affected child inherits two copies of the abnormal gene — one from each parent.

The most common cause of metachromatic leukodystrophy is a mutation in the ARSA gene. This mutation results in a lack of the enzyme that breaks down lipids called sulfatides that build up in the myelin.

Rarely, metachromatic leukodystrophy is caused by a deficiency in another kind of protein (activator protein) that breaks down sulfatides. This is caused by a mutation in the PSAP gene.

The buildup of sulfatides is toxic, destroying the myelin-producing cells — also called white matter — that protect the nerves. This results in damage to the function of nerve cells in the brain, spinal cord and peripheral nerves.